Antiepileptic and neuroprotective effects of human umbilical cord blood mononuclear cells in a pilocarpine-induced epilepsy model

Status epilepticus (SE) is a condition of persistent seizure that leads to brain damage and, frequently, to the establishment of chronic epilepsy. Cord blood is an important source of adult stem cells for the treatment of neurological disorders. The present study aimed to evaluate the effects of human umbilical cord blood mononuclear cells (HUCBC) transplanted into rats after induction of SE by the administration of lithium and pilocarpine chloride. Transplantation of HUCBC into epileptic rats protected against neuronal loss in the hippocampal subfields CA1, CA3 and in the hilus of the dentate gyrus, up to 300 days after SE induction. Moreover, transplanted rats had reduced frequency and duration of spontaneous recurrent seizures (SRS) 15, 120 and 300 days after the SE. Our study shows that HUCBC provide prominent antiepileptic and neuroprotective effects in the experimental model of epilepsy and reinforces that early interventions can protect the brain against the establishment of epilepsy.     

Elemental anomalies in the hippocampal formation after repetitive electrical stimulation: an X-ray fluorescence microscopy study

Our previous studies carried out on the pilocarpine model of seizures showed that highly resolved elemental analysis might be very helpful in the investigation of processes involved in the pathogenesis of epilepsy, such as excitotoxicity or mossy fiber sprouting. In this study, the changes in elemental composition that occurred in the hippocampal formation in the electrical kindling model of seizures were examined to determine the mechanisms responsible for the phenomenon of kindling and spontaneous seizure activity that may occur in this animal model. X-ray fluorescence microscopy was applied for topographic and quantitative analysis of selected elements in tissues taken from rats subjected to repetitive transauricular electroshocks (ES) and controls (N). The detailed comparisons were carried out for sectors 1 and 3 of the Ammon’s horn (CA1 and CA3, respectively), the dentate gyrus (DG) and hilus of DG. The obtained results showed only one statistically significant difference between ES and N groups, namely a higher level of Fe was noticed in CA3 region in the kindled animals. However, further analysis of correlations between the elemental levels and quantitative parameters describing electroshock-induced tonic and clonic seizures showed that the areal densities of some elements (Ca, Cu, Zn) strongly depended on the progress of kindling process. The areal density of Cu in CA1 decreased with the cumulative (totaled over 21 stimulation days) intensity and duration of electroshock-induced tonic seizures while Zn level in the hilus of DG was positively correlated with the duration and intensity of both tonic and clonic seizures.     

Trichosanthes tricuspidata Modulates Oxidative Toxicity in Brain Hippocampus Against Pilocarpine Induced Status Epilepticus in Mice

Epilepsy prevails to be a neurological disorder in anticipation of safer drugs with enhanced anticonvulsant efficacy as presently available drugs fails to offer adequate control of epileptic seizures in about one-third of patients. The objective of this study was to evaluate the effect of Trichosanthes tricuspidata methanolic extract (TTME) against epilepsy mediated oxidative stress in pilocarpine induced mice. Intraperitonial administration of pilocarpine (85 mg/kg) induced seizure in mice was assessed by behavior observations, which is significantly (p < 0.05) reduced by TTME (100 and 200 mg/kg; i.p) in a dose dependant manner, similar to diazepam. Seizure was accompanied by significant increase in lipid peroxidation and the hippocampal nitrite content in pilocarpine group when compared with control. Moreover, the antioxidant enzymes superoxide dismutase, catalase and glutathione levels were decreased in pilocarpine administered groups. TTME administration attenuated oxidative damage as evident by decreased lipid oxidative damage and nitrite–nitrate content and restored the level of enzymatic antioxidant defenses in hippocampus. Involvement of free radicals during epilepsy is further confirmed by histopathological analysis which showed the loss of neuronal cells in hippocampus CA1 and CA3 pyramidal region. Our findings strongly support the hypothesis that TTME has anticonvulsant activity accompanied with the strong antioxidant potential plays a crucial role in reducing the oxidative stress produced by seizure.     

GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of epilepsy, characterized by recurrent complex partial seizures and hippocampal sclerosis. The pathophysiology underlying this disorder remains unidentified. While a loss of benzodiazepine binding sites is a key diagnostic feature of MTLE, experimental studies have shown enhanced inhibitory transmission and increased expression of GABA(A)-receptors, suggesting that compensatory mechanisms are operative in epileptic hippocampus. In the present study, changes in the expression and cellular distribution of major GABA(A)-receptor subunits were investigated in the hippocampus of pilocarpine-treated rats during the phase of spontaneous recurrent seizures. A uniform decrease in GABA(A)-receptor subunit-immunoreactivity was observed in regions of extensive neuronal death (i.e. CA1, CA3, hilus). whereas a prominent increase occurred in the dentate gyrus (DG). Most strikingly, the increase was largest for the alpha3- and alpha5-subunits, which are expressed at very low levels in the DG of control rats, suggesting the formation of novel GABA(A)-receptor subtypes in epileptic tissue. Furthermore, an extensive loss of interneurons expressing the alpha1-subunit, representing presumptive basket cells, was seen in the DG. These changes were very similar to those reported in a novel mouse model of MTLE, based on the unilateral injection of kainic acid into the dorsal hippocampus (Bouilleret et al., 1999). This indicates that the regulation of GABA(A)-receptor expression is related to chronic recurrent seizures, and is not due to the extrahippocampal neuronal damage affecting pilocarpine-treated rats. These results allow causal relationships in the induction and maintenance of chronic recurrent seizures to be distinguished. The loss of a critical number of interneurons in the DG is a possible cause of seizure initiation, whereas the long-lasting upregulation of GABA(A)-receptors in granule cells represents a compensatory response to seizure activity.     

柴胡对癫痫模型电活动的调制

目的 :研究柴胡对癫痫发作的影响。方法 :以家兔和大鼠为实验对象 ,用毛果芸香碱致痫 ,采用脑电图和细胞外玻璃微电极记录技术 ,观察柴胡对癫痫模型大脑皮层放电及海马脑片场电位的影响。结果 :腹腔注射柴胡后可使癫痫发作次数及发作持续时间显著减少 ,发作间隔时间显著延长 ,(P <0 .0 5 ) ,脑片旁滴注柴胡后使致痫大鼠海马脑片诱发场电位幅度平均降低 2 0 .4 1% ,恢复时间平均为 6 .86min ,(P <0 .0 1)。结论 :柴胡注射液能明显抑制癫痫模型电活动 ,提示柴胡具有抗痫作用     

左旋组氨酸对匹罗卡品致痫大鼠癫痫发作和海马区神经细胞凋亡的影响

目的:观察左旋组氨酸(L-His)对匹罗卡品(PLO)致痫大鼠皮质脑电图及大鼠海马各区神经细胞凋亡的影响。方法:雄性SD大鼠30只,随机平均分为对照组(匹罗卡品组)、干预组(匹罗卡品+左旋组氨酸组)。各组给予相关干预处理后腹腔注射匹罗卡品建立癫痫模型,行皮质脑电图观察及海马区细胞凋亡染色观察。结果:经皮质脑电图显示,干预组潜伏期延长、痫波频率及大发作次数较对照组明显降低,差异有统计学意义(P<0.05)。凋亡染色显示,对照组的海马各区细胞在各时间点的凋亡数明显高于干预组,差异具有统计学意义(P<0.05)。结论:左旋组氨酸可以延迟匹罗卡品致痫的形成并降低点燃后癫痫发作程度,降低海马各区细胞凋亡数值,提示左旋组氨酸具有抗痫作用。     

Role of oxidative stress in epileptic seizures

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetic rat models, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment.     

脑电超慢涨落图技术在癫痫研究中的应用

目的：观察脑内多种神经递质对癫痫发作的影响。方法：以癫痫患者和ＳＤ大鼠为实验对象,用脑功能检测的最新脑电超电涨落图分析仪（ｅｎｃｅｐｈａｌｏｆｌｕｃｔｕｏｇｒａｍ ｔｅｃｈｎｏｌｏｇｙ,ＥＴ）长时程采集脑电信号,提取在脑电中载有脑神经递质调节系统的震荡信息（即Ｓ谱线）,分析癫痫发作时的脑神经递质的变化。结果：患儿癫痫发作时,Ｓ谱线中Ｓ２（谷氨酸）增高;Ｓ１（γ－氨基丁酸）降低,造成Ｓ１＜Ｓ２。Ｓ５     

Vitamin E Exerts Neuroprotective Effects in Pentylenetetrazole Kindling Epilepsy via Suppression of Ferroptosis

Epilepsy is one of the most common chronic neurological diseases. There is increasing evidence for ferroptosis playing an important role in the occurrence and development of epilepsy. Vitamin E is a common fat-soluble antioxidant that can regulate ferroptosis. The aim of this study was to investigate the effects of vitamin E on ferroptosis of hippocampal neurons in epileptic rats. Sixty-four male Sprague–Dawley (SD) rats were randomly divided into control, pentylenetetrazol (PTZ; 35 mg/kg), vitamin E (200 mg/kg)?+?PTZ, and Ferrostatin-1 (Fer-1; 2.5 μmol/kg)?+?PTZ groups, with drugs administered intraperitoneally 15 times every other day for 29 days. The behavioral manifestations (epileptic score, latency, and number of seizures in 30 min) and EEG changes were observed and recorded. Nissl staining and electrophysiological recording were used to assess neuronal damage and excitability in the hippocampal CA1 region, respectively. The levels of iron, glutathione (GSH), and malondialdehyde (MDA) in the hippocampus were assessed by spectrophotometry. Immunofluorescence staining was used to detect lipoxygenase 15 (15-LOX) expression. Western blot was used to determine glutathione peroxidase 4 (GPX4) and 15-LOX protein levels. Vitamin E treatment was associated with decreased epileptic grade, seizure latency, and number of seizures in the PTZ-kindled epileptic model. Vitamin E treatment also decreased 15-LOX expression, inhibited MDA and iron accumulation, and increased GPX4 and GSH expression. In conclusion, vitamin E can reduce neuronal ferroptosis and seizures by inhibiting 15-LOX expression.

     

调控RET依赖性GDNF信号通路对大鼠癫痫模型的影响

目的:探究双侧海马CA1区立体定向注射anti-GDNF抗体对匹鲁卡品诱导的大鼠癫痫模型的影响。方法:选择成年雄性SD大鼠60只,并随机分为3组,即假手术组(sham组,n=20)、癫痫模型组(model组,n=20)和GDNF抑制剂组(anti-GDNF组,n=20)。使用氯化锂-匹鲁卡品腹腔注射诱导癫痫模型,sham组只给予氯化锂,anti-GDNF组在造模前2 h给予大鼠双侧海马CA1区立体定向注射anti-GDNF抗体。在造模后1、3、7 d观察大鼠癫痫的发作频率,7 d后采用脑电图监测(EEG)测定脑电波的变化情况,通过免疫组化方法测定海马CA1区域神经元数量变化(Neu N表达水平),造模后1 d时使用western blot方法测定海马CA1区GDNF、RET和P53蛋白的表达。结果:Model组大鼠棘-慢波数量明显高于Sham组,anti-GDNF组以上指标较model组显著减少(P0.05);Model组海马CA1区神经元大量凋亡,但anti-GDNF组凋亡较model组显著减少(P0.05)。与Sham组比较,在癫痫发作后1 d,model组的GDNF、RET表达水平上调,P53表达水平下降(P0.05),而anti-GDNF组大鼠海马CA1区GDNF、RET表达较model组明显下调,P53表达水平显著上降(P0.05)。结论:双侧海马CA1区立体定向注射anti-GDNF抗体能够减少癫痫发作,并对海马神经元起到保护作用,可能与其抑制GDNF/RET/P53信号通路有关。     

Chronic inhibition of cortex microsomal Mg2+/Ca2+ ATPase-mediated Ca2+ uptake in the rat pilocarpine model following epileptogenesis

In the rat pilocarpine model, 1 h of status epilepticus caused significant inhibition of Mg(2+)/Ca(2+) ATPase-mediated Ca(2+) uptake in cortex endoplasmic reticulum (microsomes) isolated immediately after the status episode. The rat pilocarpine model is also an established model of acquired epilepsy. Several weeks after the initial status epilepticus episode, the rats develop spontaneous recurrent seizures, or epilepsy. To determine whether inhibition of Ca(2+) uptake persists after the establishment of epilepsy, Ca(2+) uptake was studied in cortical microsomes isolated from rats displaying spontaneous recurrent seizures for 1 year. The initial rate and total Ca(2+) uptake in microsomes from epileptic animals remained significantly inhibited 1 year after the expression of epilepsy compared to age-matched controls. The inhibition of Ca(2+) uptake was not due to individual seizures nor an artifact of increased Ca(2+) release from epileptic microsomes. In addition, the decreased Ca(2+) uptake was not due to either selective isolation of damaged epileptic microsomes from the homogenate or decreased Mg(2+)/Ca(2+) ATPase protein in the epileptic microsomes. The data demonstrate that inhibition of microsomal Mg(2+)/Ca(2+) ATPase-mediated Ca(2+) uptake in the pilocarpine model may underlie some of the long-term plasticity changes associated with epileptogenesis.     

鞘氨醇激酶1和1-磷酸鞘氨醇受体2在癫痫大鼠海马组织中表达的变化*

目的:检测鞘氨醇激酶1 (SphK1)和1-磷酸鞘氨醇受体2 (S1PR2) 在癫痫大鼠海马中的表达,探讨SphK1和S1PR2在癫痫中的作用机制。方法:成年雄性SD大鼠108只,随机分为对照(Control)组(n=48)和癫痫(PILO)组(n=60)。癫痫组腹腔注射氯化锂(127 mg/kg),18～20 h后注射匹罗卡品,首剂量为30 mg/kg,发作＜IV级的大鼠重复注射匹罗卡品(10 mg/kg);对照组给予等剂量的生理盐水代替匹罗卡品。根据造模后观察时间和行为学改变,随机分为3个大组,6个亚组:急性期组(E6 h、E1 d、E3 d)、潜伏期组(E7 d)和慢性期组(E30 d、E56 d),每个亚组中对照大鼠和癫痫大鼠各8只。每组取4只大鼠麻醉取海马,另4只取大脑组织。运用Western blot检测SphK1、S1PR2在大鼠海马组织中的表达变化,免疫荧光检测星形胶质细胞活化增生情况及SphK1、S1PR2在星形胶质细胞中的定位表达。结果:与Control组比较,SphK1在造模后急性期(E3 d)、潜伏期(E7 d)和慢性期(E30 d、E56 d)海马中的表达均明显升高(P＜0.05或P＜0.01);S1PR2在急性期(E3 d)、潜伏期(E7 d)和慢性期(E30 d、E56 d)海马组织中的表达均明显下降(P＜0.05或P＜0.01);癫痫大鼠(E7 d)海马星形胶质细胞活化、增生明显(P＜0.05),SphK1和S1PR2在E7d的表达到位为海马星形胶质细胞中。结论:SphK1和S1PR2可能通过调控海马星形胶质细胞活化增生和影响神经元兴奋性参与了癫痫的发病。     

The Neuroprotective Effect of Curcumin and Nigella sativa Oil Against Oxidative Stress in the Pilocarpine Model of Epilepsy: A Comparison with Valproate

Oxidative stress has been implicated to play a role in epileptogenesis and pilocarpine-induced seizures. The present study aims to evaluate the antioxidant effects of curcumin, Nigella sativa oil (NSO) and valproate on the levels of malondialdehyde, nitric oxide, reduced glutathione and the activities of catalase, Na⁺, K⁺-ATPase and acetylcholinesterase in the hippocampus of pilocarpine-treated rats. The animal model of epilepsy was induced by pilocarpine and left for 22 days to establish the chronic phase of epilepsy. These animals were then treated with curcumin, NSO or valproate for 21 days. The data revealed evidence of oxidative stress in the hippocampus of pilocarpinized rats as indicated by the increased nitric oxide levels and the decreased glutathione levels and catalase activity. Moreover, a decrease in Na⁺, K⁺-ATPase activity and an increase in acetylcholinesterase activity occurred in the hippocampus after pilocarpine. Treatment with curcumin, NSO or valproate ameliorated most of the changes induced by pilocarpine and restored Na⁺, K⁺-ATPase activity in the hippocampus to control levels. This study reflects the promising anticonvulsant and potent antioxidant effects of curcumin and NSO in reducing oxidative stress, excitability and the induction of seizures in epileptic animals and improving some of the adverse effects of antiepileptic drugs.     

Variations in elemental compositions of rat hippocampal formation between acute and latent phases of pilocarpine-induced epilepsy: an X-ray fluorescence microscopy study

There is growing experimental evidence that tracing the elements involved in brain hyperexcitability, excitotoxicity, and/or subsequent neurodegeneration could be a valuable source of data on the molecular mechanisms triggering or promoting further development of epilepsy. The most frequently used experimental model of the temporal lobe epilepsy observed in clinical practice is the one based on pilocarpine-induced seizures. In the frame of this study, the elemental anomalies occurring for the rat hippocampal tissue in acute and silent periods after injection of pilocarpine in rats were compared. X-ray fluorescence microscopy was applied for the topographic and quantitative elemental analysis. The differences in the levels of elements such as P, S, K, Ca, Fe, Cu, and Zn between the rats 3 days (SE72) and 6 h (SE6) after pilocarpine injection as well as naive controls were examined. Comparison of SE72 and control groups showed, for specific areas of the hippocampal formation, lower levels of P, K, Cu, and Zn, and an increase in Ca accumulation. These results as well as further analysis of the differences between the SE72 and SE6 groups confirmed that seizure-induced excitotoxicity as well as mossy fiber sprouting are the mechanisms involved in the neurodegenerative processes which may finally lead to spontaneous seizures in the chronic period of the pilocarpine model. Moreover, in the light of the results obtained, Cu seems to play a very important role in the pathogenesis of epilepsy in this animal model. For all areas analyzed, the levels of this element recorded in the latent period were not only lower than those for controls but were even lower than the levels found in the acute period. The decreased hippocampal accumulation of Cu in the phase of behavior and EEG stabilization, a possible inhibitory effect of this element on excitatory amino acid receptors, and enhanced seizure susceptibility in Menkes disease (an inherited Cu transport disorder leading to Cu deficiency in the brain) suggest a neuroprotective role rather than neurodegenerative and proconvulsive roles of Cu in pilocarpine-induced epilepsy.     

钩藤对致痫大鼠海马脑片诱发场电位的影响

目的研究钩藤对癫痫模型海马脑片诱发场电位的影响。方法以毛果芸香碱致痫大鼠为实验对象,采用脑片旁滴注给药,用细胞外玻璃微电极记录方法,观察钩藤对癫痫模型离体海马脑片CA1区锥体细胞诱发群锋电位（populationspike,PS）的影响。结果给予钩藤后使致痫大鼠海马脑片PS幅度平均降低27.64％,平均8.71min恢复(n=14,P<0.01)。结论钩藤能降低致痫大鼠海马脑片CA1区顺向诱发PS幅度,提示钩藤对中枢神经系统的突触传递过程有明显的抑制效应,具有抗癫痫作用。     

Exposure to Mozart music reduces cognitive impairment in pilocarpine-induced status epilepticus rats

Patients with temporal lobe epilepsy (TLE) often display cognitive deficits. However, current epilepsy therapeutic interventions mainly aim at how to reduce the frequency and degree of epileptic seizures. Recovery of cognitive impairment is not attended enough, resulting in the lack of effective approaches in this respect. In the pilocarpine-induced temporal lobe epilepsy rat model, memory impairment has been classically reported. Here we evaluated spatial cognition changes at different epileptogenesis stages in rats of this model and explored the effects of long-term Mozart music exposure on the recovery of cognitive ability. Our results showed that pilocarpine rats suffered persisting cognitive impairment during epileptogenesis. Interestingly, we found that Mozart music exposure can significantly enhance cognitive ability in epileptic rats, and music intervention may be more effective for improving cognitive function during the early stages after Status epilepticus. These findings strongly suggest that Mozart music may help to promote the recovery of cognitive damage due to seizure activities, which provides a novel intervention strategy to diminish cognitive deficits in TLE patients.     

Investigations of hippocampal astrocytes in lipopolysaccharide-preconditioned rats in the pilocarpine model of epilepsy

The present paper is the first work to determine the effect of lipopolysaccharide (LPS) in the pilocarpine model of epilepsy on the morphology of rat hippocampal astrocytes in vivo. The study involved adult male Wistar rats, which 72 hours prior to administration of pilocarpine hydrochloride (PILO) were intraperitoneally (ip) preconditioned with LPS at a dose of 0.5 mg/kg b.w. The control animals were administered (ip) saline or LPS alone. The astrocytes in the control animals displayed characteristic stellate morphology. Examinations of the astrocytes were performed on days one, three and 21 of the pilocarpine model of epilepsy (i.e. in the acute, silent and chronic periods). The astrocytes of the CA1 and CA3 pyramidal layers of the hippocampus were observed and analyzed at the structural and ultrastructural levels. It was demonstrated that on days one and three, glial cells from both the nonpreconditioned and the LPS-preconditioned animals displayed similar reactive changes, manifesting themselves as swelling of cell bodies, glial processes, and astrocytosis. Moreover, reduction in cell organelles aggregated at one pole and the presence of vacuoles were observed. The most pronounced astrogliosis and cell swelling occurred on day 21. We conclude that LPS has no effect on the morphology of astrocytes in the pilocarpine model of epilepsy, unlike the results obtained by other authors in vitro.     

Hippocampal neurons and glia in epileptic EL mice

Reactive changes in hippocampal astrocytes are frequently encountered in association with temporal lobe epilepsy in humans and with drug or kindling-induced seizures in animal models. These reactive changes generally involve increases in astrocyte size and number and often occur together with neuronal loss and synaptic rearrangements. In addition to producing astrocytic changes, seizure activity can also produce reactive changes in microglia, the resident macrophages of brain. In this study, we examined the effects of recurrent seizure activity on hippocampal neurons and glia in the epileptic EL mouse, a natural model of human multifactorial idiopathic epilepsy and complex partial seizures. Timm staining was used to evaluate infrapyramidal mossy fiber organization and the optical dissector method was used to count Nissl-stained neurons in hippocampus of adult (about one year of age) EL mice and nonepileptic C57BL/6J (B6) and DDY mice. Immunostaining forglial fibrillary acidic protein (GFAP) and Iba1, an actin cross-linking molecule restricted to macrophages and microglia, was used to evaluate astrocytes and microglia, respectively. The EL mice experienced about 25–30 complex partial seizures with secondary generalization during routine weekly cage changing. No significant differences were found among the mouse strains for Timm staining scores or for neuronal counts in the CA1 and CA3 pyramidal fields or in the hilus. However, the number of GFAP-positive astrocytes was significantly elevated in the stratum radiatum and hilus of EL mice, while microglia appeared hyper-ramified and were more intensely stained in EL mice than in the B6 or DDY mice in the hilus, parietal cortex, and pyriform cortex. The results indicate that recurrent seizure activity in EL mice is associated with abnormalities in hippocampal astrocytes and brain microglia, but is not associated with obvious neuronal loss or mossy fiber synaptic rearrangements. The EL mouse can be a useful model for evaluating neuron-glia interactions related to idiopathic epilepsy.     

Status epilepticus--the new mechanisms and lines of inhibition (the lithium-pilocarpine model)

This review focuses on the modeling of status epilepticus in animal brain and modern data on the mechanisms of epileptical seizures initiation using the pilocarpine binding with the muscarinic cholinoreceptors (litium pilocarpine model). The character of epileptics seizures in developing brain and adult brain of rats were investigated. The lines of modulation and inhibition epileptics statues by sacricine and intranasal application of neuropeptide thyroliberin in ultra-low doses are demonstrated. The role of the short-term changes (signal regulated kinase signaling cascade, Kv 4.2 potassium channels, hippocampal and cortical spike-wave discharges) and the long-term changes (loss of selective type of interneurons, excitatory circuits by mossy fiber sprouting) that promotion the epileptic state and recurrent seizures in limbic structure are discussed.     

Vezatin regulates seizures by controlling AMPAR-mediated synaptic activity

Although many studies have explored the mechanism of epilepsy, it remains unclear and deserves further investigation. Vezatin has been reported to be a synaptic regulatory protein involved in regulating neuronal synaptic transmission (NST). However, the role of vezatin in epilepsy remains unknown. Therefore, the aims of this study are to investigate the underlying roles of vezatin in epilepsy. In this study, vezatin expression was increased in hippocampal tissues from pilocarpine (PILO)-induced epileptic mice and a Mg²⁺-free medium-induced in vitro seizure-like model. Vezatin knockdown suppressed seizure activity in PILO-induced epileptic mice. Mechanistically, vezatin knockdown suppressed AMPAR-mediated synaptic events in epileptic mice and downregulated the surface expression of the AMPAR GluA1 subunit (GluA1). Interestingly, vezatin knockdown decreased the phosphorylation of GluA1 at serine 845 and reduced protein kinase A (PKA) phosphorylation; when PKA phosphorylation was suppressed by H-89 (a selective inhibitor of PKA phosphorylation) in vitro, the effects of vezatin knockdown on reducing the phosphorylation of GluA1 at serine 845 and the surface expression of GluA1 were blocked. Finally, we investigated the pattern of vezatin in brain tissues from patients with temporal lobe epilepsy (TLE), and we found that vezatin expression was also increased in patients with TLE. In summary, the vezatin expression pattern is abnormal in individuals with epilepsy, and vezatin regulates seizure activity by affecting AMPAR-mediated NST and the surface expression of GluA1, which is involved in PKA-mediated phosphorylation of GluA1 at serine 845, indicating that vezatin-mediated regulation of epileptic seizures represents a novel target for epilepsy.Subject terms: Cellular neuroscience, Molecular neuroscience