as a classic activating agent, a recent study of rat microglia demonstrated that prolonged lps exposure induces a distinctly different activated state from that in microglia acutely exposed to lps." streptococcus pneumoniae streptococcus pneumoniae is the most common cause of bacterial meningitis. it is primarily localized to the subarachnoid space while cytokines and chemokines are produced inside the blood–brain barrier. microglia interact with streptococcus via their tlr2 receptor; this interaction then activates microglia to produce nitric oxide which is neurotoxic. the inflammatory response, triggered by microglia, may cause intracerebral edema. role in parasitic infections plasmodium falciparum plasmodium falciparum is a parasite that causes malaria in humans. a serious complication of malaria is cerebral malaria (cm). cm occurs when red blood cells break through the blood–brain barrier, causing microhemorrhages, ischemia and glial cell growth. this can lead to microglial aggregates called durck's granulomas. recent research has indicated that microglia play a major role in the pathogenesis of cm. trichobilharzia regenti trichobilharzia regenti is a neuropathogenic schistosome which migrates in a central nervous system of birds and mammals. in mice, microglia accumulate in the parasite migratory tracks and around damaged or dying worms. in vitro, microglia produce nitric oxide and proinflammatory cytokines il-6 and tnf-alpha after exposure to parasite antigens, which suggests their role both in maintaining inflammation and tissue pathology. role in neuropathic pain microglia have been implicated in neuropathic pain. they become activated in response to nerve injury, as demonstrated by several animal models. activated microglia release substances that excite pain-sensitive neurons, including prostaglandins and reactive oxygen species, through the purinergic signaling mechanisms. moreover, microglia also release of proinflammatory molecules through the stimulation of purinergic receptors, including il1-β, il-6, and tnf-α. the release of these molecules is mediated by the p2x7 receptor and creates a positive feedback loop, exacerbating the pain response. a causal role for microglia in the pathogenesis of neuropathic pain has been demonstrated through p2x4 receptor. p2x4 receptors are upregulated following injury and the increase in purinergic signaling activates p38-mitogen-activated protein kinase (p38 mapk). the increase in p38 mapk signaling leads to greater microglial release of brain-derived neurotrophic factor (bdnf). bdnf released from microglia induces neuronal hyperexcitability through interaction with the trkb receptor. therapeutic development has focused on finding purinergic signaling blockers. there has been some success with p2x7 blockers, a-438079 and a-740003, however there are no selective p2x4 receptor antagonists to date. as a target to treat neuroinflammation inhibition of activation the retina is helpful to control neuroinflammation is to inhibit microglial activation. studies on microglia have shown that they are activated by diverse stimuli but they are dependent on activation of mitogen-activated protein kinase (mapk). previous approaches to down-regulate activated microglia focused on immunosuppressants. recently, minocycline (a tetracycline derivative) has shown down-regulation of microglial mapk. another promising treatment is cpi-1189, which induces cell death in a tnf α-inhibiting compound that also down-regulates mapk. recent study shows that nicergoline (sermion) suppresses the production of proinflammatory cytokines and superoxide anion by activated microglia. microglial activation can be inhibited by mif (microglia/macrophage inhibitory factor, tuftsin fragment 1–3, thr-lys-pro). mif-treated mice showed reduced brain injury and improved neurologic function in a mouse model of collagenase-induced intracerebral hemorrhage. regulation of chemokine receptor the chemokine receptor, cx3cr1, is expressed by microglia in the central nervous system. fractalkine (cx3cl1) is the exclusive ligand for cx3cr1 and is made as a transmembrane glycoprotein from which a chemokine can be released. cardona, et al. stated in 2006 that "using three different in vivo models, we show that cx3cr1 deficiency dysregulates microglial responses, resulting in neurotoxicity." further studies into how cx3cr1 regulates microglial neurotoxicity could lead to new therapeutic strategies for neuroprotection. inhibition of amyloid deposition inhibitors of amyloid deposition include the enzymes responsible for the production of extracellular amyloid such as β-secretase and γ-secretase inhibitors. currently the γ-secretase inhibitors are in phase ii clinical trials as a treatment for alzheimer's disease but they have immunosuppressive properties, which could limit their use. another strategy involves increasing the antibodies against a fragment of amyloid. this treatment is also in phase ii clinical trials for the treatment of alzheimer's disease. inhibition of cytokine synthesis glucocorticosteroids (gcs) are anti-inflammatory steroids that inhibit both central and peripheral cytokine synthesis and action. in a study conducted by kalipada pahan from the department of pediatrics at the medical university of south carolina, both lovastatin and sodium phenylacetate were found to inhibit tnf-α, il-1β, and il-6 in rat microglia. this shows that the mevalonate pathway plays a role in controlling the expression of cytokines in microglia and may be important in developing drugs to treat neurodegenerative diseases. naltrexone may provide a solution to the inflammatory mediators produced by microglia. although naltrexone's main action is to competitively bind to opioid receptors, new research shows that naltrexone, when given in low doses once per day (low-dose naltrexone), can inhibit cytokine synthesis by microglia cells. this mechanism is still being investigated, but there are already studies that indicate that it helps some patients suffering from fibromyalgia syndrome. naltrexone shows more promise than gcss because the gcss inhibit immune system function more generally, increase allergic reactions and, as the name implies, increase blood glucose levels.