Introduction

Neuroinflammation is a crucial marker of epilepsy and epileptogenesis, and it includes both non-neuronal and neuronal components (glial cells including microglia and astrocytes) [1, 2]. Prolonged epileptic seizures associated with brain injury are marked with inadequate neuronal impairment suggesting brain damage with loss of neurons focusing excitotoxicity [3, 4]. Seizures are the abnormal brain activities seen amongst various pathological conditions like traumatic brain injury; post-stroke patients are at high risk of developing epileptic seizures with an increased incidence of neuroinflammation [5, 6]. Neuroinflammatory responses in certain conditions may contribute to neuronal hyperexcitability underlying generation of secondary seizures mediated neuronal loss like neurologic comorbidities in epilepsy [7, 8]. Additionally, a life-threatening status epileptics the prolonged excessive seizures resulting various mechanisms with increased evidence of pro-inflammatory mediators as biomarkers highlighting the activation of the neuroimmune system indicating brain damage focusing excitotoxicity [9,10,11] Alterations in multiple neuroinflammatory mechanisms are related to prolonged seizures induced oxidative stress or apoptosis-like events seen in epileptic patients diagnosed with morphological changes in brain-like neuronal sprouting and increasing gliosis as an indicator of brain tissue injury [3, 12]. The increased expression of cytokines acts as a biomarker in the epileptic brain represents neuroinflammation in the epileptic brain and activation of group II mGluRs like receptors (NMDA) on glial cells are responsible for carrying the toxicity by releasing of cytotoxic substances TNF-α, IL-1β, and nitric oxide towards neurons [13, 14]. Therefore, indicating the relation of elevated cytokines and excitotoxicity as an adaptive mechanism of neuroimmune processes in response to the prolonged rapid epileptic seizures. The persistent activation of neuroglial cells in response to the concurrent seizures further causes neuronal excitotoxicity leading to neuronal death [3, 15]. Therefore, the various neuroinflammatory cascades get initiated in response to the prolonged seizure-induced neuronal injury, and the increase of pro-inflammatory mediators levels represents oxidative stress in the brain [3]. This aberrant migration of astrocytes and microglial cells releases cytotoxic substances like cytokines (IL-1 beta, TNF-alpha, IL-6, etc.) like factors exacerbate the blood–brain barrier and initiates the generation of secondary seizures [16, 17]. Therefore, the dysregulation of glia immune-inflammatory activity is a common factor that predisposes or leads to the generation of seizures, and brain inflammation promotes neuronal hyperexcitability and seizures manifested by neuronal damage. Seizures induced physiological changes in the epileptic brain are characterized by activation of various neuroinflammatory cascades like NF-kB, RIPK, MAPK, ERK, JNK, JAK-STAT signaling. The aberration and alteration of such molecular cascades have been adversely associated with neuroimmune responses producing cytotoxin substances like cytokines, chemokines as biomarkers for the pathogenesis of epileptogenesis [18]. Likewise, the involvement of Interleukin-1 beta seems to activate the PI3K/mTOR/Akt signaling pathways responsible for alteration in a hippocampal brain region, causing cognitive dysfunction in temporal lobe epilepsy or status epilepticus [19]. PI3K/mTOR/Akt signaling further interacts with caspase-3, BCL2 associated X, BH3 proteins inducing aberrant apoptotic hippocampal neuronal death in epileptogenesis as observed in preclinical and clinical studies [20]. Other neuroinflammatory signaling cascades, including NF-kB, RIPK, MAPK, ERK, JNK, JAK-STAT, etc., also seem to be activated under the prolonged seizure-induced oxidative stress and elevated levels of pro-inflammatory mediators interleukin1-β (pro-IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) representing neuronal damage in epilepsy [18, 21]. Thus, providing the correlation of neuroinflammation with hyperactivation of purinergic receptors, metabotropic receptors, inflammasome that are highly expressed on non-neuronal cells. The increased expression of such receptors modulates intracellular neuroinflammatory signaling cascades with impaired elevated levels of pro-inflammatory mediators that appear to be the decisive factor in the development and progression of hyperexcitation in epilepsy [18]. The current review summarized the correlation of inflammatory mediators initiating various downstream cascade-mediated neuroinflammation mechanisms manifested by elevated levels of IL-1β, IL-6, and tumor necrosis factor- α (TNF-α). Therefore, the drugs targeting various inflammatory mediators act as a therapeutic strategy in preventing the neuroinflammation mediated generation of seizures in epilepsy.

Cytokines mediated activation of various molecular pathways in epileptogenesis

Alteration of metabotropic receptors in epilepsy is linked with elevated levels of inflammatory mediators that seem to be enhanced in response to the seizure-induced excitotoxicity activating the neuroimmune system involving the activation of glial cells. The activation of microglial and astrocyte cells releases neurotoxic material (IL-1 beta, TNF-alpha, IL-6, HMGB1, etc.,) promoting the seizures mediated neuronal loss [22]. Metabotropic receptors are likely to be expressed in astrocytes and glial cells that get activated by the stimulus of elevated levels of inflammatory mediators responsible for producing excitotoxicity in the brain. Elevated levels of TNF- alpha released by the activated microglial cells during seizures stimulate the excitatory glutamate neurotransmitter release, thereby; increasing the hyperactivation metabotropic receptor (NMDA) mediated increased intracellular calcium concentration directing neuronal hyperexcitability [23]. Additionally, the release of inflammatory mediators (interleukin-1β (IL-1β) and high-mobility group protein-1 (HMGB1) from astrocytes and glial cell activation during rapid seizure-induced neuronal injury have an impact on the GABAergic inhibitory transmission by altering the production of GABA with a consequent increase of the NMDA transmission [23]. Whereas the cytokine HMGB1 is released by glial cells in response to the concurrent seizures induced neuronal oxidative stress further binding to TLR4 promoting the activity of postsynaptic NMDA receptor and increasing the calcium influx leading to potentiates NMDA-induced excitotoxicity [24, 25]. Increased NMDA transmission and decreased GABAergic transmission focuses the excitotoxicity by enhancing the influx of calcium ions influx mediated neuronal oxidative stress by disrupting mitochondrial functioning [26]. Therefore, the increased ROS and elevated levels of inflammatory mediators initiate the excitotoxicity in epilepsy.

Furthermore, activation of transcriptional factor NF-kB in microglial cells is the feature of elevated levels of pro-inflammatory mediators representing involvement of NF-kB in overproduction of neurotoxic substances exacerbating the development of seizures mediated neuronal cell death [27]. Elevated levels of inflammatory mediators are the biomarkers in the epileptic brain indicating the neuronal damage [28] with activation of NF-kB upregulating mediators (IL-1β, IL-6, TNF-α, and Transforming-Growth-Factor Beta (TGF-β),) and reactive oxygen and nitrogen species (ROS)) (Fig. 1) [26, 29]. Studies evidence the alterations in NF-kB activity promoting neuronal death by upregulating pro-inflammatory mediators suggesting the degeneration of hippocampal neurons recognized with cognitive dysfunction seen in temporal lobe epilepsy and status epilepticus [18]. Increased immunoreactive responses of invasive migration of glial cells to the emotive neuronal insult in epilepsy further represent the neuroinflammation marked with activated intracellular neuroinflammatory NF-kB signaling increasing expression of pro-inflammatory mediators [30]. Elevated levels of pro-inflammatory mediators like high-mobility group box-1 (HMGB1), interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF-β), nitric oxide (NO) are the indicator of neuron injury carries the noxious stimuli of amplifying the inflammatory signaling. Likewise, the elevated levels of tumor necrosis factor (TNF)-α binds to TNFR1, initiating RIPK1 signaling, further initiating NF-kB and MAPK/ERK signaling mediated neuronal death under the chronic seizure-induced oxidative stress [18]. Thus, the highly inducible expression of NF-kB and MAPK/ERK is further responsible for facilitating the p38/ JNK cascades regulating activator protein 1 (AP-1) mediated apoptotic neuronal death seen under prolonged seizures induced excitotoxicity [18]. Similarly, the upregulation of IL-6 inflammatory mediator stimuli activates JAK-STAT signaling pathway mediated neuronal death in epilepsy and activation of downstream cascades (MAPK, ERK, JNK, and p38) along with PI3K (phosphatidylinositol-3-kinase). Further amplifies the downstream intracellular signaling by protein kinase B mediated neuronal apoptosis along with neuroinflammation generating oxidative stress (ROS) under chronic epileptic seizures [18, 26]. Therefore, targeting inflammatory mediators can prevent the alteration of metabotropic receptor-mediated excitotoxicity in the epileptic brain (Fig. 1).

Fig. 1
figure 1

Correlation of neuroimmune system and various cascades showing the neurodegeneration and excitotoxicity related to the brain damage and blood–brain barrier. Inhibitors of cytokines as a preventive approach in epilepsy

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Pharmacotherapy targeting inflammatory mediators linked neuroinflammatory signaling cascades involved in epilepsy (Table 1)

Table 1 Drugs targeting inflammatory mediators (cytokines) correlating neuroinflammatory cascades in epilepsy (Fig. 1)
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Anakinra

Anakinra, an interleukin -1 type 1 (IL-1R1), receptor antagonist seems effective as an anticonvulsant in reducing neuroinflammation in epilepsy. In the epileptic brain, the high expression of a pro-inflammatory mediator (IL-1 beta) might get implicated in response to the excessive continuous seizures mediated neuronal injury and contributing to neuronal degeneration in epilepsy [31]. Therefore, targeting Il-1 beta tends to be a successful therapy for neuroprotection in epilepsy along with further suppressing activation of intracellular NF-kB, MAPK pathway representing the structural changes in neuroimmune cells (microglial cells), the excessive migration as well activation of glial cells further contributes to epileptogenesis as a long-term effect of seizure-induced brain stress [32]. Along with the production and release of the inflammatory mediator, the elevated level of interleukin-1 beta is a rapid effect. Further, it activates PI3K linked to the hyperactivation of excitatory receptors (NMDA-R & AMPA-R), contributing to hyperexcitability resulting in neuronal death in epilepsy [32, 33]. Therefore, anti-inflammatory drugs like anakinra and VX-765, widely used in neuroinflammatory diseases, seem to be effective in epilepsy by inhibiting the IL-1R1 and suppressing the activation of such intracellular pathways, mediated neurodegeneration in epilepsy [34, 35]. In conclusion, anakinra (Kineret) and VX-765 protect excitotoxicity by overactivation of GluN2B-containing NMDA receptors and showed an antiepileptic effect [36].

COX inhibitors

Prostaglandin D2 (PGD2), PGE2, PGF2, and PGI2, as well as thromboxane A2 (TXA2), are synthesized by cyclooxygenase (COX) [37]. COX-2 is a significant pro-inflammatory mediator that is generally undetectable in tissues but is strongly activated by fever, inflammation, infection, and other conditions such as high neuronal activity and growth factors. The selective COX-2 inhibitors etoricoxib, celecoxib, and nonselective COX-2 inhibitors nimesulide, indomethacin, parecoxib (valdecoxib), aspirin, NS398, SC58236, and SC58125 have been shown antiepileptic and neuroprotective effects [38, 39]. Cyclooxygenase (COX) inhibitors are Adjuvant therapy with AED. COX-2 regulates the expression of P-gp, a multidrug transporter known to be overexpressed in drug-resistant antiepileptic drugs [40]. The upregulation of COX-2 results in higher amounts of PGE2, which binds to the EP-1 receptor and activates transcription factor NF-kB increasing P-gp expression. Therefore, the increased expression of P-gp is a prominent cause of drug resistance in epilepsy. The increased levels of pro-inflammatory mediator COX-2 have a role in increasing the expression of P-gp in initiating drug resistance in epilepsy [42]. Therefore, the COX-2 inhibitors (celecoxib, NS398, and indomethacin heptyl ester) tend to possess therapeutic value in epilepsy by reducing drug resistance with the decrease in levels of P-gp, further suppressing the neuroinflammation by inhibiting the activation of NF-kB transcribing pro-inflammatory mediators in epilepsy [43, 44] (Table 2).

Table 2 Preclinical and Clinical Profiling of drugs in epilepsy with toxicological data at different doses
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Minocycline

Minocycline is an anti-inflammatory drug that belongs to the second generation of tetracycline antibiotics. During the epilepsy attack, the inflammatory reaction also enhanced the chemokine, cytokine, and prostaglandins in the rodent's brain [45]. Therefore, anti-inflammatory drugs like minocycline could be a good alternative for reducing epileptic attacks. The Minocycline has both anti-inflammatory effects and antimicrobial properties, and it can also penetrate the BBB then affect the brain cells activity [46]. In the central nervous system, minocycline lowers both microglia activation and the release of inflammatory cytokines IL-1β, TNF-α, and IL-6, in the brain of mice. After the seizure, the IL-6 increased at the level of mRNA and protein and cause neuroinflammation [47]. The excessive released neuroinflammation cytokine can cause seizures by having cytotoxic effects on neurons. The minocycline is effective in decreasing the mRNA level of IL-1β and TLR2 and also the inflammatory gene such as MHCII (major histocompatibility complex class II), IL-6, IL-1β, and TLR2 had their mRNA expression reduced by minocycline [48]. That drug is effective and has shown a protective effect in neuroinflammation and reducing the seizure threshold by inhibiting the release of cytokine and inhibiting the effects on the surface of the cell [49].

SC-51089, SC-51322

SC-51089, SC-51322 is a selective prostaglandin-E2; EP1 receptor antagonist decreases cell death, brain edema and improves neurobehavioral/neuroprotective function after surgically induced brain injury [50]. The EP1 receptor is found in a variety of organs and tissues in rodents and guinea pigs, including the kidney, lung, and stomach, as well as multiple CNS sites. EP1 expression is restricted to a few organs and tissues in higher species such as humans, including the colon, mast cells, myometrium, pulmonary veins, and skin [52]. The EP1 receptor is linked to the G protein complex, which includes the Gq/11 and G/ dimer proteins then after PGE2 binding, Gaq is released from the complex, activating phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol triphosphate (IP3) and diacyl glycerol (DAG) [53]. IP3 regulates Ca2+ -sensitive signalling pathways by increasing cytosolic Ca2+ levels by interacting to IP3 receptors in the endoplasmic reticulum (ER) that function as calcium channels; whereas DAG acts as a second messenger by activating certain isoforms of protein kinase C (PKC) [54]. The EP1 receptor showed a neurotoxicity The EP1 receptor has long been implicated in neurotoxicity occurring from NMDA receptor overactivity and Ca2+ dysregulation from NMDA receptor overactivity and Ca2+ dysregulation after epileptic seizure. In Wistar rats, centrally administered EP1 receptor antagonist SC-19220 decreased acute seizures induced by pentylenetetrazol (PTZ) [52, 55].

SJN2511 or SB431542 and losartan

TGF-β signaling was also linked to quick changes in extracellular potassium and glutamate, as well as a decreased activation threshold for neurons. SJN2511, an effective and specific TGF-β/ALK5 inhibitor, can prevent albumin-induced synaptogenesis and seizures. [38]. The ALK5 antagonists SJN2511 or SB431542 inhibit albumin-induced TGF-β, IL-6 secretion, and SMAD2/3 phosphorylation. [56]. Losartan, an angiotensin-II receptor antagonist, has been shown to efficiently block albumin-induced TGF-activation in the brain and prevent spontaneous seizures [56]. In epilepsy, the specific inflammatory pathway involvement determined the epileptogenic role of transforming growth factor-beta-β (TGF-β) signaling in BBB dysfunction. The BBB disruption has been associated with serum components like albumin and IgGs in a wide variety of cell types [57]. Neurons, astrocytes, and microglia all take up albumin, although to a lesser extent. In contrast, IgG uptake has been found in neurons. TGF-βRs (transforming growth factor-β receptors) promote albumin endocytosis in endothelial cells, resulting in phosphorylation of Smad2, the proximate effector of the canonical TGF-β signaling pathway, and translocation of the activated Smad2/Smad4 complex to the nucleus, thereby modifying astrocytic function. [58]. TGF-β signaling was also linked to quick changes in extracellular potassium and glutamate, as well as a decreased activation threshold for neurons [59, 60]. Specifically, astrocytes were shown to regulate synaptogenesis through the molecule antagonist for angiotensin II receptor type 1 (AT1) that has been reported to block the peripheral TGF-β signaling, can effectively suppress albumin-induced TGF-β activation in the brain and prevent the subsequent spontaneous seizures. These results reinforce the notion that targeting TGF-β signaling is a feasible strategy for disease modification and prevention of epilepsy [63].

TG4-155 and TG6-10-1

The selective antagonist of the EP2 receptor (TG4-155 and TG6-10-1) is a subtype of prostaglandin E2. The COX pathway mediates many physiological and pathological activities by its prostanoid products [64, 65]. In response to seizure, the arachidonic acid is released and converts into PGH2 in presence of COX, the COX-1 (constitutive) and COX-2 (inducible) are the two types of COX then after the PGH2 is quickly converted to five different types of prostanoids such as PGD2, PGF2α, PGE2, thromboxane TXA2, and prostacyclin PGI2 by prostanoid synthases that are tissue-specific [66, 67]. PGE2 stimulates the action of the GPCR receptor and four E-type prostanoid receptors EP1, EP2, EP3, and EP4. PGE2 and its receptors play a major role in inflammatory prostaglandin signaling activation causing neuroinflammation in epilepsy. Therefore, the TG4-155 and TG6-10-1 antagonist of EP2 receptor possess a neuroprotective effect in epilepsy [68].

Resveratrol (3,5,4′-trihydroxystilbene)

The Antioxidant compounds have been considered a successful therapeutic approach in various neurological diseases [69]. The antioxidant compound resveratrol has shown an antiepileptic effect by decreasing oxidative stress and regulating Sirtuin (SIRT) mechanism; the sirtuin protein regulates mitochondrial dysfunction-related apoptotic pathway [70]. The mitochondrial dysfunction in epilepsy also plays a significant factor in epileptogenesis by increasing the production of reactive oxygen species with long-term elevated pro-inflammatory mediators, further initiating the neuronal apoptotic death [71,72,73]. Therefore, resveratrol possesses anticonvulsant activity by preventing mitochondrial oxidative stress in epilepsy [74,75,76]. Furthermore, resveratrol also restores peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha and regulates oxidative stress and mitochondrial dysfunction [77, 78]. Resveratrol also increases the expression of antioxidant Nrf2 protein and erythroid 2-related factor 2, decreasing the reactive oxygen species and preventing neuroinflammation in epilepsy [79,80,81]. Resveratrol efficiently prevents chronic seizures induced oxidative stress and suppresses neuroinflammation by preventing NF-kB activation that promotes the production of inflammatory molecules such as iNOS, COX-2, and IL-1ß [82,83,84]. Also, the stimulation of AMP-activated kinase (AMPK) by resveratrol further inhibited the NF-kB activation and the production of pro-inflammatory molecules that initiates hyperexcitability in epilepsy [85, 86].

LPS-Rs, pseudo-peptide BOX A

In LPS-induced neuroinflammation, LPS-Rs, a TLR4 (Toll-like receptors-4) antagonist, suppress inflammatory mediators levels such as IL-6, TNF-α, COX-2, IL-1, iNOS, and NO in a substantial way in tissue. LPS-Rs modulates levels of various signaling pathways like MAPKs, JNK/p38, and p65-NF-kB in neuronal tissue [90]. The activation of the neuroimmune system represented by excessive migration of microglial cells is the progressive events of neuroinflammation mediated neurodegeneration in epilepsy by modulating further intracellular inflammatory pathways exacerbating neurotoxicity. The implication of toll-like receptors (TLRs) in microglial cells further modulating TLR dependent signaling of activation of MAPKs, JNK/p38, and p65-NF-kB cascades mediating neuroinflammation and exacerbated neurodegeneration in epilepsy [91, 92]. The various studies suggested the involvement of microglia cells infiltration of neuroimmune cells (T-cells) that acts as a marker for neuroinflammation or neuronal tissue damage in response to chronic seizure-induced brain injury. Therefore, the elevated levels of pro-inflammatory mediators (IL-1beta, IL-6, TNF-α, COX-2, iNOS, and NO) are seen to be elicited centrally propagating extracellular diffusion pathways involving the activation of NF-kB influencing neuroinflammation in epilepsy [92]. Therefore, the LPS-Rs, a lipopolysaccharide of bacterium Rhodobacter sphaeroides, is a potent TLR4 antagonist that has inhibited neuroinflammation and neuronal apoptotic death. TLR4, an endogenous danger signal protein produced in the CNS by immune cells, neurons, and glia in response to cell injury or neuronal hyperexcitability, can be activated by pro-inflammatory cytokines HMGB1 [89, 91]. The elevated levels of HMGB1 in epileptic brain tissues when seizures are persistent further binds to TLR4, promoting the activity of postsynaptic NMDA receptor and increasing the calcium influx leading to potentiates NMDA-induced excitotoxicity [24, 25]. The hyperactivation of metabotropic glutamate receptors group I (NMDAR) mediates excitatory synaptic transmission in epilepsy. Thus, the TLR4 inhibitor LPS-Rs tends to be a protective strategy in reducing the HMGB1 that prevents postsynaptic NMDA receptor hyperactivation mediated excitotoxicity in epilepsy [9, 24, 92]

Clinical & future prospective

Despite the treatment approaches in epilepsy targeting inflammatory pathways have been explored in the current review suggesting the immunomodulatory treatment in epilepsy indicating inflammatory processes. Several inflammatory targets broadly discuss the consequences like cognitive dysfunction, excitotoxicity, and drug resistance from invasive neuroinflammation in epilepsy. Further in the future, the understanding of mRNAs-based gene therapy in epilepsy is a recent promising strategy in preventing the neuroinflammation-mediated neuronal dysfunction in epilepsy. The epileptic studies suggested the dysregulation of miRNA under pathological state associated with hyperexcitability. The Gene expression data (RNA-Seq) and miRNA suggested the role of miRNAs regulating inflammatory responses neuronal necrosis and apoptosis genes in epilepsy. The inflammatory mediators are the biomarkers for the brain tissue injury in epilepsy that are marked by the upregulated levels of cytotoxic substances like interleukin-1 β (IL1 β), tumor necrosis factor-α (TNF-α), and high mobility group protein (HMGB1) [95]. Further, miRNAs have a role in regulating the genes encoding for proteins controlling the functioning of neuronal and non-neuronal cells and the receptors that seem to be altered under epileptogenesis. Therefore, the microarray studies screened the alterations in miRNAs as an early phase controller for the occurrence of the disease that is responsible for the regulation for pathogenic processes of neuroinflammation destroying the blood–brain barrier and aggravated damages in the brain promoting neuronal excitability in epilepsy [95, 96] (Fig. 2). The miRNAs like miR-34c-5p have been downregulated in epileptic patients of drug resistance, indicating the disruption of the blood–brain barrier and elevated levels of inflammatory mediators (HMGB1, IL-1β) indicates the potential role of neuroinflammation in the development of epileptogenesis. Furthermore, the other upregulation of miR-27a-3p and downregulation of miR-125a5p also found to be altered in epileptic brain tissue, increasing the expression of IL-1, INF-α, and TNF-α) representing the neuroinflammation in epilepsy [95, 96]. Likewise, the miRNA 146a, 155, 221, 122, 22 is upregulated during seizures induced neuronal injury as an indicator of activation of glial cells and providing a future targeted therapy of miRNAs as master regulators of immune responses [95]. The upregulation of miRNA 155 and 122 expression indicates the increase of the neurotrophic factors (BDNF, TGF-beta) promoting glial cells dysfunctioning mediated neuroinflammation by increasing the expression of TNF- alpha mediated excitotoxicity in epilepsy [95]. Therefore, the MRG-106 or Cobomarsen, an inhibitor of miRNA 155, and SPC3649 (miravirsen) an inhibitor of miRNA 122 tend to effectively prevent inflammatory disease, which might be a future targeted therapy for neuroinflammation in epilepsy [95, 98]. The decreased miRNA 122 in epilepsy also indicates the neuroinflammation in epilepsy, as the miRNA 122 has a role in preventing pro-inflammatory cytokines by inhibiting the transcriptional factor (NF-kB) [95, 97].

Fig. 2
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Alterations in microRNAs and neuroinflammation in epilepsy. Illustration of various microRNAs as regulators of neuroinflammatory processes likely to be unregulated or down-regulated under the pathological condition of epileptogenesis

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Conclusion

Elevated inflammatory biomarkers are the evidence of neuroinflammation and structural changes like hippocampal cell degeneration and mossy fiber sprouting, increasing excitability in epilepsy. Neuroimmune responses of activation of glial cells give rise to overproduction of cytokines (IL-1β, IL-6, TNF-α, and reactive oxygen and nitrogen species (ROS)) as well disrupting blood–brain barrier causing drug resistance. The elevated levels of cytokines attributed to the neuronal excitability underlying neuroinflammatory pathways mechanisms causing excitotoxicity in epilepsy. Therefore, the initiators like SC-58236, NS-398, anakinra, resveratrol, etc., are effective therapies by suppressing the cytokines and preventing the neuroinflammation producing secondary seizures, including neuronal dysfunction and providing the correlation of cytokines and various cascades mediated excitotoxicity.