inflammatory responses in the brain parenchyma have been associated with the etiopathogenesis of different neurological disorders , including central nervous system ( cns ) infection , brain ischemia , multiple sclerosis , alzheimer 's disease , and parkinson 's disease [ 17 ] .
then , it is presently clear that neuroinflammation is a key feature shared by many neurodegenerative disorders [ 8 , 9 ] .
different cns cells , such as microglia , astrocytes , oligodendrocytes , and neurons produce a plethora of inflammatory mediators , which act either in a paracrine or an autocrine fashion , leading to an intricate cross - talk between these different cell types . among these mediators
, many studies have demonstrated that cns cells produce prostanoids and that these mediators might contribute to the normal cns function or to enhance the neuroinflammatory and neurodegenerative processes .
herein , we review the current knowledge on the role of prostaglandins , as well as the enzymes that synthesize them , in neuroinflammatory and neurodegenerative diseases .
due to the variety of prostaglandins presently known , it is reasonable to speculate that these lipid mediators might play different roles in the cns .
below , we describe some in vivo and in vitro data with regard to the potential role of specific prostanoids in neuroinflammation .   to date
, three prostaglandin ( pg ) e synthases ( pgess ) have been characterized : the microsomal pgess ( mpges-1 and mpges-2 ) and the cytosolic pges ( cpges ) [ 1114 ] .
mpges-1 is an inducible enzyme and is expressed also in activated microglia [ 15 , 16 ] .
there are at least four characterized pge2 receptors , namely , ep1 , ep2 , ep3 , and ep4 .
for example , pge2 and ep agonists inhibited the expression of inducible nitric oxide synthase ( inos ) and nitric oxide ( no ) generation   and enhanced the expression of cyclooxygenase ( cox)-2 induced by lypopolysaccharide ( lps ) in cultured microglia .
moreover , an ep2 agonist inhibited interleukin ( il)-1 release by cultured primary rat microglia stimulated with lps , although no reduction of this cytokine was observed with ep1 , ep3 , and ep4 agonists .
intraperitoneal injection of lps increased the expression of ep4 receptors in microglial cells and in the hippocampus of mice .
interestingly , activation of ep4 receptors reduced the expression of different cytokines , cox-2 and inos in bv-2 and primary mouse microglial cells .
a 6-day infusion of lps in the fourth cerebral ventricle of rats enhanced the pgd2 production in the brain .
it has been shown that pgd2 produced by microglia acts on dp1 receptors of astrocytes , leading to astrogliosis . moreover ,
oligodendroglial apoptosis was reduced by hematopoietic prostaglandin d synthase ( hpgds ) inhibitor and in hpgds - null mice , suggesting an important effect of pgd2 in demyelination in twitcher mice , a model of krabbe disease .
expression of dp1 and hpgds is also increased in the brains of patients with alzheimer 's disease .
pgd2 also induced apoptosis of mouse oligodendrocyte precursor ( mop ) cells , what could interfere in the demyelination process that occurs in multiple sclerosis .
it was shown that mice deficient in lipocalin - pgds reveal an increased number of apoptotic neurons and olygodendrocytes , suggesting a protective role of lipocalin - type pgds in the genetic demyelinating mouse twitcher .
15d - pgj2 is a metabolite of pgd2 and is formed from pgd2 by the elimination of two molecules of water . at least some effects mediated by 15d - pgj2 are mediated by activation of the peroxisome proliferator - activated receptors ( ppars). this prostaglandin has been shown to inhibit no and tumor necrosis factor ( tnf)- production as well as expression of major histocompatibility complex ( mhc ) class ii in activated microglia , suggesting that this prostaglandin might be important to modulate microglia functions .
similar effects , such as downregulation of inos and cytokines , have also been observed in astrocytes .
few studies were carried out to investigate the role of pgi2 in the cns . in general , these studies suggest a neuroprotective role for pgi2 against different stimuli . for example , enhancement of pgi2 synthesis in neuron - glia cultures by adenoviral gene transfer of pgi synthase ( pgis ) reduces the expression of different inflammatory mediators induced by lps , such as tnf- , and pgi2 receptor ligands prevented the death of hippocampal neurons induced by high oxygen , xanthine + xanthine oxidase , or serum deprivation . interestingly ,
15-deoxy-(16-m - tolyl)-17,18,19,20-tetranorisocarbacyclin methyl ester , a selective central type pgi2 receptor ligand , reduced brain damage induced by middle cerebral artery occlusion . in rat primary neuronal culture , hypoxia increased pgf2 content .
pgf2 reduced tnf- in primary spinal cord cultures stimulated with lps . in a model of unilateral middle cerebral artery occlusion ,
knockout ( ko ) mice to fp , the receptor for pgf2 , have less neurological deficit and smaller infarct volumes .
the ko animals were also less sensitive to excitotoxicity induced by unilateral intrastriatal n - methyl - d - aspartate injection .
in agreement with that , in the same model , the fp agonist latanoprost increased neurological deficit and infarct size in wildtype ( wt ) mice .
as previously mentioned , there are strong evidences that inflammation contributes to etiopathogenesis of neuroinflammatory and neurodegenerative diseases .
ms is an autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits attributable to white matter lesions .
it is the most common of the demyelinating disorders , which affects predominantly northern europeans .
the disease becomes clinically apparent at any age , although onset in childhood or after 50 years of age is relatively rare .
the frequency of relapses tends to decrease during the course of the disease , but there is a steady neurologic deterioration in a subset of patients .
modeling clinical aspects of any human disease in rodents and cells is a big challenge in all fields of research .
however , it is especially more challenging to model ms , because this is an exclusively human disease , its etiopathogenesis is unknown , and this disease is multifaceted , which occur in a relapsing - remitting manner . as the toxin - induced models of demyelination such as those induced by cuprizone , ethidium bromide and lysolecithin are important to understand demyelination and remyelination but do not resemble the human disease as efficiently as the autoimmune model ( experimental autoimmune encephalomyelitis eae ) , this paper will be focused on the roles played by prostaglandins in this model because of its presumed higher predictive validity .
there is a large body of evidence demonstrating the role played by prostanoids in the onset and progression of eae in a wide variety of animal models as well as in in vitro studies . within the last decade
, some studies have demonstrated that cytosolic pla2 ( cpla2 ) plays a key role in the etiopathogenesis of eae [ 3639 ] .
there are evidences supporting distinct roles played by different isoforms of pla2 in the onset or progression of eae .
cpla2 plays a role in the onset of eae , calcium - independent pla2 in the onset and progression , and secretory type ii pla2 in the later remission phase .
immunohistochemical labeling of cpla2 was shown in either immune or endothelial cells in the spinal cord lesions of mice with eae induced by myelin oligodendrocyte glycoprotein ( mog ) . both preemptive and therapeutic treatments with
a selective cpla2 inhibitor resulted in marked reduction in the onset and progression of eae .
accordingly , the reduced clinical score parallels with reduced spinal protein concentration of cox-2 and both gene expression and protein concentrations of dozens of inflammatory mediators , including several cytokines and chemokines which are implicated with the etiopathogenesis of eae .
cpla2 inhibitors diminish the ability of antigen - presenting cells to induce antigen - specific effector t - cell proliferation and inflammatory cytokine production , inhibit microglial activation , and increase oligodendrocyte survival .
the latter study also showed that if cpla2 inhibitors are administered at the peak of disease or during remission  relapsing - remitting model , the subsequent relapse is abolished . consistently with these pharmacological studies , a genetic study showed that cpla2-deficient mice are resistant to eae .
cox-1 and -2 are upregulated in the cns of animals in different eae models [ 36 , 38 , 41 ] . accordingly , different selective and nonselective inhibitors of cox isoforms induce beneficial effects in different animal models of eae .
eae onset is delayed if diet is supplemented with acetylsalicylic acid shortly after its induction in lewis rats .
pge2 seems to be the eicosanoid which is more strongly implicated with eae onset and progression .
bolton and colleagues investigated the cns concentrations of pge2 , 6-oxo - pgf1 , and pgf2 in acute eae - affected guinea pigs .
they showed that a pge2 concentration increase in spinal cord and cerebellum precedes eae onset , whereas the other two prostanoids were found to peak after the observation of the first clinical signs of eae .
the behavioral syndrome associated with eae is also preceded by increased cns concentration of pge2 in mice . a wide screening that examined the correlation between many arachidonic acid ( aa ) pathway products and eae onset and progression showed that pge2 ( concomitantly with its receptors ep1 , ep2 , and ep4 ) is synthesized more markedly than other eicosanoids , suggesting an important role in exacerbating eae .
pge2 exacerbates th1 and th2 responses via ep2 and ep4 receptors during mouse eae onset and protects the brain from immune cell infiltration via ep4 receptor .
mpges-1 upregulation occurs in microglia / macrophages in the spinal cord lesions of mice with eae induced by mog as well as in brain tissues from ms patients .
mpges-1-deficient mice exhibit a better clinical score and suppressed th1 and th17 responses when compared with those of nongenetically modified control mice after eae induction .
regarding the untoward gastric and cardiovascular effects induced by cox inhibitors , there is an eagerness to discover compounds that target mpges-1 for treating inflammatory diseases [ 4951 ] because this enzyme is downstream to cox-2 in aa pathway .
systemic treatment with 15d - pgj2 inhibits eae progression in mice , and this is associated with reduced demyelination , neuroinflammation , il-12 production by macrophage / microglial cells , t - cell proliferation , and il-12-induced t - cell responses .
moreover , pretreatment with this agonist of ppar delays the onset of eae and reduces the spinal cord infiltration of cd4 t cells and macrophages .
15d - pgj2 suppresses the production of cytokines and/or chemokines in cultured t cells , microglia , and astrocytes [ 5355 ] . providing further support to the role played by 15d - pgj2 in eae etiopathogenesis
, it was shown that ppar antagonists reverse the inhibition of eae clinical signs and th1 response by this cyclopentanone prostaglandin . as there is a correlation between increased spinal pgds concentration and the initiation of relapsing phase of eae
indeed , pgd2 is released from mast cells in allergic reactions , and it is suggested to modulate allergic inflammation [ 58 , 59 ] . on the other hand , a more recent study showed that pgd2 , pgi2 and 5-lipoxygenase pathways are suppressed in the acute phase of eae and returns to constitutive levels in the chronic phase .
however , in a relapsing - remitting model , pgd2 remained unaffected throughout all phases .
the first evidences supporting a role played by inflammation on ad onset rose up in the late 1980s , when many signs of inflammation in postmortem brains from ad patients were observed , such as activated lymphocytes and microglial cells in plaque and tangle lesions , presence of complement proteins , cell lysis , and opsonisation of debris [ 6064 ] .
it was hypothesized that the long - term use of nonsteroidal anti - inflammatory drugs ( nsaids ) could reduce the risk for ad or delay disease onset .
observed a clear negative correlation between the prevalence of ad in general population versus that in rheumatoid arthritis patients taking nsaids , mainly salicylates . reinforcing this evidence ,
a clinical trial conducted shortly afterwards , showed that treatment with indomethacin , a nonselective cox inhibitor , improves cognitive deficits in ad patients .
since then , epidemiological studies have been showing either beneficial or detrimental effects induced by cox inhibitors on ad risk and delay of onset , though beneficial effects are mostly observed . despite controversy
cpla2 , which cleaves aa from cellular membrane phospholipids , is elevated in ad brain .
the cyclooxygenation and subsequent isomerization of aa produces prostaglandins , which regulate immune responses and neurotransmission [ 69 , 70 ] .
accordingly , increased expression of cox-1 and -2 is observed in ad - affected brains [ 71 , 72 ] .
one of the most versatile products of this cascade is pge2 , which is produced by glial cells and neurons . an increased expression of mpges-1 and mpges-2 is observed in the brain of ad brains [ 73 , 74 ] .
moreover , patients with probable ad have higher cerebrospinal fluid ( csf ) concentrations of pge2 than age - matched control subjects .
it has been shown that pge2 increases amyloid precursor protein ( app ) gene expression and production in vitro [ 7678 ] .
this effect is inhibited by immunosuppressants in astrocytes   and is associated with ep2 receptor activation in microglial cells . on the other hand , there is evidence supporting an anti - inflammatory role played by pge2 mediated by ep4 receptor in lps - stimulated cultured microglial cells .
however , pge2 increases app production via both ep2 and ep4 receptors ( but not via ep1 and ep3 ones ) both in vitro and in vivo [ 76 , 79 ] .
.   showed that pge2-dependent internalization of ep4 receptor increases -secretase activity , which in turn leads to higher proteolysis of app . in transgenic mice overexpressing app , selective inhibition of cox-2 blocks amyloid  ( a)-induced suppression of hippocampal long - term potentiation ( ltp ) and memory function independently of reductions in a42 and inflammatory cytokines , but markedly dependent on pge2 concentrations , showing an additional mechanism by which nsaids may protect against ad progression and an important synaptic role of pge2 in this setting .
ep2 receptors are important mediators of pge2 actions on electrophysiological properties of hippocampal neurons , as ep mice exhibit cognitive deficits in social memory tests associated with a deficit in long - term depression in hippocampus .
not exogenously applied pgd2 or pgf2 , regulates hippocampal neuronal plasticity [ 69 , 70 ] .
one of the first studies which assessed prostaglandins concentrations in postmortem cerebral cortices of probable ad patients showed that only pgd2 was increased in comparison with age - matched control subjects .
indeed , pgds expression was found to be localized in microglial cells surrounding senile plaques , and dp1 receptor expression was observed in microglial cells and astrocytes within senile plaques in human ad brains . in tg2576 transgenic mice  a model of ad disease , the dp1 receptor expression increases in parallel with a deposition .
as 15d - pgj2 induces neuronal apoptosis , it was initially suggested that this prostanoid is associated with neurodegeneration .
however , it was shown afterwards that 15d - pgj2 reduces microglial production of no , il-6 , and tnf- induced by a40 , which suggests anti - inflammatory indirect neuroprotective effect . accordingly , not only 15d - pgj2 , but also troglitazone and ciglitazone , other compounds known to activate ppar and attenuate the a-induced impairment of hippocampal ltp in vitro , supporting a possible beneficial effect on ad progression .
pd is the second most common neurodegenerative disease , characterized by abnormal motor symptoms such as stiffness , postural instability , slowness of movement , resting tremor , and bradykinesia .
the neuropathological features of pd are progressive death of dopaminergic neurons in the substantia nigra ( sn ) pars compacta that project to the striatum .
the exact cause of this cell death is not clear , but recent studies have shown that the process may involve inflammatory reactions , in addition to oxidative stress , mitochondrial dysfunction , neural excitotoxicity , and insufficient neurotrophic factors [ 8587 ] .
it is known that , in the sn of pd brains , microglia is activated , and its activation has been strongly associated with cns pathology of pd , by production of proinflammatory and cytotoxic factors , such as cytokines , chemokines , no , reactive oxygen species ( ros ) , and aa metabolites [ 88 , 89 ] .
it has been shown that mice carrying a mutation of the cpla2 gene , leading to an absence of cpla2 activity , are resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( mptp ) , a precursor to 1-methyl-4-phenylpyridinium ( mpp ) -induced neurotoxicity , a well - known model of pd .
in fact , different studies have shown an upregulation of cox-2 in animal models of pd [ 9294 ] .
cox-2 increased expression has been also demonstrated in the sn of postmortem pd specimens in comparison to normal controls [ 95 , 96 ] .
moreover , it has been shown that cox inhibition [ 93 , 94 , 97 , 98 ] and cox transgenic ablation [ 99101 ] in in vivo models of pd increased survival of dopaminergic neurons . however
rofecoxib , a cox-2 inhibitor , did not change mptp - induced neurodegeneration and , paradoxically , caused a significantly augmented basal prostaglandin production .
regular use of nsaids is associated with a lower risk of pd compared with nonregular users of these drugs [ 85 , 102 ] . however ,
this is still controversial , since recent studies could not demonstrate a protective effect of nsaids in pd [ 103105 ] .
considering that these drugs might have other mechanisms of action unrelated to cox inhibition , it is important to evaluate the effect of specific compounds in the prevention or treatment of pd .
it has been observed that pge2 is significantly elevated in the csf and sn of pd patients in comparison to control subjects .
moreover , incubation of slices of sn with aa induced an increased production of pge2 synthesis , suggesting an enhancement of the enzymes responsible to its production .
release of aggregated -synuclein , a major component of lewy bodies in pd , after neuronal damage , may activate microglia .
this activation could , in turn , lead to production of proinflammatory mediators , such as pge2 , contributing to the progression of nigral neurodegeneration .
a pretreatment of primary mesencephalic neuron - glia mouse cultures with -synuclein enhances the production of pge2 .
apparently , phagocytosis of -synuclein activates nadph oxidase , which produces ros , and has a crucial role in microglial activation and associated neurotoxicity . in primary mesencephalic mixed neuron - microglia cultures , mpp , a neurotoxin that causes dopaminergic neuronal death , induced pge2 production .
however , this effect was not observed in enriched microglia and enriched neuron cultures , indicating that is necessary an interaction between microglia and neurons for mpp - induced increase of the pge2 production , probably due to cox-2 activity .
moreover , pge2 was not enhanced neither in enriched astroglia nor in neuron - astroglia cultures .
conversely , pge2 was significantly reduced in the hippocampus , striatum , and cortex of animals injected with 6-hydroxydopamine ( 6-ohda ) .
it has been shown that ep receptors are expressed differently in the sn . to date , in the rat , ep1 is restricted to dopaminergic neurons , while ep3 is expressed exclusively by nondopaminergic cells .
on the other hand , ep2 is localized to both dopaminergic and nondopaminergic cells . in rats ,
ep1 , but not ep2 and ep3 receptor antagonists , reduced the dopaminergic neuronal death induced by 6-ohda , suggesting an important effect of ep1 receptor in the neurotoxicity induced by pge2 .
also , culture of dopaminergic neurons displayed ep2 receptors after 6-ohda neurotoxicity , and butaprost , a selective ep2 agonist , significantly increased survival of tyrosine hydroxylase positive cells , suggesting a possible neuroprotective role of ep2 of activation .
interestingly , in comparison to microglia obtained of wt animals , microglia of ep2 ko mice reveal an enhanced capacity to clear aggregated -synuclein in human mesocortex tissue of patients with lewy body disease .
moreover , ep2 mice were more resistant to neurotoxicity induced by mptp , an effect that is associated with attenuated formation of aggregated -synuclein in the sn and striatum .
pgj2 and its metabolites might alter the process of protein folding and aggregation , contributing to the development of pd . in human neuroblastoma
sk - n - sh cells , pgj2 disrupts the structural integrity of microtubules and actin filaments . in vitro , this molecule also hindered the polymerization of highly purified tubulin from bovine brain .
interestingly , in cells treated with pgj2 , microtubule / endoplasmatic reticulum collapse coincides with the formation of protein aggregates , such as ubiquitinated proteins and -synuclein . in mouse and human neuroblastoma cells , as well as in rat primary embryonic mesencephalic cultures , pga1 , pgd2 , pgj2 , and its metabolite -pgj2 induced accumulation of ubiquitinated proteins and cell death .
the ubiquitination induced by -pgj2 might be due to inhibition of ubiquitin c - terminal hydrolase ( uch ) l3 and uch - l1 , implicating in an alteration of de - ubiquitinating enzymes , possibly contributing to the accumulation and aggregation of ubiquitinated proteins , what leads to inflammation associated with the neurodegenerative process .
modification of uch - l1 , an enzyme that functions predominantly during monoubiquitin recycling in the ubiquitin - proteosome system , by cyclopentenone prostaglandins , induced unfolding and aggregation of the protein .
therefore , the deleterious effect of cox-2 in pd could be due to the production of cyclopentenone prostaglandins .
in addition to that , pga1 has been shown to reduce nuclear factor kappa b translocation to the nucleus , caspase 3 activation , and apoptosis of human dopaminergic sh - sy5y cells induced by rotenone .
this neuropathological condition can be classified as familial , in which mutations in the enzyme superoxide dismutase-1 ( sod1 ) can occur , or as sporadic , which encompasses 90% of als patients .
neuroinflammation seems to play an important role in the progress of this disorder . in als , microglia activation and proliferation
is observed in regions where there is neuron loss , like motor cortex , motor nuclei of the brainstem and corticospinal tract .
it has been shown that cpla2 is expressed in astrocytes and motor neurons of the spinal cord of transgenic mice carrying the gene encoding a mutant form of human sod1 [ 120 , 121 ] . in agreement with that ,
cpla2 immunoreactivity was also observed in the spinal cord of human sod1-mutated familial als and in sporadic als patients [ 120 , 122 ] . an increase in cox-2 expression is observed in the spinal cord of sod1 transgenic mice [ 123 , 124 ] and human cases of als [ 125 , 126 ] .
postmortem examination of the ventral horn of the spinal cord of sporadic als patients revealed that cox-2 immunoreactivity was increased in motor and interneurons , as well as in glia , in comparison with non - als controls . on the other hand ,
cox-1 expression was detected in microglia , but not in neurons , of als and controls tissues , albeit no difference was observed between the two groups of patients .
few attempts have also been made to elucidate the effect induced by cox inhibitors in models of als . in organotypic spinal cord cultures ,
the cox-2 selective inhibitor sc236 significantly reduced the excitotoxic damage of motor neurons induced by threo - hydroxyaspartate , a compound that inhibits astroglial transport of glutamate .
therefore , it is possible that cox-2 might be involved in the excitotoxicity induced by glutamate .
moreover , in vivo studies also suggested that cox might be a potential target for als treatment .
it has been shown that traditional nsaids and cox-2 inhibitors reduced different pathological features developed by sod1 transgenic mice , such as loss of motor neurons and glial activation in the spinal cord , motor impairment and weight loss , as well as these compounds prolonged the survival of the animals [ 120 , 129131 ] . considering these evidences , minghetti   suggested that cox-2 enhancement could be deleterious in als not only due to the enhancement of glutamate release by pge2 , but also because of the ros produced by cox peroxidase activity .
on the other hand , almer et al .   have shown a drastically reduced pge2 production in the spinal cord of transgenic sod1/cox-1 mice , suggesting a minor role for cox-2 in the production of pge2 in the disease .
moreover , deficiency of cox-1 did not affect motor neuron loss and survival of the animals .
pge2 is elevated in the spinal cord of sod1 mice   and in the serum and csf of als patients [ 127 , 135 ] , though the levels of this prostaglandin did not correlate with clinical state of the patients .
the role of pge2 was further investigated in in vitro models of als . in an organotypic spinal cord slice model , motor neuronal death induced by d
, l - threo - hydroxyaspartate is reduced by pge2 , as well as butaprost and sulprostone , ep2 and ep3 receptor agonists , respectively .
interestingly , in the same study , sc58236 , a cox-2 inhibitor , also reduced motor neuron loss .
ep2 receptor expression is increased in astrocytes and microglia of sod1 mice and in astrocytes of human als spinal cord .
deficiency of ep2 receptor in sod1 mice increased the survival and grip strength in comparison with sod1/ep2 and sod1/ep2 mice .
the absence of ep2 receptor also reduced the production of different inflammatory mediators in this animal model of als .
recently , it has been shown that mpges-1 is enhanced in the spinal cord of sod1 in comparison with wt mice .
interestingly , aad-2004 , a molecule that inhibits mpges-1 and free radical formation , reduced microglia activation and motor neuron loss , as well as it improved motor function and increased survival .
15d - pgj2 immunoreactivity is increased not only in motor neurons , but also in astrocytes and reactive microglia in the spinal cord of als patients .
hd is a progressive neurodegenerative disease that reveals movement disorders and dementia as main features .
this pathological condition is an autosomal - dominant pathological condition disease [ 139 , 140 ] .
although there are evidences that neuroinflammation is present in hd , it is not known whether it contributes to the etiopathogenesis of the disease or whether it is solely an epiphenomenon .
it has been shown that in r6/2 mice , an animal model of hd , the number of microglia is reduced in some brain regions in comparison with their wt littermates .
microglia of animals at 14.5 weeks of age were also smaller in size than the same cells in the animals at 7 weeks of age , and they also revealed condensed nucleus and fragmentation of the cytoplasm within processes , suggesting an impaired function of these cells in this pathological condition . on the other hand , activated microglia are present in the neostriatum , cortex , and globus pallidus of hd brains .
importantly , the reactive microglia appeared in association with pyramidal neurons presenting huntingtin - positive intranuclear inclusions .
although a causal link between neuroinflammation and hd onset or progression has not been demonstrated , it is reasonable to assume that microglia might play a role in its development .
although there are different genetic models of hd , some compounds such as 3-nitropropionic acid ( 3-np ) and quinolinic acid ( qa ) are also used to induce striatal neuron toxicity , being therefore considered hd animal models [ 144146 ] .
cox-2 immunoreactivity is enhanced in striatal tissues 12  h after treatment of animals with qa .
this enhancement was observed predominantly in neurons and microglia . chronic treatment with different cox inhibitors , such as rofecoxib , celecoxib , nimesulide , and meloxicam improved spontaneous locomotor activity and the motor performance , as well as these medicines reduced biochemical and mitochondrial alteration induced by qa [ 148150 ] .
naproxen and valdecoxib , two cox inhibitors , also reduced 3-np - induced motor and cognitive impairment .
this study suggested that these effects could be due to a reduction in the oxidative stress induced by the drugs .
although beneficial effects were observed induced by cox inhibitors in drug - induced models of hd , similar effects are not observed in transgenic mice .
for example , administration of acetylsalicylate from weaning did not induce any alteration of rotarod performance and ventricle enlargement n171 - 82q mice in comparison with untreated animals .
rofecoxib also did not change motor performance and lifespan of r6/2 mice . on the other hand , acetylsalicylate and celecoxib
shortened life expectancy of r6/2 and n171 - 82q mice , respectively [ 152 , 153 ] .
administration of 3-np enhances pge2 and pgf2 in the striatum [ 154 , 155 ] .
these prostaglandins are reduced by licofelone , a competitive inhibitor of cox-1 , cox-2 , and 5-lox isoenzymes .
in addition , this compound reduced the impairment in locomotor activity and motor performance , as well as it reduced apoptotic markers .
expression of cox-2 , as well as pge2 production , is increased in the ipsilateral side compared with the contralateral vehicle - injected side in the striatum and cortex of rats by unilateral intrastriatal injection of qa .
moreover , it has also been shown that qa injection induced ep3-positive striatal neuronal loss , whereas activated microglia expressed ep3 in vivo after excitotoxicity injury . a role for pga1 has also been suggested .
this prostaglandin attenuated dna fragmentation and neuronal loss and increased dopamine d1 receptor expression induced by qa in the striatum it also reduced the qa - induced activation of nuclear factor kappa b , but not activator protein-1 , in this brain region .
acute inflammation in the cns is triggered by a neuronal injury or infection and is short - lived .
this acute response is believed to have protective aspects , since it could avoid further injury and induce tissue repair .
although an acute stimulus may trigger , for example , oxidative stress , this short - term event would not interfere with long - term neuronal survival .
it is known that moderate microglia activation might induce neuroprotective effects , such as to scavenger neurotoxins , remove cell debris and secrete mediators which are important for neuronal survival .
acute activation of these cells is a normal response to injuries , and it contributes to wound healing . on the other hand ,
chronic neuroinflammation persists for a long time after the initial insult and normally is self - perpetuating .
this condition induces neuronal death , and the molecules released by the dead neurons can further activate microglia , which enhances cell death .
this vicious cycle , together with the continuous production of factors that activate microglia , contributes to the chronicity of this process .  
intense activation and accumulation of these cells at the site of injury can induce neuronal damage , since they release a variety of neurotoxic substances .
for example , the a protein , which is involved in ad , can activate microglia and lead them to release neurotoxic factors such as no , tnf- , and superoxide , leading to the progression of this disorder .
an interesting finding is that a chronic inflammation induced by the infusion of lps ( a substance that strongly activates microglia ) in the brain of rats resembles different features observed in ad patients .
actually , it is presently not clear why the neuronal or glial cells can not prevent the chronicity of the inflammatory process .
abnormal synthesis of some proteins by neurons could continuously activate microglia , leading them to the release of neurotoxic factors .
moreover , oxidative stress is another important event that contributes to the neuronal damage observed in chronic neuroinflammation .
it is also possible that the senescence of immune system in the cns could contribute to chronicity of this process .
for example , it has been shown that microglia from old transgenic ps1-app mice release an increased amount of inflammatory mediators and do not phagocytose a properly in comparison to microglia from young mice .
therefore , microglia senescence could play a role in the development of some neurodegenerative conditions [ 161 , 166 ] . despite these facts ,
the adaptive immune system might also play a role , as it has been shown that it is involved in the etiopathogenesis of pd . in this context
, one might assume that the production of lipid mediators , such as prostaglandins , might differently modulate neuroinflammation and neurodegeneration .
considering the roles of prostaglandins and depending on the stage of inflammation , as well as different microenvironments generated by a variety of substances , these lipid mediators could determine the survival or death of neurons .
here we summarized the evidences that prostaglandins might play a key role in the etiopathogenesis of neuroinflammatory and neurodegenerative diseases .
prostaglandins have a plethora of actions in cns cells that differently affect the progress of inflammation and neuronal death or survival .
therefore , inhibition of the production of a specific prostanoid or its action on its receptor would be a better mechanism to control some pathological processes .
on the other hand , inhibiting the effects of some prostaglandins could also be deleterious .
thus , further studies are important to make a more complete idea the role of these lipid mediators in neuroinflammation and neurodegeneration
. this knowledge might serve to develop pharmacological strategies for the treatment of neurological diseases .
 increasing data demonstrates that inflammation participates in the pathophysiology of neurodegenerative diseases . among the different inflammatory mediators involved 
 , prostaglandins play an important role . 
 the effects induced by prostaglandins might be mediated by activation of their known receptors or by nonclassical mechanisms . in the present paper 
 , we discuss the evidences that link prostaglandins , as well as the enzymes that produce them , to some neurological diseases . 
1. Neuroinflammation and Neurodegeneration
2. Roles of Prostaglandins in Neuroinflammation: 
3. Roles of Prostaglandins in Neurodegenerative Diseases
4. Discussion
5. Conclusion