epilepsy is a chronic neurological disorder characterized by recurrent seizures and is often accompanied by cognitive deficits and mood disorders [ 13 ] . because seizures are the result of uncontrollable neural excitation in the brain , epilepsy has been considered to primarily be a neuronal disease . the targeting of neuronal ion channels and both gamma - aminobutyric acid ( gaba ) and glutamate receptors has been the primary approach to eliminate seizures . however , studies that have focused exclusively on neurons fail to address the questions that arise from more complex models of epileptogenesis . to date , studies using animal models and human patients with epilepsy have shown that the pathogenesis of epilepsy may be associated with both neuronal and nonneuronal components such as glial cells , brain vasculature , and leucocytes from the periphery . glial abnormalities , including chronically activated astrocytes and microglia , glial scars , and various gliomas , are likely to form epileptic foci in the brain . the mechanisms through which glial cells can promote epileptogenesis can include increased neuronal excitability and inflammatory processes . the key roles of inflammatory processes in relation to epilepsy have been clarified over the last decade . studies of the mechanisms of antiepileptic drugs ( aeds ) have focused on ion channels , transporters , and excitatory / inhibitory neurotransmission . however , the anti - inflammatory effects of aeds have received recent attention due to their relevance to antiepileptic properties . for example , carbamazepine and levetiracetam can reduce the expression of inflammatory mediators in glial cell cultures [ 8 , 9 ] . one of the anticonvulsive effects of levetiracetam could be mediated through suppression of astroglial activation by inflammatory mediators . in addition , dysfunction of the blood - brain barrier ( bbb ) may be responsible for abnormal neuronal firing . disruption of the bbb causes the leakage of serum protein and leucocyte invasion into the brain . these exogenous inflammatory mediators have the potential to lower seizure thresholds [ 4 , 5 , 10 , 11 ] , which could alter channel sensitivity , neurotransmitter uptake or release , and glia - associated regulation of extracellular environments , such as potassium concentration [ 4 , 5 , 10 , 11 ] . accordingly , brain inflammation is one of the etiological factors that promote epileptogenesis and ictogenesis . in this review , we discuss seizure - induced inflammatory mediators and the mechanisms through which these factors exacerbate epilepsy . direct anti - inflammatory treatments have been reported to suppress some type of epileptic seizures that are resistant to conventional aeds . for example , adrenocorticotropic hormone ( acth ) has been a first - line treatment for infantile spasms . anti - inflammatory effects of increased steroid hormone by acth treatment could play a crucial role in the suppression of refractory epilepsy in west syndrome . in addition , intravenous immunoglobulin ( ivig ) can suppress seizures in some types of intractable epilepsy , an effect that may be partially mediated through a reduction in cytokines and a suppression of astrocyte activation [ 15 , 16 ] . these drugs are also able to confer protection against seizures in mice with some types of epilepsy that are resistant to conventional aeds . combined with antiglial functions of conventional aeds described above , anti - inflammatory medication could be a new promising treatment for refractory epilepsy . research with rodent models of epilepsy has uncovered roles for brain inflammation in epileptogenesis and ictogenesis . pharmacological or electrical stimulation produces epileptic seizures accompanied by robust inflammatory responses in the brains of rodents [ 1832 ] . the administration of proinflammatory or anti - inflammatory reagents has also been used to elucidate the effects of inflammatory mediators on seizure latency , frequency , duration , and severity [ 33 , 34 ] . for instance , lipopolysaccharide , a provocative agent for inflammation , exacerbates seizure severity , whereas an inhibitory peptide against high - mobility group box-1 ( hmgb1 ) inflammatory mediator decreased acute and chronic seizure recurrence . transgenic mouse models have also been used to evaluate the relationship between inflammatory mediators and seizure severity . mice overexpressing cytokines , such as tumor necrosis factor- ( tnf- ) or interleukin-6 ( il-6 ) , within astrocytes developed age - dependent neurological dysfunctions including a reduction in seizure threshold , spontaneous seizure frequency , and neuronal cell loss [ 35 , 36 ] . inflammatory cytokines , including interleukin-1 ( il-1 ) and hmgb1 , are released from astrocytes and microglia after seizures [ 2224 , 37 ] . il-1 and hmgb1 activate il-1r type i   and toll - like receptor 4 ( tlr4 ) , respectively . il-1r / tlr signaling can regulate neuronal excitability , including the alteration of synaptic transmission , the reduction in gaba production , and the inhibition of outward current of ca channels [ 10 , 4042 ] . il1r / tlr signaling may activate the src kinase - mediated phosphorylation of n - methyl - d - aspartate ( nmda ) receptor subunit 2b ( nr2b ) . consequently , this nmda - mediated ca influx could be enhanced in neurons , leading to increased neuronal excitability and excitotoxicity [ 34 , 44 ] . thus , the activation of il-1/il-1r or hmgb1/tlr4 signaling resulting from epileptic insults might result in a rapid change in neuronal excitability and a decreased seizure threshold ( figure 1(a ) ) . tnf- is another inflammatory factor , and its expression is also upregulated following seizures [ 18 , 36 ] . tnf- is mainly released by microglia in the brain , and it can stimulate astrocytes to release glutamate . an extracellular increase in glutamate concentration may stimulate glutamatergic neurons , thereby depolarizing their membrane potential . taken together , postseizure production of inflammatory mediators can trigger neuronal hyperexcitability through modulations of ion channels and glutamate release in neurons and glia , respectively ( figure 1(a ) ) . in addition , the endothelial cells that make up the bbb could be another center for inflammatory processes in the brain . the activation of the il-1 system following seizures induces neuronal cell loss and a breakdown in the bbb . albumin entry can induce a further upregulation in inflammatory mediators and reduce the potassium and glutamate uptake of astrocytes , which leads to increased neural excitability [ 4850 ] . these findings indicate that a breakdown in the bbb can increase neuronal excitability by enhancing inflammatory responses in the brain ( figure 1(a ) ) . taken together , epileptic seizures can provoke inflammatory responses , which enhance calcium influx into neurons , activate glial cells to increase extracellular potassium and glutamate , and induce further inflammatory response via bbb break down . , epileptic seizures and inflammatory mediators can form a positive feedback loop , reinforcing each other ( figure 1(a ) ) . in addition to inflammatory cytokines , prostaglandins ( pgs ) are major factors that stimulate inflammation processes . pgs are known to markedly increase following seizures and may contribute to epileptogenesis and reduction in seizure threshold [ 10 , 52 ] . the enzyme cyclooxygenase ( cox ) converts arachidonic acid to pgh2 , and the specific pg synthase converts pgh2 to various pgs such as thromboxane a2 , pgf2a , pge2 , pgi2 , or pgd2 . consistent with the robust production of pgs in the brain following seizures , an inducible type of cox ( cox-2 ) , but not the constitutively expressed cox-1 , is rapidly induced in the brain following seizures [ 16 , 53 ] . because pgs play an important role in inflammatory responses , the functions of pgs in epileptogenesis have been studied for a considerable amount of time [ 52 , 54 ] ; however , data on the roles of cox-2 in epilepsy appear to be bidirectional . for example , following an injection of kainic acid ( ka ) , postseizure treatment with the selective cox-2 inhibitor ns-398 prevented neuronal cell loss in the hippocampus . however , the administration of another cox-2 inhibitor , nimesulide , prior to an injection of ka strongly aggravated ka - induced seizures and increased the mortality rate . these conflicting results might be partly explained by possible dual roles for cox-2 , which has been shown to play early neuroprotective and late neurotoxic roles following seizures . thus , the timing of cox-2 inhibitor administration may be crucial when treating epilepsy ( figure 1(b ) ) . the bifunctional aspects of cox-2 in epileptogenesis can also be explained by the diversity of pgs . pgd2 synthase h - pgds - knockout ( ko ) mice or pgd2 receptor dp1r - ko mice showed more severe seizures after pentylenetetrazol ( ptz ) treatment than wild type ( wt ) mice , whereas deficiencies of the other synthase l - pgds or receptor dp2r did not alter seizure severity . additionally , the intracisternal administration of pgf2 after ka treatment reduced the seizure score and mortality . the administration of pge2 receptor ( ep ) antagonists reduced seizure severity and neuronal injury following pilocarpine- or ptz - induced seizures [ 6163 ] . three pge2 synthase ( pges ) genes have been identified , including membrane - bound pges ( mpges)-1 , mpges-2 , and cytosolic pges ( cpges ) . mpges-1 is induced in the venous endothelia of the brain following an injection of ka , and its expression is upregulated in conditions of inflammation , pain , and fever [ 16 , 65 , 66 ] . mpges-2 and cpges show constitutive levels of expression , and their physiological functions remain unknown . the finding that the activity of mpges-1 is tightly coupled to that of cox-2   could support the importance of pge2 function under epileptic conditions . several lines of evidence suggest that pge2 could have an important role in epileptic neuronal cell death and the reduction in seizure threshold . mpges-1-ko mice show little postictal production of pge2 , and the lack of increased pge2 production resulted in the promotion of neuronal survival following ka injection [ 64 , 68 ] . furthermore , the intraventricular injection of pge2 decreased the latency to methylmalonate- ( mma- ) induced seizures and increased the amplitude of spikes measured by an electroencephalogram ( eeg ) in rats . thus , cox-2-coupled pge2 production can promote seizures through mechanisms that drive epileptogenesis . to determine whether mpges-1-derived pge2 is directly involved in epileptogenesis , we used mpges-1-ko mice . to mimic the gradual exacerbation of epileptic seizures , a subconvulsive dose of ptz was administered to wt or mpges-1-ko mice every other day ( ptz chemical kindling ) . wt mice showed rapid increases in seizure severity , whereas mpges-1-ko mice showed a significantly slower elevation in seizure score ( figure 2(a ) ) . immunohistochemical analyses revealed that glial fibrillary acidic protein- ( gfap- ) positive astrocytes were increased in the hippocampal ca3 region of the wild type mice after the kindling , indicating that pge2 production promotes reactive astrogliosis ( figure 2(b ) ) . interestingly , mpges-1-ko mice did not show any increase in gfap - positive astrocytes after the kindling ( figure 2(c ) ) . reactive astrogliosis is one of the pathological hallmarks of temporal lobe epilepsy , which include segmental neuronal loss and increases in gfap - positive cells in the hippocampus and associated temporal lobe structures . our results indicate that mpges-1-ko mice are resistant to the development of ptz kindling and also to kindling - induced astrogliosis . pge2 acts on four g protein - coupled receptors named ep1 , ep2 , ep3 , and ep4 . ep receptors have been shown to be localized in the brain cells [ 70 , 71 ] ; however , it still remains unclear on which cells pge2 acts to produce its epileptogenic effects . the administration of a selective ep2 antagonist prevented neuronal cell loss after pilocarpine - induced seizures . furthermore , the pharmacological inhibition of other receptors , ep1 , ep3 , or ep4 , resulted in increases in ptz - induced seizure latency . these results suggest that pge2 may cause neuronal cell death and neuronal hyperexcitability via hippocampal ep receptors ( figure 1(b ) ) . the effects of pge2 on neurons might be partly similar to those of other inflammatory mediators in terms of their enhancement of neuronal excitability . several studies have shown that pg synthesis is upregulated by il-1 treatment . in a lung fibroblast cell line , il-1 induced mpges-1 mrna expression . additionally , il-1 treatment increased cox-2 mrna levels in cultured murine primary astrocytes . the application of pge2 led to significant increases in firing frequency and excitatory postsynaptic potential ( epsp ) amplitude in rat hippocampal slice cultures . pge2-induced increases in neuronal excitability may be partly attributable to an inhibition of potassium currents , resulting in boosted ca influx . however , given that the mpges-1 enzyme is preferentially expressed in the brain microvasculature , it may be more likely that pge2 acts on glial cells but not on neurons . we previously reported that the ep3 receptor was localized to astroglial end feet around microvessels . additionally , mpges-1-ko mice showed decreased astrogliosis compared to wt mice following ka treatment . these findings suggest that endothelial pge2 may act on glial ep3 receptors and alter glial function . in fact , glutamate release from astrocytes was drastically reduced in mpges-1-ko mice compared to wt mice [ 66 , 75 ] . thus , pge2 is both an inflammatory mediator and a promoter of extracellular gliotransmission via astrocytic ep receptors   ( figure 1(b ) ) . in conclusion , epileptic seizures rapidly induce cox-2 mrna in neurons and afterwards upregulate both cox-2 and mpges-1 mrnas in venous endothelia [ 16 , 6466 ] . treatment with ns-398 and nimesulide prior to seizure induction aggravates neuronal damage in the hippocampus , whereas postseizure treatments with ns-398 prevent the damages [ 55 , 56 ] . neuronal cox-2-derived pgs appear to protect neurons against seizures , whereas endothelial pg ( pge2 ) might participate in seizure - induced neuronal cell death by stimulating astrocytes to release glutamate . thus , pg - mediated inflammation may also form a positive feedback loop to exacerbate epileptic seizures in a late phase after seizures ( figure 1(b ) ) . . however , this neuronal upregulation of cox-2 and pge2 is transient and simultaneous robust increases in brain pgd2 levels could surpass the effects of pge2 , resulting in suppression of seizures . by contrast , late induction of endothelial cox-2 and mpges-1 lasts longer than early phase and this sustained production of pge2 may promote neurodegeneration via astrocytes . thus , time course and cell type - specific expression of cox-2 could cause the dual effects of pg production on epileptogenesis . first , even with optimal aed therapy , 20~30% of patients have poor seizure control and become intractable . second , as these medications act as general central nervous system ( cns ) depressants and must be taken chronically for seizure suppression , they also have marked inhibitory effects on cognitive development . therefore , the development of new aeds that can modulate seizures through another mechanism is required for refractory epilepsy treatment . animal models and clinical evidence have emphasized the involvement of inflammatory mediators in seizure susceptibility and epileptogenesis [ 7678 ] . robust and general inflammatory responses in the brain lower the seizure threshold , enhance neuronal excitability , increase bbb permeability , and promote epileptogenesis . cox-2 and mpges-1 are known to play key roles in the inflammatory responses to insults and consequently increase postseizure inflammation and the resulting hyperexcitability of brain neurons . cox-2 inhibitors such as celecoxib have been developed and prescribed for chronic inflammatory pain and rheumatoid arthritis . hence , they can be used in conjunction with aeds to treat brain inflammation and reduce neuronal hyperexcitability . although celecoxib suppresses epileptogenesis , for example , the development of ptz - kindling , this inhibitor may be more effective for postseizure inflammation than for the prevention of seizure incidence . however , given that chronic celecoxib treatment can be accompanied by serious cardiovascular side effects , persistent cox-2 inhibition would not be beneficial as a therapeutic strategy for intractable epilepsy . by contrast , the regulation of specific pg signaling should offer more selective actions and fewer complicating adverse effects . although pge2 synthase inhibitors may be good candidates for epilepsy treatment , specific inhibitors are still under development . an ep2 inhibitor appears to suppress neurodegenerative pathology following epileptic seizures , and the inhibition of the other ep receptors , ep1 , ep3 , and ep4 , might delay seizure induction [ 6163 ] . the discovery of selective ep receptor antagonist(s ) could contribute to avoid the serious side effects of chronic cox-2 inhibition and provide more selective therapies for refractory epilepsy . modulators of pg receptor function could also improve our understanding of the roles of pgs in the brain immune system and inflammation . consequently , more precise molecular roles of pgs in epileptogenesis will need to be clarified .
epilepsy is one of the most common chronic brain disorders worldwide , affecting 1% of people across different ages and backgrounds . 
 epilepsy is defined as the sporadic occurrence of spontaneous recurrent seizures . 
 accumulating preclinical and clinical evidence suggest that there is a positive feedback cycle between epileptogenesis and brain inflammation . 
 epileptic seizures increase key inflammatory mediators , which in turn cause secondary damage to the brain and increase the likelihood of recurrent seizures . 
 cytokines and prostaglandins are well - known inflammatory mediators in the brain , and their biosynthesis is enhanced following seizures . 
 such inflammatory mediators could be therapeutic targets for the development of new antiepileptic drugs . in this review , 
 we discuss the roles of inflammatory mediators in epileptogenesis .