Section 1 Neurobiology

**3**

**Chapter 1**

**Abstract**

diseases.

oligodendrocytes, gliosis

**1. Introduction**

system (PNS) [1].

Diseases

Targeting Neuroglial Sodium

Channels in Neuroinflammatory

*Yu Yao, Xiaoli Wang, Shuzhang Zhang, Zhiping Zhang,*

*Wei Wang, Yudan Zhu, Jiwei Cheng, Guoyi Li and Jie Tao*

The Hodgkin-Huxley model, at its 66th anniversary, remains a footing stone of neuroscience, which describes how the action potential (AP) is generated. As the core player of AP initiation, voltage-gated sodium channels (VGSCs) are always considered to be required for electrogenesis in excitable cells. Cells which are not traditionally been considered to be excitable, including glial cells, also express VGSCs in physiological as well as pathological conditions. The dysfunction of glial VGSCs is seemingly not related to abnormal excitation of neurons, but of importance in the astrogliosis and M1 polarization of microglia, which could induce refractory neuroinflammatory diseases, such as multiple sclerosis, stroke, epilepsy, and Alzheimer's and Parkinson's diseases. Therefore, in this chapter, we aim to describe the physiological and pathological roles of VGSCs contributing to the activity of glial cells and discuss whether VGSC subtypes could be used as a novel drug target, with an eye toward therapeutic implications for neuroinflammatory

**Keywords:** glial VGSCs, neuroinflammatory diseases, astrocytes, microglial cells,

So far, the pathogenesis of neuroinflammatory diseases, including multiple sclerosis (MS), epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), etc., is still unclear, of which therapeutic effects are not satisfactory, bringing great challenges to public health care. The pathological processes of these diseases are often accompanied by the production of neuroinflammation that cause a series of bad effects such as firing pro-inflammatory signaling pathways and even neuron pyroptosis, as well as cell death. The accumulated data show that neuroinflammation is characterized by the activation of glial cells and production of inflammatory mediators in the central nervous system (CNS) and peripheral nervous

Activated glial cells, triggering neuroinflammation, include Schwann cells as well as satellite glial cells in PNS and microglia, astrocytes, and oligodendrocytes in CNS [2]. Glial cells are of importance for critical responses to neurological diseases and injuries, including active tissue remodeling, phagocytosis, etc. [3].

#### **Chapter 1**

## Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases

*Yu Yao, Xiaoli Wang, Shuzhang Zhang, Zhiping Zhang, Wei Wang, Yudan Zhu, Jiwei Cheng, Guoyi Li and Jie Tao*

#### **Abstract**

The Hodgkin-Huxley model, at its 66th anniversary, remains a footing stone of neuroscience, which describes how the action potential (AP) is generated. As the core player of AP initiation, voltage-gated sodium channels (VGSCs) are always considered to be required for electrogenesis in excitable cells. Cells which are not traditionally been considered to be excitable, including glial cells, also express VGSCs in physiological as well as pathological conditions. The dysfunction of glial VGSCs is seemingly not related to abnormal excitation of neurons, but of importance in the astrogliosis and M1 polarization of microglia, which could induce refractory neuroinflammatory diseases, such as multiple sclerosis, stroke, epilepsy, and Alzheimer's and Parkinson's diseases. Therefore, in this chapter, we aim to describe the physiological and pathological roles of VGSCs contributing to the activity of glial cells and discuss whether VGSC subtypes could be used as a novel drug target, with an eye toward therapeutic implications for neuroinflammatory diseases.

**Keywords:** glial VGSCs, neuroinflammatory diseases, astrocytes, microglial cells, oligodendrocytes, gliosis

#### **1. Introduction**

So far, the pathogenesis of neuroinflammatory diseases, including multiple sclerosis (MS), epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), etc., is still unclear, of which therapeutic effects are not satisfactory, bringing great challenges to public health care. The pathological processes of these diseases are often accompanied by the production of neuroinflammation that cause a series of bad effects such as firing pro-inflammatory signaling pathways and even neuron pyroptosis, as well as cell death. The accumulated data show that neuroinflammation is characterized by the activation of glial cells and production of inflammatory mediators in the central nervous system (CNS) and peripheral nervous system (PNS) [1].

Activated glial cells, triggering neuroinflammation, include Schwann cells as well as satellite glial cells in PNS and microglia, astrocytes, and oligodendrocytes in CNS [2]. Glial cells are of importance for critical responses to neurological diseases and injuries, including active tissue remodeling, phagocytosis, etc. [3].

What's more, glial cells often acting as double-edged swords not only evoke the neuronal damage but also promote tissue repair [4]. Under pathological conditions, microglial cells, as one kind of resident immune cells in CNS [5], could secrete a large number of cellular inflammatory factors, increase oxidative stress of neurons, and induce apoptosis or pyroptosis of neurons. At the same time, M2 microglia secrete various neurotrophic factors and anti-inflammatory factors such as IL-4 and IL-3, which play a neuroprotective role in cerebral ischemia and hypoxia [6, 7].

Astrocytes are widely distributed in the nervous system, showing its function by providing nutrition and support to adjoining neurons [8]. Therefore, the excitability of neurons could be regulated by the neurotransmitters secreted from astrocytes. At the same time, it could synthesize and release a variety of immune factors to participate in the neuronal immune response. Oligodendrocytes are the unique neuroglial cells that form the myelin sheath, which is the key structure for neurons to propagate APs. CNS myelin hypoplasia or demyelinating changes are the pathogenic factors of neuroinflammatory diseases [9].

In the mid-twentieth century, after the discovery of AP, Hodgkin and Huxley, who firstly proposed the concept of ion channels, record sodium currents by using voltage clamp technology [10, 11]. Traditionally, glial cells were considered as nonexcitatory cells, but with the development of research in this field, sodium channels have been found also to play crucial roles in physiological and pathological function of these cells [12, 13].

The activation of sodium channel is triggered by membrane depolarization, which produces transient sodium current and AP [14]. In neurons, sodium channels are composed of a single α-subunit, which forms ion-selective and voltage-sensitive pores, and one or two auxiliary β-subunits, which seems to affect channel gating and expression [15].

These channels drive electrical generation in neurons (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8), muscle cells (Nav1.4), and myocardial cells (Nav1.5). The typical role of Nav channels has been widely studied [16]. The dysfunction of sodium channels could result in neurological diseases, including neuropathic pain [17–19], peripheral neuropathy [20], epilepsy [21], and MS [22, 23].

However, the dysfunction of glial VGSCs is seemingly not related to abnormal excitation of neurons, but of importance in the astrogliosis and M1 polarization of microglia, which could induce refractory neuroinflammatory diseases. Glial sodium channels are closely related to phagocytosis, secretion of cytokines (IL-α, TNF-α), and migration. Then, glial cells are activated after tissue damage or disturbance, accompanied by morphological changes, enhanced migration, phagocytosis, secretion of inflammatory molecules (such as cytokines and nitric oxide), and antigen presentation [24].

Although glial cells do not produce AP under physiological conditions, they can show excitability through ion flux, especially in the form of [Ca2+]i oscillation. Ca2+ kinetics is involved in microglial activation and regulation of many effector functions, including cell migration [25, 26] and release of chemokines/cytokines and nitric oxide [27].

The Na+ /Ca2+ exchanger (NCX) operates in a forward mode, transmits Na+ ions down the concentration gradient to the cell, and then returns to output Ca2+, or if the electrochemical gradient of Na+ decreases or the cell depolarizes, the operation realizes the reverse mode by outputting Na+ ions in exchange for Ca2+ [28]. Therefore, sodium channel activity has the ability to increase [Ca2+]i through the reverse mode of NCX.

The research shows that Nav1.6 can generate continuous sodium current [29], drive the reverse operation of NCX, and generate the inlet. Ca2+ enters the cytoplasm. In this respect, like all eukaryotic cells, the intracellular free Ca2+ level is strictly regulated, which is crucial in the signal transduction pathway of microglia.

**5**

microglia [34].

**Figure 1.**

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases*

Studies have shown that Nav1.1 and Nav1.6 were persistently reduced during epileptogenesis [30]. Under the MS pathological condition, the results showed that the removal of Nav1.5 from astrocytes could significantly worsen the clinical outcome of experimental autoimmune encephalomyelitis (EAE) [31] and the sodium channel Nav1.2 is expressed by scar and reactive astrocytes in plaque [32]. Studies have shown that under PD pathological conditions, Nav1.1 [33] in hippocampal astrocytes is significantly increased, and Nav1.6 is highly expressed in activated

*Structure of Nav channels. Schematic representation of Nav channel subunits. The Nav channel α subunit is often illustrated together with auxiliary subunits β1 and β2; extracellular domains of the β subunits are shown as immunoglobulin-like folds (shown in blue), interacting with the extracellular loops of α subunits. Roman numerals indicate the domains of the α subunit; segments 5 and 6 (shown in purple) are considered as porelining segments, and S4 helices (green) make up the voltage sensors. The yellow circle in the intracellular loop*

There is a close relationship between the structure and the function of sodium channels (**Figure 1**). Therefore, in this chapter, we aim to describe the physiological and pathological roles of VGSCs contributing to the activity of glial cells and discuss whether VGSC subtypes could be used as a novel drug target, with an eye toward

MS, a chronic inflammatory disease of the CNS, is characterized by demyelination, axonal injury, neuronal loss, and progressive inflammatory responses in the brain and spinal cord [35]. EAE is a classic model of MS, of which the pathological progress is very similar to MS. Under pathological conditions, glial cells (microglia, astrocytes, oligodendrocytes, glial stem cells) can act as regulators, effectors, and even targets of inflammatory response, not only causing tissue damage but also promoting tissue repair [4]. Glial cells are essential for critical responses to neurological diseases and injuries, including active tissue remodeling and phagocytosis [3]. Studies have shown that sodium channels are not only traditionally associated with the generation and transmission of neuronal APs, but also can be expressed in electrically inexcitable cell types including astrocytes [36, 37], oligodendrocyte precursor cells [38–40], Schwann cells [41], microglia [42, 43], and cancer cells [44–46]. The regulation of glial function by sodium channels is of special signifi-

cance for the response of reactive glial to CNS diseases and insults [14].

Microglial cells are the resident immune cells of the CNS. Under physiological conditions, microglial cells are usually highly branched cells with dynamic

**2.1 Microglial sodium channels in multiple sclerosis**

therapeutic implications for neuroinflammatory diseases.

*of domains III and IV represents the inactivation gating ball, IFM motif.*

**2. Neuroglial sodium channels in multiple sclerosis**

*DOI: http://dx.doi.org/10.5772/intechopen.92127*

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases DOI: http://dx.doi.org/10.5772/intechopen.92127*

#### **Figure 1.**

*Neuroimaging - Neurobiology, Multimodal and Network Applications*

pathogenic factors of neuroinflammatory diseases [9].

of these cells [12, 13].

and expression [15].

presentation [24].

nitric oxide [27]. The Na+

electrochemical gradient of Na+

the reverse mode by outputting Na+

What's more, glial cells often acting as double-edged swords not only evoke the neuronal damage but also promote tissue repair [4]. Under pathological conditions, microglial cells, as one kind of resident immune cells in CNS [5], could secrete a large number of cellular inflammatory factors, increase oxidative stress of neurons, and induce apoptosis or pyroptosis of neurons. At the same time, M2 microglia secrete various neurotrophic factors and anti-inflammatory factors such as IL-4 and IL-3, which play a neuroprotective role in cerebral ischemia and hypoxia [6, 7]. Astrocytes are widely distributed in the nervous system, showing its function by providing nutrition and support to adjoining neurons [8]. Therefore, the excitability of neurons could be regulated by the neurotransmitters secreted from astrocytes. At the same time, it could synthesize and release a variety of immune factors to participate in the neuronal immune response. Oligodendrocytes are the unique neuroglial cells that form the myelin sheath, which is the key structure for neurons to propagate APs. CNS myelin hypoplasia or demyelinating changes are the

In the mid-twentieth century, after the discovery of AP, Hodgkin and Huxley, who firstly proposed the concept of ion channels, record sodium currents by using voltage clamp technology [10, 11]. Traditionally, glial cells were considered as nonexcitatory cells, but with the development of research in this field, sodium channels have been found also to play crucial roles in physiological and pathological function

The activation of sodium channel is triggered by membrane depolarization, which produces transient sodium current and AP [14]. In neurons, sodium channels are composed of a single α-subunit, which forms ion-selective and voltage-sensitive pores, and one or two auxiliary β-subunits, which seems to affect channel gating

These channels drive electrical generation in neurons (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8), muscle cells (Nav1.4), and myocardial cells (Nav1.5). The typical role of Nav channels has been widely studied [16]. The dysfunction of sodium channels could result in neurological diseases, including neuropathic pain

However, the dysfunction of glial VGSCs is seemingly not related to abnormal excitation of neurons, but of importance in the astrogliosis and M1 polarization of microglia, which could induce refractory neuroinflammatory diseases. Glial sodium channels are closely related to phagocytosis, secretion of cytokines (IL-α, TNF-α), and migration. Then, glial cells are activated after tissue damage or disturbance, accompanied by morphological changes, enhanced migration, phagocytosis, secretion of inflammatory molecules (such as cytokines and nitric oxide), and antigen

Although glial cells do not produce AP under physiological conditions, they can show excitability through ion flux, especially in the form of [Ca2+]i oscillation. Ca2+ kinetics is involved in microglial activation and regulation of many effector functions, including cell migration [25, 26] and release of chemokines/cytokines and

/Ca2+ exchanger (NCX) operates in a forward mode, transmits Na+

decreases or the cell depolarizes, the operation realizes

ions in exchange for Ca2+ [28]. Therefore, sodium

down the concentration gradient to the cell, and then returns to output Ca2+, or if the

channel activity has the ability to increase [Ca2+]i through the reverse mode of NCX. The research shows that Nav1.6 can generate continuous sodium current [29], drive the reverse operation of NCX, and generate the inlet. Ca2+ enters the cytoplasm. In this respect, like all eukaryotic cells, the intracellular free Ca2+ level is strictly regulated, which is crucial in the signal transduction pathway of microglia.

ions

[17–19], peripheral neuropathy [20], epilepsy [21], and MS [22, 23].

**4**

*Structure of Nav channels. Schematic representation of Nav channel subunits. The Nav channel α subunit is often illustrated together with auxiliary subunits β1 and β2; extracellular domains of the β subunits are shown as immunoglobulin-like folds (shown in blue), interacting with the extracellular loops of α subunits. Roman numerals indicate the domains of the α subunit; segments 5 and 6 (shown in purple) are considered as porelining segments, and S4 helices (green) make up the voltage sensors. The yellow circle in the intracellular loop of domains III and IV represents the inactivation gating ball, IFM motif.*

Studies have shown that Nav1.1 and Nav1.6 were persistently reduced during epileptogenesis [30]. Under the MS pathological condition, the results showed that the removal of Nav1.5 from astrocytes could significantly worsen the clinical outcome of experimental autoimmune encephalomyelitis (EAE) [31] and the sodium channel Nav1.2 is expressed by scar and reactive astrocytes in plaque [32]. Studies have shown that under PD pathological conditions, Nav1.1 [33] in hippocampal astrocytes is significantly increased, and Nav1.6 is highly expressed in activated microglia [34].

There is a close relationship between the structure and the function of sodium channels (**Figure 1**). Therefore, in this chapter, we aim to describe the physiological and pathological roles of VGSCs contributing to the activity of glial cells and discuss whether VGSC subtypes could be used as a novel drug target, with an eye toward therapeutic implications for neuroinflammatory diseases.

#### **2. Neuroglial sodium channels in multiple sclerosis**

MS, a chronic inflammatory disease of the CNS, is characterized by demyelination, axonal injury, neuronal loss, and progressive inflammatory responses in the brain and spinal cord [35]. EAE is a classic model of MS, of which the pathological progress is very similar to MS. Under pathological conditions, glial cells (microglia, astrocytes, oligodendrocytes, glial stem cells) can act as regulators, effectors, and even targets of inflammatory response, not only causing tissue damage but also promoting tissue repair [4]. Glial cells are essential for critical responses to neurological diseases and injuries, including active tissue remodeling and phagocytosis [3]. Studies have shown that sodium channels are not only traditionally associated with the generation and transmission of neuronal APs, but also can be expressed in electrically inexcitable cell types including astrocytes [36, 37], oligodendrocyte precursor cells [38–40], Schwann cells [41], microglia [42, 43], and cancer cells [44–46]. The regulation of glial function by sodium channels is of special significance for the response of reactive glial to CNS diseases and insults [14].

#### **2.1 Microglial sodium channels in multiple sclerosis**

Microglial cells are the resident immune cells of the CNS. Under physiological conditions, microglial cells are usually highly branched cells with dynamic

processes that can actively monitor the microenvironment of the CNS to protect nerve homeostasis [47]. However, under pathological conditions such as MS, microglia cells could be activated and recruited [48]. Microglial cells undergo significant immunophenotype and cellular and morphological plasticity in response to damage in the activation pathway [49]. The activation of microglial cells is related to the pathological conditions of the CNS. In addition, migration of microglial cells to damaged cells and pathogens plays an important role in microglial-mediated CNS injury and infection [50].

Microglial cells activated in EAE and MS are widely distributed and promote disease processes through a variety of mechanisms, including inducing effector T cell proliferation [51], production of pro-inflammatory cytokines [52], and phagocytosis of myelin. Moreover, studies have found that microglial cells activated in newly formed MS lesions are thought to be the main cell type that triggers the neuroinflammatory cascade after oligodendrocyte apoptosis [53]. Increased intracellular calcium and subsequent stimulation of the signaling cascade have been shown to be central events in the regulation of the function of activated microglial cells [54]. Studies by Matthew et al. have demonstrated that activation of microglial cells as well as macrophages is accompanied by upregulation of sodium channel Nav1.6 in EAE and MS [13]. In both the Nav1.6 blocker model and the Nav1.6 knockout model, the extent of inflammatory infiltration in EAE and the phagocytosis of activated microglia cells were effectively reduced, thus confirming that Nav1.6 was a key contributor to the activation and pathophysiological function of microglial cells [13, 55].

In another important pathological manifestation, migration of microglial cells to lesions of the CNS is a complex and highly coordinated process involving multiple intersecting cellular pathways such as membrane adhesion and retraction, cellular polarization, and receptors transducing external migratory signals [56]. One of the preliminary structural events in chemotaxis is the formation of membrane protrusions and high enrichment in the aggregated F-actin network [57]. In addition, actin-binding protein, calmodulin, and GTP-binding signaling protein Rac also are located at the protrusions [58–60]. The activity of MAP kinase and the reorganization of actin filament also play important roles in cell migration [61]. Importantly, Ca2+ signaling seems to have an effect on protrusions and movement [62], as intracellular Ca2+ levels can regulate cell migration, and the activity of a variety of migration-related effector molecules including Rac and MAP kinase is modulated by the levels of intracellular Ca2+ [63–65]. Studies support the contribution of the sodium channel Nav1.6 in a pathway that controls the extension of lamellipodial protrusion at the initial stage of cell migration [66, 67]. Sodium channels regulate Ca2+ transients in ATP-stimulated microglia and play a role in the activation of two key migrating proteins, Rac1 and ERK1/2 [48] (**Figure 2**).

In summary, Nav1.6 sodium channel is involved in the activation and functional regulation of microglia in EAE and MS and has potential value as a therapeutic target.

#### **2.2 Astroglial sodium channels in multiple sclerosis**

Astrocytes participate in ionic homeostasis, neuronal metabolic support, and the formation and maintenance of the blood–brain barrier in the normal CNS and react to form glial scars when injured [8]. With the deepening understanding of the importance of astrocytes in CNS pathology, it has been proven that astrocytes play a key immunoregulatory role in damaged CNS [68–70]. Though astrocytes have traditionally been considered to be electrically unexcitable, studies have

**7**

(**Figure 2**).

MS lesions [71].

**Figure 2.**

*functions.*

is to transport Na<sup>+</sup>

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases*

demonstrated that these cells express VGSCs [71, 72], including the subtype Nav1.5 [73, 74]. It is worth noting that the expression of astrocyte sodium channels in rodents is not a static process, but a dynamic process that changes with the age of astrocytes, exposure to extracellular factors, and damage [75, 76]. The voltagegated sodium channel Nav1.5 is less expressed in astrocytes in non-pathological human brain but shows a strong upregulation of Nav1.5 in both acute and chronic

*Neuroglial Nav channels evoking Ca2+ signaling pathway. Schematic of putative cell signaling of Nav channel contribution to intracellular Ca2+ levels and downstream pathways. Depolarization of neuroglial membrane*

*NCX, which contribute to the level of Ca2+. The Ca2+ signaling initiates downstream effects on neuroglial cell*

*. Increased [Na<sup>+</sup>*

*]i causes reverse operation of*

Different from excitable neurons, astrocytes exhibit their excitability by mainly in the form of [Ca2+]i oscillations. Cytoplasmic Ca2+ levels in astrocytes come from multiple regions, including the endoplasmic reticulum [77], mitochondrial sodiumcalcium exchange [78], and extracellular space [79]. The [Ca2+]i flux of astrocytes not only regulates neuronal synaptic transmission, but is also important for many steady-state cell functions, including migration and proliferation, of astrocytes [78, 80, 81]. An important mechanism by which [Ca2+]i is regulated in astrocytes is the reverse (Ca2+ import) activity of the NCX [82]. The positive pattern of NCX

electrochemical gradient is reduced or the cell depolarizes, NCX outputs Na + in exchange for Ca2+ by running in reverse mode [82, 83]. Therefore, sodium channel activity has the ability to increase [Ca2+]i through the reverse pattern of NCX [82].

operate in a reverse mode in cortical astrocytes, increasing the level of [Ca2+]i [84]. Recent studies have shown that Nav1.5 plays an important role in in vitro models of glial injury by triggering the reverse mode operation of the NCX [71, 74]. Laura et al. confirmed that in the conditional knockout Nav1.5 model in astrocytes, the absence of Nav1.5 leads to a significant deterioration in the clinical outcome of EAE and an increase in inflammatory infiltration [31]. While the previous studies of MS in vivo models have shown that a variety of voltage-gated sodium channel blockers, including phenytoin [85], lamotrigine [86], carbamazepine [85], and safinamide and flecainide (Nav1.5 blocker) [87], could improve the clinical status and axonal damage, this suggests that Nav1.5 and NCX may be potential targets for the treatment of MS by acting on [Ca2+]i to regulate astrocyte proliferation

Interestingly, mechanical strain injury increases intracellular Na<sup>+</sup>

to the cell and then return Ca2+ to the cell [28]. When the Na+

, causing NCX to

*DOI: http://dx.doi.org/10.5772/intechopen.92127*

*leads to activation of VGSCs (Nav) allowing influx of Na<sup>+</sup>*

#### *Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases DOI: http://dx.doi.org/10.5772/intechopen.92127*

#### **Figure 2.**

*Neuroimaging - Neurobiology, Multimodal and Network Applications*

key migrating proteins, Rac1 and ERK1/2 [48] (**Figure 2**).

**2.2 Astroglial sodium channels in multiple sclerosis**

injury and infection [50].

microglial cells [13, 55].

processes that can actively monitor the microenvironment of the CNS to protect nerve homeostasis [47]. However, under pathological conditions such as MS, microglia cells could be activated and recruited [48]. Microglial cells undergo significant immunophenotype and cellular and morphological plasticity in response to damage in the activation pathway [49]. The activation of microglial cells is related to the pathological conditions of the CNS. In addition, migration of microglial cells to damaged cells and pathogens plays an important role in microglial-mediated CNS

Microglial cells activated in EAE and MS are widely distributed and promote disease processes through a variety of mechanisms, including inducing effector T cell proliferation [51], production of pro-inflammatory cytokines [52], and phagocytosis of myelin. Moreover, studies have found that microglial cells activated in newly formed MS lesions are thought to be the main cell type that triggers the neuroinflammatory cascade after oligodendrocyte apoptosis [53]. Increased intracellular calcium and subsequent stimulation of the signaling cascade have been shown to be central events in the regulation of the function of activated microglial cells [54]. Studies by Matthew et al. have demonstrated that activation of microglial cells as well as macrophages is accompanied by upregulation of sodium channel Nav1.6 in EAE and MS [13]. In both the Nav1.6 blocker model and the Nav1.6 knockout model, the extent of inflammatory infiltration in EAE and the phagocytosis of activated microglia cells were effectively reduced, thus confirming that Nav1.6 was a key contributor to the activation and pathophysiological function of

In another important pathological manifestation, migration of microglial cells to lesions of the CNS is a complex and highly coordinated process involving multiple intersecting cellular pathways such as membrane adhesion and retraction, cellular polarization, and receptors transducing external migratory signals [56]. One of the preliminary structural events in chemotaxis is the formation of membrane protrusions and high enrichment in the aggregated F-actin network [57]. In addition, actin-binding protein, calmodulin, and GTP-binding signaling protein Rac also are located at the protrusions [58–60]. The activity of MAP kinase and the reorganization of actin filament also play important roles in cell migration [61]. Importantly, Ca2+ signaling seems to have an effect on protrusions and movement [62], as intracellular Ca2+ levels can regulate cell migration, and the activity of a variety of migration-related effector molecules including Rac and MAP kinase is modulated by the levels of intracellular Ca2+ [63–65]. Studies support the contribution of the sodium channel Nav1.6 in a pathway that controls the extension of lamellipodial protrusion at the initial stage of cell migration [66, 67]. Sodium channels regulate Ca2+ transients in ATP-stimulated microglia and play a role in the activation of two

In summary, Nav1.6 sodium channel is involved in the activation and functional

Astrocytes participate in ionic homeostasis, neuronal metabolic support, and the formation and maintenance of the blood–brain barrier in the normal CNS and react to form glial scars when injured [8]. With the deepening understanding of the importance of astrocytes in CNS pathology, it has been proven that astrocytes play a key immunoregulatory role in damaged CNS [68–70]. Though astrocytes have traditionally been considered to be electrically unexcitable, studies have

regulation of microglia in EAE and MS and has potential value as a therapeu-

**6**

tic target.

*Neuroglial Nav channels evoking Ca2+ signaling pathway. Schematic of putative cell signaling of Nav channel contribution to intracellular Ca2+ levels and downstream pathways. Depolarization of neuroglial membrane leads to activation of VGSCs (Nav) allowing influx of Na<sup>+</sup> . Increased [Na<sup>+</sup> ]i causes reverse operation of NCX, which contribute to the level of Ca2+. The Ca2+ signaling initiates downstream effects on neuroglial cell functions.*

demonstrated that these cells express VGSCs [71, 72], including the subtype Nav1.5 [73, 74]. It is worth noting that the expression of astrocyte sodium channels in rodents is not a static process, but a dynamic process that changes with the age of astrocytes, exposure to extracellular factors, and damage [75, 76]. The voltagegated sodium channel Nav1.5 is less expressed in astrocytes in non-pathological human brain but shows a strong upregulation of Nav1.5 in both acute and chronic MS lesions [71].

Different from excitable neurons, astrocytes exhibit their excitability by mainly in the form of [Ca2+]i oscillations. Cytoplasmic Ca2+ levels in astrocytes come from multiple regions, including the endoplasmic reticulum [77], mitochondrial sodiumcalcium exchange [78], and extracellular space [79]. The [Ca2+]i flux of astrocytes not only regulates neuronal synaptic transmission, but is also important for many steady-state cell functions, including migration and proliferation, of astrocytes [78, 80, 81]. An important mechanism by which [Ca2+]i is regulated in astrocytes is the reverse (Ca2+ import) activity of the NCX [82]. The positive pattern of NCX is to transport Na<sup>+</sup> to the cell and then return Ca2+ to the cell [28]. When the Na+ electrochemical gradient is reduced or the cell depolarizes, NCX outputs Na + in exchange for Ca2+ by running in reverse mode [82, 83]. Therefore, sodium channel activity has the ability to increase [Ca2+]i through the reverse pattern of NCX [82]. Interestingly, mechanical strain injury increases intracellular Na<sup>+</sup> , causing NCX to operate in a reverse mode in cortical astrocytes, increasing the level of [Ca2+]i [84].

Recent studies have shown that Nav1.5 plays an important role in in vitro models of glial injury by triggering the reverse mode operation of the NCX [71, 74]. Laura et al. confirmed that in the conditional knockout Nav1.5 model in astrocytes, the absence of Nav1.5 leads to a significant deterioration in the clinical outcome of EAE and an increase in inflammatory infiltration [31]. While the previous studies of MS in vivo models have shown that a variety of voltage-gated sodium channel blockers, including phenytoin [85], lamotrigine [86], carbamazepine [85], and safinamide and flecainide (Nav1.5 blocker) [87], could improve the clinical status and axonal damage, this suggests that Nav1.5 and NCX may be potential targets for the treatment of MS by acting on [Ca2+]i to regulate astrocyte proliferation (**Figure 2**).

#### **2.3 Oligodentroglial sodium channels in multiple sclerosis**

During the development of CNS, oligodendrocytes (NG2 cells) originating in different regions of the brain migrate to their destinations to participate in the development [88, 89]. The directed migration of these glial progenitor cells is critical not only for the formation of myelin in the developing brain, but also for the repair of myelin after injury [90, 91]. Although NG2 cells express VGSC, they only trigger transient depolarization and fail to produce typical APs [92, 93]. Studies have found that intracellular Na<sup>+</sup> and Ca2+ levels, membrane depolarization, and migration ability of NG2 cells increased after the application of GABA [93]. While in the siRNA knockdown or blocking sodium channel model, the increasing tendency of [Na<sup>+</sup> ]i and [Ca2+]i was significantly reduced, and cell migration was suppressed [93]. Moreover, a similar reduced [Ca2+]i and decreased cell migration were also shown in the NCX siRNA knockdown and blocker models [93].

In general, GABA induced the depolarization of the NG2 cells and activated the sustained Na<sup>+</sup> current, which reverted the activity of type I Na+ /Ca2+ exchangers (NCX1) to evoke the increase of [Ca2+]i [93]. Significantly, further evidence suggests that this unique pathway is associated with NG2 cell migration [93, 94]. Therefore, the important role of non-inactivated Na<sup>+</sup> channels and NCXs in the development and function of NG2 glial cells in the brain suggests its potential values in myelin repair.

#### **3. Neuroglial sodium channels in epilepsy**

Epilepsy is a kind of chronic brain dysfunction syndrome caused by abnormal firing of neurons, which has been listed as one of the five major neuropsychiatric diseases by the World Health Organization (WHO). At present, the number of epilepsy patients has reached 65 million worldwide [95], and especially the developing countries account for four fifths of this number [96], bringing serious economic burden to the patients' families and their country.

The previous studies on epilepsy were focused on clarifying the mechanisms of neuron dysfunction as well as neural network. In recent years, the researches on glial cells regulating neuron activity have surfaced with increasing frequency, which provide sufficient evidence for the involvement of glial cells in inducing epilepsy [95]. Glial hyperplasia is an important hallmark in the course of epilepsy; it refers to a spectrum of physicochemical and physiological changes in glial cells, particularly in astrocytes and microglia. The activation of astrocytes after epileptic seizure may be beneficial to the recovery of extracellular homeostasis [97]. However, more and more evidence proved that reactive glial cells could induce neuroinflammation by releasing the cytokines, chemokines, and other molecules, which is likely to cause neuron death, tissue damage, and microglial hyperplasia [98]. Unrestrained reactive gliosis might also cause hippocampal sclerosis, disturbing the normal physiological regulation function and promoting the epileptic seizure [99].

Glial cells express several types of ion channels. The Cl<sup>−</sup>, K+ , H+ , and Ca2+ channels have been found to express in microglia, and the Kir [100] and Na+ channels are highly expressed in astrocytes, which have been implicated in multiple functions of these cells [101]. These channels of different subtypes can be involved in regulating the membrane potential, migration, phagocytosis, intracellular ion concentration, and secretion of various cytokines and chemokines in glial cells [102].

Genetic studies have shown that the mutations associated with epilepsy mainly occur in genes encoding sodium channels [103]. VGSCs are a class of voltagedependent ion channels that are highly expressed not only in excitable cells [104],

**9**

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases*

tion [95]. Normally, a single AP can increase the extracellular K+

12 mM [106]. In normal brain, neurons rapidly regulate K+

work of intercellular synapses in the process of epilepsy [111].

**3.2 Microglial sodium channels in epilepsy**

ATPase, and Na<sup>+</sup>

but also in non-excited cells, such as astrocytes, oligodendrocytes, microglial cells, etc. [105]. Recently, it has been found that sodium channel plays an important role in the activation of glial cells and may become a new target for antiepileptic drugs.

Neuronal excitability is closely related to the movement of sodium or potassium across the extracellular space (ECS). Because of the narrow volume of this space, the extremely small fluxes could also evoke significant changes in anion concentra-

by nearly 1 mM. However, at the epileptic seizure period, the continuous neuron firing could raise the potassium concentration from the normal level ~3 mM to

activates Na<sup>+</sup>

extracellular space and maintaining stability of the central nervous system [106]. Thus far more and more reports have mentioned that sodium channel subtypes are widely distributed in most CNS glial cells [72, 107], including the TTX-S sodium channel Nav1.3 and Nav1.6 as well as TTX-R sodium channel Nav1.5 [14]. In the post-status epilepticus (SE) model induced by kainic acid (KA) intrahippocampal injection, the expression of Nav1.6 in ipsilateral hippocampal peaked at 21 days in astrocytes. On the contrary, there was no change in the expression of astrocyte Nav1.6 in the PTZ-induced epileptic seizure models, indicating that astrocyte Nav1.6 played a crucial role in promoting the epileptic process, but not in seizure

It is known to all that the voltage-gated sodium channel is composed of one α subunit and two auxiliary β subunits [109]. Co-expressed with α subunits, β subunits could significantly increase the current density of sodium channels, which is partly due to the enhancement effects of β subunits on the expression of sodium channels [110]. In the chronic epilepsy model induced by electrical stimulation, sodium channel β1 subunits are colocalized with the reactive astrocytes, and the number of positive cells significantly enhanced a week after SE, so it is speculated that the β1 subunits could interact with extracellular matrix, promoting the net-

Microglia, as resident cells in the CNS, provide continuous immunosurveillance for the brain as well as the spinal cord [47]. When the body is invaded by exogenous substances, microglial cells respond to ATP or other cell signals, activated rapidly so as to provide immune defense. However, microglia cells can produce inflammatory factors in pathological conditions, causing damage to the body [49]. Microglial cells always express a large number of ion channels and surface receptors, which can induce relevant signaling pathways to convert extracellular changes into intracel-

VGSCs are also distributed in microglial cells. Studies have shown that microglia

not only express the TTX sensitivity sodium channels (Nav1.6 [13] and Nav1.1 [14]), but also express the Nav1.5 [14] (a TTX-resistant sodium channel) [14]. The blockade sodium channels of TTX and phenytoin could significantly weaken a variety of functions of activated microglia cells [12], such as the release of inflammatory cytokines [12, 102]. After a week of spontaneous epilepsy induced by electrical stimulation, the sodium channel subtypes were found to be highly expressed in microglial cells [112]. The Nax channel encoded by the SCN7A gene was observed

in astrocytes, providing an important feedback pathway for regulating K<sup>+</sup>

/K+

concentration

concentration to 3 mM

level in

ATPase activity through VGSCs

*DOI: http://dx.doi.org/10.5772/intechopen.92127*

**3.1 Astroglial sodium channels in epilepsy**

through Na<sup>+</sup>

period [108].

lular responses.

/K+

but also in non-excited cells, such as astrocytes, oligodendrocytes, microglial cells, etc. [105]. Recently, it has been found that sodium channel plays an important role in the activation of glial cells and may become a new target for antiepileptic drugs.

#### **3.1 Astroglial sodium channels in epilepsy**

*Neuroimaging - Neurobiology, Multimodal and Network Applications*

**2.3 Oligodentroglial sodium channels in multiple sclerosis**

Studies have found that intracellular Na<sup>+</sup>

Therefore, the important role of non-inactivated Na<sup>+</sup>

**3. Neuroglial sodium channels in epilepsy**

burden to the patients' families and their country.

regulation function and promoting the epileptic seizure [99]. Glial cells express several types of ion channels. The Cl<sup>−</sup>, K+

nels have been found to express in microglia, and the Kir [100] and Na+

and secretion of various cytokines and chemokines in glial cells [102].

occur in genes encoding sodium channels [103]. VGSCs are a class of voltagedependent ion channels that are highly expressed not only in excitable cells [104],

highly expressed in astrocytes, which have been implicated in multiple functions of these cells [101]. These channels of different subtypes can be involved in regulating the membrane potential, migration, phagocytosis, intracellular ion concentration,

Genetic studies have shown that the mutations associated with epilepsy mainly

tendency of [Na<sup>+</sup>

the sustained Na<sup>+</sup>

values in myelin repair.

During the development of CNS, oligodendrocytes (NG2 cells) originating in different regions of the brain migrate to their destinations to participate in the development [88, 89]. The directed migration of these glial progenitor cells is critical not only for the formation of myelin in the developing brain, but also for the repair of myelin after injury [90, 91]. Although NG2 cells express VGSC, they only trigger transient depolarization and fail to produce typical APs [92, 93].

and migration ability of NG2 cells increased after the application of GABA [93]. While in the siRNA knockdown or blocking sodium channel model, the increasing

suppressed [93]. Moreover, a similar reduced [Ca2+]i and decreased cell migration

In general, GABA induced the depolarization of the NG2 cells and activated

ers (NCX1) to evoke the increase of [Ca2+]i [93]. Significantly, further evidence suggests that this unique pathway is associated with NG2 cell migration [93, 94].

development and function of NG2 glial cells in the brain suggests its potential

current, which reverted the activity of type I Na+

Epilepsy is a kind of chronic brain dysfunction syndrome caused by abnormal firing of neurons, which has been listed as one of the five major neuropsychiatric diseases by the World Health Organization (WHO). At present, the number of epilepsy patients has reached 65 million worldwide [95], and especially the developing countries account for four fifths of this number [96], bringing serious economic

The previous studies on epilepsy were focused on clarifying the mechanisms of neuron dysfunction as well as neural network. In recent years, the researches on glial cells regulating neuron activity have surfaced with increasing frequency, which provide sufficient evidence for the involvement of glial cells in inducing epilepsy [95]. Glial hyperplasia is an important hallmark in the course of epilepsy; it refers to a spectrum of physicochemical and physiological changes in glial cells, particularly in astrocytes and microglia. The activation of astrocytes after epileptic seizure may be beneficial to the recovery of extracellular homeostasis [97]. However, more and more evidence proved that reactive glial cells could induce neuroinflammation by releasing the cytokines, chemokines, and other molecules, which is likely to cause neuron death, tissue damage, and microglial hyperplasia [98]. Unrestrained reactive gliosis might also cause hippocampal sclerosis, disturbing the normal physiological

were also shown in the NCX siRNA knockdown and blocker models [93].

]i and [Ca2+]i was significantly reduced, and cell migration was

and Ca2+ levels, membrane depolarization,

channels and NCXs in the

, H+

, and Ca2+ chan-

channels are

/Ca2+ exchang-

**8**

Neuronal excitability is closely related to the movement of sodium or potassium across the extracellular space (ECS). Because of the narrow volume of this space, the extremely small fluxes could also evoke significant changes in anion concentration [95]. Normally, a single AP can increase the extracellular K+ concentration by nearly 1 mM. However, at the epileptic seizure period, the continuous neuron firing could raise the potassium concentration from the normal level ~3 mM to 12 mM [106]. In normal brain, neurons rapidly regulate K+ concentration to 3 mM through Na<sup>+</sup> /K+ ATPase, and Na<sup>+</sup> activates Na<sup>+</sup> /K+ ATPase activity through VGSCs in astrocytes, providing an important feedback pathway for regulating K<sup>+</sup> level in extracellular space and maintaining stability of the central nervous system [106].

Thus far more and more reports have mentioned that sodium channel subtypes are widely distributed in most CNS glial cells [72, 107], including the TTX-S sodium channel Nav1.3 and Nav1.6 as well as TTX-R sodium channel Nav1.5 [14]. In the post-status epilepticus (SE) model induced by kainic acid (KA) intrahippocampal injection, the expression of Nav1.6 in ipsilateral hippocampal peaked at 21 days in astrocytes. On the contrary, there was no change in the expression of astrocyte Nav1.6 in the PTZ-induced epileptic seizure models, indicating that astrocyte Nav1.6 played a crucial role in promoting the epileptic process, but not in seizure period [108].

It is known to all that the voltage-gated sodium channel is composed of one α subunit and two auxiliary β subunits [109]. Co-expressed with α subunits, β subunits could significantly increase the current density of sodium channels, which is partly due to the enhancement effects of β subunits on the expression of sodium channels [110]. In the chronic epilepsy model induced by electrical stimulation, sodium channel β1 subunits are colocalized with the reactive astrocytes, and the number of positive cells significantly enhanced a week after SE, so it is speculated that the β1 subunits could interact with extracellular matrix, promoting the network of intercellular synapses in the process of epilepsy [111].

#### **3.2 Microglial sodium channels in epilepsy**

Microglia, as resident cells in the CNS, provide continuous immunosurveillance for the brain as well as the spinal cord [47]. When the body is invaded by exogenous substances, microglial cells respond to ATP or other cell signals, activated rapidly so as to provide immune defense. However, microglia cells can produce inflammatory factors in pathological conditions, causing damage to the body [49]. Microglial cells always express a large number of ion channels and surface receptors, which can induce relevant signaling pathways to convert extracellular changes into intracellular responses.

VGSCs are also distributed in microglial cells. Studies have shown that microglia not only express the TTX sensitivity sodium channels (Nav1.6 [13] and Nav1.1 [14]), but also express the Nav1.5 [14] (a TTX-resistant sodium channel) [14]. The blockade sodium channels of TTX and phenytoin could significantly weaken a variety of functions of activated microglia cells [12], such as the release of inflammatory cytokines [12, 102]. After a week of spontaneous epilepsy induced by electrical stimulation, the sodium channel subtypes were found to be highly expressed in microglial cells [112]. The Nax channel encoded by the SCN7A gene was observed

to be significantly increased during the onset and development of epilepsy, and especially the high expression of Nax was detected in hippocampal sclerosis tissues from drug-resistant patients [113].

Ocasepine, as a clinical drug that targeted on VGSCs, is often used to suppress the epileptic seizure clinically. This drug has been found that it could significantly reduce the number of activated astrocytes as well as microglial cells in the hippocampus CA1 region in cerebral ischemia model, which also reduce the neuron death in the hippocampus caused by ischemia [14]. It implies that sodium channels are involved in microglia activation, which could also promote the progression of neuroinflammatory disease, such as epileptogenesis.

#### **4. Neuroglial sodium channels in neurodegenerative diseases**

#### **4.1 Neuroglial sodium channels in Alzheimer's disease**

AD is the most common progressive neurodegenerative disease, which is characterized by dystrophic neurites, neurofibrillary tangles, brain atrophy amyloid plaques, and loss of neurons and synapses [114]. In addition, AD is the cause of dementia and seriously affects the quality of life of the elderly [115]. Accumulated data show that the genetic mechanism of AD is mainly the accumulation of Aβ peptides and their aggregation in and deposition in amyloid plaques [116, 117]. The human genetics of familial AD also suggested that excessive production of amyloidogenic Aβ is a cause of early-onset AD; mutations in amyloid precursor protein (APP) or in its processing enzyme result in increased β-site cleavage of APP or favored production of longer, aggregation-prone variants of Aβ peptide [118]. In recent years, however, many studies found that microglia play an important role in the pathogenesis of AD. The reactive gliosis of AD histopathology revealed the abnormal morphology and proliferation of microglia [119, 120]. Several reports have linked microglia dysfunctions to AD, by showing microglial motility impairment in AD mice models [121]. Recently, it was recognized that microglia express voltage-gated ion channels, including Nav1.1, Nav1.5, and Nav1.6 [122, 123]. Furthermore, pharmacological block of the sodium channels has been attempted as a symptomatic treatment of epileptic features often associated with AD, as well as a relief to detrimental behavioral and psychological symptoms of dementia [124]. An interesting debate is if sodium channel activators could just be enough to compensate microglial dysfunctions to altered physiological properties of dysfunctional neuronal networks in AD patients [125].

#### **4.2 Neuroglial sodium channels in Parkinson's disease**

PD is the second most common age-related disabling neurodegenerative disorder, estimated to affect over 10 million people worldwide, which PD presents clinically as bradykinesia, muscular rigidity, arresting tremor, and postural stability [126–128]. In addition, PD is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. The potential causes of PD remain uncertain, but recent studies suggest neuroinflammation and microglia activation play important roles in PD pathogenesis [129, 130]. However, persistent activation of microglia can mediate neuronal death and neurodegeneration by increasing the secretion of inflammatory molecules and cytokines, including tumor necrosis factor alpha (TNF-α) and reactive oxygen species (ROS) [131, 132]. Microglia express a number of ion channels, including sodium channels that regulate various aspects of inflammatory process, providing a potential target for intervention [14, 133]. Several studies demonstrated that VGSC can regulate a

**11**

**6. Conclusion**

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases*

ute to its reported neuroprotective role in preclinical models of PD.

experimental results both more abundant and accurate.

number of cellular functions such as morphological transformation, migration, and phagocytosis of microglia [12, 35]. This also indicates the well potential immunomodulatory properties of VGSC. 6-Hydroxydopamine (6-OHDA)-induced PD rat model found that the expressions of Nav1.1, Nav1.3, and Nav1.6 in the hippocampus were dynamically increased at different time points after dopamine depletion. Furthermore, cognitive deficits were effectively improved by phenytoin (sodium channel blocker) that has inhibitory effects on VGSCs in the brain [33]. Other study suggested that zonisamide, targeting VGSCs, may reduce neuroinflammation through the downregulation of microglial Nav 1.6 [134]. Those studies may contrib-

**5. Application of neuroimaging in studying neuroglial sodium channels**

Electrophysiological patch clamp is a classic technique for traditionally recording neuronal sodium channels. Neuroglial cells are non-excitable cells, of which the cell membrane depolarization is not obvious. The bioproperties of neuroglial sodium channels evoked by high voltage in patch clamp recordings might be different from the actual situation in vivo. Therefore, this method has certain limitations in the process of studying neuroglial cells. With the development of ion probes, especially the recent discovery of visible light sodium ion probes as well as calcium ion probes, which could provide more intuitive results (such as higher resolution, better observation) for the functional study of glial cell Nav channels and Nav-NCX complexes [14]. The combined use of ion probes and patch clamping will make the

In addition, the invention of the miniature two-photon microscope in 2017 [135] provided a powerful means for the functional research of nerve cells as well as glial cells. During studying brain activities and the development of neuroinflammatory diseases, glial cells could be labeled by GCaMP6 or dTomato to explore the function of the glial Nav-NCX complex. Two-photon imaging combined with EEG could not only explain the relationship between glial cell activity and EEG frequency more effectively, but also elucidate the important role of glial cells in neurological disorders, such as epilepsy. By using the miniature two-photon microscope, the conditional knockout mice could be applied to study the role of glial sodium channels in regulating the function of glial cells or the interaction between glial cells and neurons, including pruning of neuron synapses by microglial cells or regulating the neuroexcitability in vivo.

In view of the central role of glia in CNS health and disease, it is necessary to further understand the physiological correlation of glial sodium channels and characterize the molecular pathways that control the function of sodium channels in these cells. There has been much work performed in cell culture, but further in vivo studies are of crucial importance for determination of the therapeutic implications of targeting glial sodium channels in neurological disorders. Therefore, novel neuroimaging techniques are of importance for studying the roles of neuroglial sodium channels in neuroinflammatory diseases. Meanwhile, with the heightened focus on developing sodium channel specific blockers, it is increasingly relevant to assess the roles of individual sodium channel isoforms in neuroglia cells (e.g., Nav1.6 in microglial cells, Nav1.5 in astrocytes). Further understanding of the signaling cascade linking sodium channel activity to glial effector function will facilitate the

development of specific therapeutic targets for neurological diseases.

*DOI: http://dx.doi.org/10.5772/intechopen.92127*

#### *Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases DOI: http://dx.doi.org/10.5772/intechopen.92127*

*Neuroimaging - Neurobiology, Multimodal and Network Applications*

neuroinflammatory disease, such as epileptogenesis.

**4.1 Neuroglial sodium channels in Alzheimer's disease**

**4. Neuroglial sodium channels in neurodegenerative diseases**

properties of dysfunctional neuronal networks in AD patients [125].

PD is the second most common age-related disabling neurodegenerative disorder, estimated to affect over 10 million people worldwide, which PD presents clinically as bradykinesia, muscular rigidity, arresting tremor, and postural stability [126–128]. In addition, PD is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. The potential causes of PD remain uncertain, but recent studies suggest neuroinflammation and microglia activation play important roles in PD pathogenesis [129, 130]. However, persistent activation of microglia can mediate neuronal death and neurodegeneration by increasing the secretion of inflammatory molecules and cytokines, including tumor necrosis factor alpha (TNF-α) and reactive oxygen species (ROS) [131, 132]. Microglia express a number of ion channels, including sodium channels that regulate various aspects of inflammatory process, providing a potential target for intervention [14, 133]. Several studies demonstrated that VGSC can regulate a

**4.2 Neuroglial sodium channels in Parkinson's disease**

from drug-resistant patients [113].

to be significantly increased during the onset and development of epilepsy, and especially the high expression of Nax was detected in hippocampal sclerosis tissues

Ocasepine, as a clinical drug that targeted on VGSCs, is often used to suppress the epileptic seizure clinically. This drug has been found that it could significantly reduce the number of activated astrocytes as well as microglial cells in the hippocampus CA1 region in cerebral ischemia model, which also reduce the neuron death in the hippocampus caused by ischemia [14]. It implies that sodium channels are involved in microglia activation, which could also promote the progression of

AD is the most common progressive neurodegenerative disease, which is characterized by dystrophic neurites, neurofibrillary tangles, brain atrophy amyloid plaques, and loss of neurons and synapses [114]. In addition, AD is the cause of dementia and seriously affects the quality of life of the elderly [115]. Accumulated data show that the genetic mechanism of AD is mainly the accumulation of Aβ peptides and their aggregation in and deposition in amyloid plaques [116, 117]. The human genetics of familial AD also suggested that excessive production of amyloidogenic Aβ is a cause of early-onset AD; mutations in amyloid precursor protein (APP) or in its processing enzyme result in increased β-site cleavage of APP or favored production of longer, aggregation-prone variants of Aβ peptide [118]. In recent years, however, many studies found that microglia play an important role in the pathogenesis of AD. The reactive gliosis of AD histopathology revealed the abnormal morphology and proliferation of microglia [119, 120]. Several reports have linked microglia dysfunctions to AD, by showing microglial motility impairment in AD mice models [121]. Recently, it was recognized that microglia express voltage-gated ion channels, including Nav1.1, Nav1.5, and Nav1.6 [122, 123]. Furthermore, pharmacological block of the sodium channels has been attempted as a symptomatic treatment of epileptic features often associated with AD, as well as a relief to detrimental behavioral and psychological symptoms of dementia [124]. An interesting debate is if sodium channel activators could just be enough to compensate microglial dysfunctions to altered physiological

**10**

number of cellular functions such as morphological transformation, migration, and phagocytosis of microglia [12, 35]. This also indicates the well potential immunomodulatory properties of VGSC. 6-Hydroxydopamine (6-OHDA)-induced PD rat model found that the expressions of Nav1.1, Nav1.3, and Nav1.6 in the hippocampus were dynamically increased at different time points after dopamine depletion. Furthermore, cognitive deficits were effectively improved by phenytoin (sodium channel blocker) that has inhibitory effects on VGSCs in the brain [33]. Other study suggested that zonisamide, targeting VGSCs, may reduce neuroinflammation through the downregulation of microglial Nav 1.6 [134]. Those studies may contribute to its reported neuroprotective role in preclinical models of PD.

#### **5. Application of neuroimaging in studying neuroglial sodium channels**

Electrophysiological patch clamp is a classic technique for traditionally recording neuronal sodium channels. Neuroglial cells are non-excitable cells, of which the cell membrane depolarization is not obvious. The bioproperties of neuroglial sodium channels evoked by high voltage in patch clamp recordings might be different from the actual situation in vivo. Therefore, this method has certain limitations in the process of studying neuroglial cells. With the development of ion probes, especially the recent discovery of visible light sodium ion probes as well as calcium ion probes, which could provide more intuitive results (such as higher resolution, better observation) for the functional study of glial cell Nav channels and Nav-NCX complexes [14]. The combined use of ion probes and patch clamping will make the experimental results both more abundant and accurate.

In addition, the invention of the miniature two-photon microscope in 2017 [135] provided a powerful means for the functional research of nerve cells as well as glial cells. During studying brain activities and the development of neuroinflammatory diseases, glial cells could be labeled by GCaMP6 or dTomato to explore the function of the glial Nav-NCX complex. Two-photon imaging combined with EEG could not only explain the relationship between glial cell activity and EEG frequency more effectively, but also elucidate the important role of glial cells in neurological disorders, such as epilepsy. By using the miniature two-photon microscope, the conditional knockout mice could be applied to study the role of glial sodium channels in regulating the function of glial cells or the interaction between glial cells and neurons, including pruning of neuron synapses by microglial cells or regulating the neuroexcitability in vivo.

#### **6. Conclusion**

In view of the central role of glia in CNS health and disease, it is necessary to further understand the physiological correlation of glial sodium channels and characterize the molecular pathways that control the function of sodium channels in these cells. There has been much work performed in cell culture, but further in vivo studies are of crucial importance for determination of the therapeutic implications of targeting glial sodium channels in neurological disorders. Therefore, novel neuroimaging techniques are of importance for studying the roles of neuroglial sodium channels in neuroinflammatory diseases. Meanwhile, with the heightened focus on developing sodium channel specific blockers, it is increasingly relevant to assess the roles of individual sodium channel isoforms in neuroglia cells (e.g., Nav1.6 in microglial cells, Nav1.5 in astrocytes). Further understanding of the signaling cascade linking sodium channel activity to glial effector function will facilitate the development of specific therapeutic targets for neurological diseases.

### **Acknowledgements**

This chapter was supported by National Natural Science Foundation of China (Nos. 81603410 and 81903995), Youth Talent Promotion Project of China Association of Chinese Medicine (No. CACM-2019-QNRC2-C10), Shanghai Municipal Commission of Health and Family Planning Fund (Nos. 20184Y0086 and 2018JQ003), Project for Capacity Promotion of Putuo District Clinical Special Disease (2019tszb02), Science and Technology Innovation Project of Putuo District Health System (Nos. ptkwws201902 and ptkwws201908), Project within the Budget of Shanghai University of Traditional Chinese Medicine (Nos. 18-DX-06 and 2019LK040), the Key Speciality Program (No. 2016102A), and Research Project (Nos. 2016208A, 2018302, 2018314, and 2018313) of Putuo Hospital, Shanghai University of Traditional Chinese Medicine.

### **Conflict of interest**

The authors confirm that this article content has no conflict of interest.

### **Author details**

Yu Yao1,2† , Xiaoli Wang2† , Shuzhang Zhang2 , Zhiping Zhang2 , Wei Wang1 , Yudan Zhu1 , Jiwei Cheng1 , Guoyi Li1 \* and Jie Tao1 \*

1 Department of Neurology and Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

2 Institute of Biomembrane and Biopharmaceutics, Shanghai University, Shanghai, China

\*Address all correspondence to<EMAIL_ADDRESS>and<EMAIL_ADDRESS>
† These authors have contributed equally to this chapter.

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**13**

bbi.2013.02.005

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases*

2010;**133**(Pt 3):835-846. DOI: 10.1093/

[9] Barateiro A, Brites D, Fernandes A. Oligodendrocyte development and myelination in neurodevelopment: Molecular mechanisms in health and disease. Current Pharmaceutical Design. 2016;**22**(6):656-679. DOI: 10.2174/13816

brain/awq003

12822666151204000636

1952;**117**(4):500-544

bbrc.2000.3756

glia.20830

glia.20112

glia.22967

roles of Na<sup>+</sup>

[10] Hodgkin AL, Huxley AF. A quantitative description of

membrane current and its application to conduction and excitation in nerve. Journal of Physiology.

[11] Peter M Jr, Hajdu P, Varga Z, et al. Blockage of human T lymphocyte Kv1.3 channels by Pi1, a novel class of scorpion toxin. Biochemical and Biophysical Research Communications. 2000;**278**(1):34-37. DOI: 10.1006/

[12] Black JA, Liu S, Waxman SG. Sodium channel activity modulates multiple functions in microglia. Glia. 2009;**57**(10):1072-1081. DOI: 10.1002/

[13] Craner MJ, Damarjian TG, Liu S, et al. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS. Glia. 2005;**49**(2):220-229. DOI: 10.1002/

[14] Pappalardo LW, Black JA, Waxman SG. Sodium channels in astroglia and microglia. Glia.

[15] Patino GA, Isom LL.

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Electrophysiology and beyond: Multiple

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channel beta subunits in

*DOI: http://dx.doi.org/10.5772/intechopen.92127*

Neuroinflammation, bone marrow stem cells, and chronic pain. Frontiers in Immunology. 2017;**8**:1014. DOI:

Peskind E. Traumatic brain injury, neuroinflammation, and post-traumatic headaches. Headache. 2013;**53**(9):1523-

[3] Healy LM, Yaqubi M, Ludwin S, et al. Species differences in immunemediated CNS tissue injury and repair: A (neuro) inflammatory topic. Glia.

Neuroinflammation in the central nervous system: Symphony of glial cells. Glia. 2019;**67**(6):1017-1035. DOI:

Thompson RW, et al. Quantitative assessment of macrophage functions in repair and fibrosis. Current Protocols in Immunology. 2011; Chapter

[6] Xiong XY, Liu L, Yang QW.

14:Unit14.22. DOI: 10.1002/0471142735.

Functions and mechanisms of microglia/ macrophages in neuroinflammation and neurogenesis after stroke. Progress in Neurobiology. 2016;**142**:23-44. DOI: 10.1016/j.pneurobio.2016.05.001

[7] Chhor V, Le Charpentier T, Lebon S, et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain, Behavior, and Immunity. 2013;**32**:70-85. DOI: 10.1016/j.

[8] Black JA, Newcombe J, Waxman SG. Astrocytes within multiple sclerosis lesions upregulate sodium channel Nav1.5. Brain: A Journal of Neurology.

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10.3389/fimmu.2017.01014

[2] Mayer CL, Huber BR,

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im1422s93

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[5] Wynn TA, Barron L,

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases DOI: http://dx.doi.org/10.5772/intechopen.92127*

#### **References**

*Neuroimaging - Neurobiology, Multimodal and Network Applications*

University of Traditional Chinese Medicine.

This chapter was supported by National Natural Science Foundation of China (Nos. 81603410 and 81903995), Youth Talent Promotion Project of China Association of Chinese Medicine (No. CACM-2019-QNRC2-C10), Shanghai Municipal Commission of Health and Family Planning Fund (Nos. 20184Y0086 and 2018JQ003), Project for Capacity Promotion of Putuo District Clinical Special Disease (2019tszb02), Science and Technology Innovation Project of Putuo District Health System (Nos. ptkwws201902 and ptkwws201908), Project within the Budget of Shanghai University of Traditional Chinese Medicine (Nos. 18-DX-06 and 2019LK040), the Key Speciality Program (No. 2016102A), and Research Project (Nos. 2016208A, 2018302, 2018314, and 2018313) of Putuo Hospital, Shanghai

The authors confirm that this article content has no conflict of interest.

**Acknowledgements**

**Conflict of interest**

**12**

**Author details**

, Xiaoli Wang2†

, Jiwei Cheng1

, Shuzhang Zhang2

\* and Jie Tao1

2 Institute of Biomembrane and Biopharmaceutics, Shanghai University, Shanghai,

\*Address all correspondence to<EMAIL_ADDRESS>and<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Neurology and Central Laboratory, Putuo Hospital, Shanghai

, Guoyi Li1

University of Traditional Chinese Medicine, Shanghai, China

† These authors have contributed equally to this chapter.

provided the original work is properly cited.

, Zhiping Zhang2

\*

, Wei Wang1

,

Yu Yao1,2†

China

Yudan Zhu1

[1] Huh Y, Ji RR, Chen G. Neuroinflammation, bone marrow stem cells, and chronic pain. Frontiers in Immunology. 2017;**8**:1014. DOI: 10.3389/fimmu.2017.01014

[2] Mayer CL, Huber BR, Peskind E. Traumatic brain injury, neuroinflammation, and post-traumatic headaches. Headache. 2013;**53**(9):1523- 1530. DOI: 10.1111/head.12173

[3] Healy LM, Yaqubi M, Ludwin S, et al. Species differences in immunemediated CNS tissue injury and repair: A (neuro) inflammatory topic. Glia. 2020;**68**(4):811-829

[4] Yang QQ, Zhou JW. Neuroinflammation in the central nervous system: Symphony of glial cells. Glia. 2019;**67**(6):1017-1035. DOI: 10.1002/glia.23571

[5] Wynn TA, Barron L, Thompson RW, et al. Quantitative assessment of macrophage functions in repair and fibrosis. Current Protocols in Immunology. 2011; Chapter 14:Unit14.22. DOI: 10.1002/0471142735. im1422s93

[6] Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia/ macrophages in neuroinflammation and neurogenesis after stroke. Progress in Neurobiology. 2016;**142**:23-44. DOI: 10.1016/j.pneurobio.2016.05.001

[7] Chhor V, Le Charpentier T, Lebon S, et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain, Behavior, and Immunity. 2013;**32**:70-85. DOI: 10.1016/j. bbi.2013.02.005

[8] Black JA, Newcombe J, Waxman SG. Astrocytes within multiple sclerosis lesions upregulate sodium channel Nav1.5. Brain: A Journal of Neurology.

2010;**133**(Pt 3):835-846. DOI: 10.1093/ brain/awq003

[9] Barateiro A, Brites D, Fernandes A. Oligodendrocyte development and myelination in neurodevelopment: Molecular mechanisms in health and disease. Current Pharmaceutical Design. 2016;**22**(6):656-679. DOI: 10.2174/13816<PHONE_NUMBER>1204000636

[10] Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. Journal of Physiology. 1952;**117**(4):500-544

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[16] Catterall WA. Voltage-gated sodium channels at 60: Structure, function and pathophysiology. The Journal of Physiology. 2012;**590**(11):2577-2589. DOI: 10.1113/jphysiol.2011.224204

[17] Dib-Hajj SD, Cummins TR, Black JA, et al. From genes to pain: Na v 1.7 and human pain disorders. Trends in Neurosciences. 2007;**30**(11):555-563. DOI: 10.1016/j.tins.2007.08.004

[18] Dib-Hajj SD, Yang Y, Black JA, et al. The Na(V)1.7 sodium channel: From molecule to man. Nature Reviews Neuroscience. 2013;**14**(1):49-62. DOI: 10.1038/nrn3404

[19] Wood JN. Ion channels in analgesia research. Handbook of Experimental Pharmacology. 2007;**177**:329-358. DOI: 10.1007/978-3-540-33823-9\_12

[20] Hoeijmakers JG, Faber CG, Merkies IS, et al. Painful peripheral neuropathy and sodium channel mutations. Neuroscience Letters. 2015;**596**:51-59. DOI: 10.1016/j. neulet.2014.12.056

[21] Oliva M, Berkovic SF, Petrou S. Sodium channels and the neurobiology of epilepsy (vol 53, pg 1849, 2012). Epilepsia. 2013;**54**(3):570

[22] Waxman SG. Axonal conduction and injury in multiple sclerosis: The role of sodium channels. Nature Reviews Neuroscience. 2006;**7**(12):932-941. DOI: 10.1038/nrn2023

[23] Waxman SG. Mechanisms of disease: Sodium channels and neuroprotection in multiple sclerosiscurrent status. Nature Clinical Practice Neurology. 2008;**4**(3):159-169. DOI: 10.1038/ncpneuro0735

[24] Nakajima K, Kohsaka S. Microglia: Activation and their significance in the central nervous system. Journal of Biochemistry. 2001;**130**(2):169-175

[25] Ifuku M, Farber K, Okuno Y, et al. Bradykinin-induced microglial migration mediated by B1-bradykinin receptors depends on Ca2+ influx via reverse-mode activity of the Na<sup>+</sup> /Ca2+ exchanger. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2007;**27**(48):13065-13073. DOI: 10.1523/jneurosci.3467-07.2007

[26] Noda M, Ifuku M, Mori Y, et al. Calcium influx through reversed NCX controls migration of microglia. Advances in Experimental Medicine and Biology. 2013;**961**:289-294. DOI: 10.1007/978-1-4614-4756-6\_24

[27] Ikeda M, Tsuno S, Sugiyama T, et al. Ca(2+) spiking activity caused by the activation of store-operated Ca(2+) channels mediates TNF-alpha release from microglial cells under chronic purinergic stimulation. Biochimica et Biophysica Acta. 2013;**1833**(12):2573- 2585. DOI: 10.1016/j.bbamcr.2013.06.022

[28] Annunziato L, Pignataro G, Di Renzo GF. Pharmacology of brain Na+ /Ca2+ exchanger: From molecular biology to therapeutic perspectives. Pharmacological Reviews. 2004;**56**(4):633-654. DOI: 10.1124/ pr.56.4.5

[29] Chatelier A, Zhao J, Bois P, et al. Biophysical characterisation of the persistent sodium current of the Nav1.6 neuronal sodium channel: A single-channel analysis. Pflugers Arch. 2010;**460**(1):77-86

[30] Cheng Y, Zhao J, Qiao W, et al. Recent advances in diagnosis and treatment of gliomas using chlorotoxinbased bioconjugates. American Journal of Nuclear Medicine and Molecular Imaging. 2014;**4**(5):385-405

[31] Pappalardo LW, Samad OA, Liu S, et al. Nav1.5 in astrocytes plays a sexspecific role in clinical outcomes in a mouse model of multiple sclerosis. Glia.

**15**

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases*

1989;**24**(4):496-500. DOI: 10.1002/

[39] Kressin K, Kuprijanova E, Jabs R, et al. Developmental regulation of

of mouse hippocampal brain slices. Glia. 1995;**15**(2):173-187. DOI: 10.1002/

[40] Chen PH, Cai WQ, Wang LY, et al. A morphological and electrophysiological study on the postnatal development of oligodendrocyte precursor cells in the rat brain. Brain Research. 2008;**1243**:27-37. DOI: 10.1016/j.

[41] Howe JR, Ritchie JM. Sodium currents in Schwann cells from

myelinated and non-myelinated nerves of neonatal and adult rabbits. The Journal of Physiology. 1990;**425**:169-210. DOI: 10.1113/jphysiol.1990.sp018098

[42] Korotzer AR, Cotman CW. Voltage-

microglia in culture. Glia. 1992;**6**(2):81- 88. DOI: 10.1002/glia.440060202

[44] Fraser SP, Salvador V, Manning EA, et al. Contribution of functional

cell behaviors involved in the metastatic cascade in rat prostate cancer: I. lateral motility. Journal of Cellular Physiology. 2003;**195**(3):479-487. DOI: 10.1002/

[45] Fraser SP, Diss JK, Chioni AM, et al. Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clinical Cancer Research: An Official Journal of the American Association for Cancer

channel expression to

gated currents expressed by rat

[43] Norenberg W, Illes P, Gebicke-Haerter PJ. Sodium channel in isolated human brain macrophages (microglia). Glia. 1994;**10**(3):165-172. DOI: 10.1002/

glia.440100303

voltage-gated Na<sup>+</sup>

jcp.10312

conductances in glial cells

jnr.490240406

and K+

glia.440150210

brainres.2008.09.029

Na+

*DOI: http://dx.doi.org/10.5772/intechopen.92127*

2018;**66**(10):2174-2187. DOI: 10.1002/

[32] Black JA, Newcombe J, Trapp BD, et al. Sodium channel expression within chronic multiple sclerosis plaques. Journal of Neuropathology and Experimental Neurology. 2007;**66**(9):828-837. DOI: 10.1097/

[33] Wang Z, Lin Y, Liu W, et al. Voltagegated sodium channels are involved in cognitive impairments in Parkinson's disease-like rats. Neuroscience. 2019;**418**:231-243. DOI: 10.1016/j.

[34] Hossain MM, Blair W, Kenneth R, et al. The anti-parkinsonian drug zonisamide reduces neuroinflammation:

nen.0b013e3181462841

neuroscience.2019.08.024

Role of microglial Na(v) 1.6. Experimental Neurology.

[35] Stevens M, Timmermans S, Bottelbergs A, et al. Block of a subset of sodium channels exacerbates experimental autoimmune encephalomyelitis. Journal of

[36] Sontheimer H, Black JA,

Neuroimmunology. 2013;**261**(1-2):21- 28. DOI: 10.1016/j.jneuroim.2013.04.012

Ransom BR, et al. Ion channels in spinal cord astrocytes in vitro. I. Transient expression of high levels of Na+

channels. Journal of Neurophysiology. 1992;**68**(4):985-1000. DOI: 10.1152/

[37] Barres BA, Chun LL, Corey DP. Ion channel expression by white matter glia: I. Type 2 astrocytes and oligodendrocytes. Glia. 1988;**1**(1):10-30.

[38] Sontheimer H, Perouansky M, Hoppe D, et al. Glial cells of the oligodendrocyte lineage express proton-activated Na+ channels. Journal of Neuroscience Research.

DOI: 10.1002/glia.440010104

and K+

2018;**308**:111-119

jn.19<IP_ADDRESS>5

glia.23470

*Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases DOI: http://dx.doi.org/10.5772/intechopen.92127*

2018;**66**(10):2174-2187. DOI: 10.1002/ glia.23470

*Neuroimaging - Neurobiology, Multimodal and Network Applications*

[25] Ifuku M, Farber K, Okuno Y, et al. Bradykinin-induced microglial migration mediated by B1-bradykinin receptors depends on Ca2+ influx via reverse-mode activity of the Na<sup>+</sup>

exchanger. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2007;**27**(48):13065-13073. DOI: 10.1523/jneurosci.3467-07.2007

[26] Noda M, Ifuku M, Mori Y, et al. Calcium influx through reversed NCX controls migration of microglia. Advances in Experimental Medicine and Biology. 2013;**961**:289-294. DOI: 10.1007/978-1-4614-4756-6\_24

[27] Ikeda M, Tsuno S, Sugiyama T, et al. Ca(2+) spiking activity caused by the activation of store-operated Ca(2+) channels mediates TNF-alpha release from microglial cells under chronic purinergic stimulation. Biochimica et Biophysica Acta. 2013;**1833**(12):2573- 2585. DOI: 10.1016/j.bbamcr.2013.06.022

[28] Annunziato L, Pignataro G, Di Renzo GF. Pharmacology of brain

2004;**56**(4):633-654. DOI: 10.1124/

[29] Chatelier A, Zhao J, Bois P, et al. Biophysical characterisation of the persistent sodium current of the Nav1.6 neuronal sodium channel: A single-channel analysis. Pflugers Arch.

[30] Cheng Y, Zhao J, Qiao W, et al. Recent advances in diagnosis and treatment of gliomas using chlorotoxinbased bioconjugates. American Journal of Nuclear Medicine and Molecular

[31] Pappalardo LW, Samad OA, Liu S, et al. Nav1.5 in astrocytes plays a sexspecific role in clinical outcomes in a mouse model of multiple sclerosis. Glia.

Imaging. 2014;**4**(5):385-405

Pharmacological Reviews.

2010;**460**(1):77-86

/Ca2+ exchanger: From molecular biology to therapeutic perspectives.

Na+

pr.56.4.5

/Ca2+

[16] Catterall WA. Voltage-gated sodium channels at 60: Structure, function and pathophysiology. The Journal of Physiology. 2012;**590**(11):2577-2589. DOI: 10.1113/jphysiol.2011.224204

[17] Dib-Hajj SD, Cummins TR, Black JA, et al. From genes to pain: Na v 1.7 and human pain disorders. Trends in Neurosciences. 2007;**30**(11):555-563.

DOI: 10.1016/j.tins.2007.08.004

10.1038/nrn3404

neulet.2014.12.056

10.1038/nrn2023

Epilepsia. 2013;**54**(3):570

[18] Dib-Hajj SD, Yang Y, Black JA, et al. The Na(V)1.7 sodium channel: From molecule to man. Nature Reviews Neuroscience. 2013;**14**(1):49-62. DOI:

[19] Wood JN. Ion channels in analgesia research. Handbook of Experimental Pharmacology. 2007;**177**:329-358. DOI:

10.1007/978-3-540-33823-9\_12

[20] Hoeijmakers JG, Faber CG, Merkies IS, et al. Painful peripheral neuropathy and sodium channel mutations. Neuroscience Letters. 2015;**596**:51-59. DOI: 10.1016/j.

[21] Oliva M, Berkovic SF, Petrou S. Sodium channels and the neurobiology of epilepsy (vol 53, pg 1849, 2012).

[22] Waxman SG. Axonal conduction and injury in multiple sclerosis: The role of sodium channels. Nature Reviews Neuroscience. 2006;**7**(12):932-941. DOI:

[23] Waxman SG. Mechanisms of disease: Sodium channels and neuroprotection in multiple sclerosiscurrent status. Nature Clinical Practice Neurology. 2008;**4**(3):159-169. DOI:

[24] Nakajima K, Kohsaka S. Microglia: Activation and their significance in the central nervous system. Journal of Biochemistry. 2001;**130**(2):169-175

10.1038/ncpneuro0735

**14**

[32] Black JA, Newcombe J, Trapp BD, et al. Sodium channel expression within chronic multiple sclerosis plaques. Journal of Neuropathology and Experimental Neurology. 2007;**66**(9):828-837. DOI: 10.1097/ nen.0b013e3181462841

[33] Wang Z, Lin Y, Liu W, et al. Voltagegated sodium channels are involved in cognitive impairments in Parkinson's disease-like rats. Neuroscience. 2019;**418**:231-243. DOI: 10.1016/j. neuroscience.2019.08.024

[34] Hossain MM, Blair W, Kenneth R, et al. The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Na(v) 1.6. Experimental Neurology. 2018;**308**:111-119

[35] Stevens M, Timmermans S, Bottelbergs A, et al. Block of a subset of sodium channels exacerbates experimental autoimmune encephalomyelitis. Journal of Neuroimmunology. 2013;**261**(1-2):21- 28. DOI: 10.1016/j.jneuroim.2013.04.012

[36] Sontheimer H, Black JA, Ransom BR, et al. Ion channels in spinal cord astrocytes in vitro. I. Transient expression of high levels of Na+ and K+ channels. Journal of Neurophysiology. 1992;**68**(4):985-1000. DOI: 10.1152/ jn.19<IP_ADDRESS>5

[37] Barres BA, Chun LL, Corey DP. Ion channel expression by white matter glia: I. Type 2 astrocytes and oligodendrocytes. Glia. 1988;**1**(1):10-30. DOI: 10.1002/glia.440010104

[38] Sontheimer H, Perouansky M, Hoppe D, et al. Glial cells of the oligodendrocyte lineage express proton-activated Na+ channels. Journal of Neuroscience Research.

1989;**24**(4):496-500. DOI: 10.1002/ jnr.490240406

[39] Kressin K, Kuprijanova E, Jabs R, et al. Developmental regulation of Na+ and K+ conductances in glial cells of mouse hippocampal brain slices. Glia. 1995;**15**(2):173-187. DOI: 10.1002/ glia.440150210

[40] Chen PH, Cai WQ, Wang LY, et al. A morphological and electrophysiological study on the postnatal development of oligodendrocyte precursor cells in the rat brain. Brain Research. 2008;**1243**:27-37. DOI: 10.1016/j. brainres.2008.09.029

[41] Howe JR, Ritchie JM. Sodium currents in Schwann cells from myelinated and non-myelinated nerves of neonatal and adult rabbits. The Journal of Physiology. 1990;**425**:169-210. DOI: 10.1113/jphysiol.1990.sp018098

[42] Korotzer AR, Cotman CW. Voltagegated currents expressed by rat microglia in culture. Glia. 1992;**6**(2):81- 88. DOI: 10.1002/glia.440060202

[43] Norenberg W, Illes P, Gebicke-Haerter PJ. Sodium channel in isolated human brain macrophages (microglia). Glia. 1994;**10**(3):165-172. DOI: 10.1002/ glia.440100303

[44] Fraser SP, Salvador V, Manning EA, et al. Contribution of functional voltage-gated Na<sup>+</sup> channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer: I. lateral motility. Journal of Cellular Physiology. 2003;**195**(3):479-487. DOI: 10.1002/ jcp.10312

[45] Fraser SP, Diss JK, Chioni AM, et al. Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clinical Cancer Research: An Official Journal of the American Association for Cancer

Research. 2005;**11**(15):5381-5389. DOI: 10.1158/1078-0432.ccr-05-0327

[46] Gillet L, Roger S, Besson P, et al. Voltage-gated Sodium Channel activity promotes cysteine Cathepsin-dependent invasiveness and colony growth of human cancer cells. The Journal of Biological Chemistry. 2009;**284**(13):8680-8691. DOI: 10.1074/jbc.M806891200

[47] Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;**308**(5726):1314-1318. DOI: 10.1126/science.1110647

[48] Persson AK, Estacion M, Ahn H, et al. Contribution of sodium channels to lamellipodial protrusion and Rac1 and ERK1/2 activation in ATP-stimulated microglia. Glia. 2014;**62**(12):2080-2095. DOI: 10.1002/glia.22728

[49] Kreutzberg GW. Microglia: A sensor for pathological events in the CNS. Trends in Neurosciences. 1996;**19**(8):312-318. DOI: 10.1016/0166-2236(96)10049-7

[50] Davalos D, Grutzendler J, Yang G, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience. 2005;**8**(6):752- 758. DOI: 10.1038/nn1472

[51] Cash E, Rott O. Microglial cells qualify as the stimulators of unprimed CD4+ and CD8+ T lymphocytes in the central nervous system. Clinical and Experimental Immunology. 1994;**98**(2):313-318. DOI: 10.1111/j.1365- 2249.1994.tb06143.x

[52] Renno T, Krakowski M, Piccirillo C, et al. TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis. Regulation by Th1 cytokines. Journal of Immunology (Baltimore, MD: 1950). 1995;**154**(2):944-953

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*Neuroimaging - Neurobiology, Multimodal and Network Applications*

[53] Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion. Annals of Neurology. 2004;**55**(4):458-

Ohlemeyer C, et al. Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia): Suppression of receptor-evoked calcium signaling and control of release function. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience.

[55] Kohrman DC, Harris JB, Meisler MH. Mutation detection in the med and medJ alleles of the sodium channel Scn8a. Unusual splicing due to a minor class AT-AC intron. The Journal of Biological Chemistry. 1996;**271**(29):17576-17581.

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2003;**23**(11):4410-4419

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[57] Ridley AJ. Membrane ruffling and signal transduction. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology. 1994;**16**(5):321-327. DOI: 10.1002/

[58] Honda S, Sasaki Y, Ohsawa K, et al. Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2001;**21**(6):1975-1982

[59] Siddiqui TA, Lively S, Vincent C, et al. Regulation of podosome formation, microglial migration and invasion by Ca(2+)-signaling molecules

10.1186/1742-2094-9-250

expressed in podosomes. Journal of Neuroinflammation. 2012;**9**:250. DOI:

bies.950160506

Research. 2005;**11**(15):5381-5389. DOI:

10.1158/1078-0432.ccr-05-0327

[46] Gillet L, Roger S, Besson P, et al. Voltage-gated Sodium Channel activity promotes cysteine Cathepsin-dependent invasiveness and colony growth of human cancer cells. The Journal of Biological Chemistry. 2009;**284**(13):8680-8691. DOI: 10.1074/jbc.M806891200

[47] Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;**308**(5726):1314-1318. DOI:

[48] Persson AK, Estacion M, Ahn H, et al. Contribution of sodium channels to lamellipodial protrusion and Rac1 and ERK1/2 activation in ATP-stimulated microglia. Glia. 2014;**62**(12):2080-2095.

[49] Kreutzberg GW. Microglia: A sensor for pathological events in the CNS. Trends in Neurosciences.

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[51] Cash E, Rott O. Microglial cells qualify as the stimulators of unprimed CD4+ and CD8+ T lymphocytes in the central nervous system. Clinical and Experimental Immunology.

1994;**98**(2):313-318. DOI: 10.1111/j.1365-

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10.1126/science.1110647

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1996;**19**(8):312-318. DOI: 10.1016/0166-2236(96)10049-7

758. DOI: 10.1038/nn1472

2249.1994.tb06143.x

1995;**154**(2):944-953

**16**

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**23**

CFS symptoms.

**Chapter 2**

**Abstract**

Hypothalamic-Pituitary-Adrenal

(HPA) Axis and Chronic Fatigue

*Frank Ho-Yin Lai, Maria Uscinska and Elaine Wai-hung Yan*