Deferasirox exerts anti-epileptic effects by improving brain iron homeostasis via regulation of ITPRIP.

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.

Anticonvulsant effects of Cymbopogon giganteus extracts with possible effects on fully kindled seizures and anxiety in experimental rodent model of mesio-temporal epilepsy induced by pilocarpine.

ETHNOPHARMACOLOGICAL RELEVANCE: Epilepsy is a neurological disorder of the brain characterized by periodic and unpredictable occurrence of a transient behavior alteration due to the rhythmic, synchronous and disordered firing of brain neuron. Worldwide, approximately 50 million people currently live with epilepsy and close to 80% of people with epilepsy live in poor countries. However, it was noticed in many countries worldwide that people with epilepsy and their families suffer from stigma and discrimination and that situation exposes them to high psychological conditions such as depression and anxiety as well as more physical problems including bruising and fractures from injuries related to seizures. However, several plants-based products used for epilepsy and anxiety treatments in different system of folk medicine have exhibited a significant anti-epileptic and antianxiety activities using animal models with fewer side effects. AIM OF THE STUDY: The study aimed at evaluating the antiepileptic, status post-epilepticus and anxiolytic effects of Cymbopogon giganteus decoction in rat model induced by pilocarpine. MATERIALS AND METHODS: A total of 90 rats were partitioned into 7 groups and treated as follow: animals of groups I (normal control) and II (considered the negative control) received distilled water (10 mL/kg); while groups III, IV, V, and VI were treated with the C. giganteus extract at 34, 85, 170 and 340 mg/kg p.o, respectively; and the group VII (considered positive control) received sodium valproate at 300 mg/kg, i.p. After 40 min post-treatment, a single dose of n-methyl-scopolamine (1 mg/kg, i.p) was administered to animals of groups (II, III, IV, V, VI, VII) followed by pilocarpine (360 mg/kg, i.p). Animal of group I (normal group) received distilled water. Rats were further observed for 6 h to evaluate the severity and the duration of the acute seizures of epilepsy according to Racine scale. Anxious behavior status post-epilepticus was also assessed in the same rats used above in the Elevated Plus Maze and number of entries into the open or closed arms and the time spent on either open or closed arms of the platform were recorded. Animals were also evaluated on Open Field Test and the number of rearing, crossing, grooming, defecation and center time were registered. RESULTS: C. giganteus decoction significantly (P < 0.05) reduced the animal mortality, the number and duration of convulsions and effectively increased the latency of convulsions. The plant extract significantly (P < 0.05) improved GSH level and SOD activity, reduced MDA and CAT activity, increased GABA level and decreased GABA-t activity in hippocampus. The anxiety induced by pilocarpine was also significantly (P < 0.05) inhibited by the extract of the plant. CONCLUSIONS: Thus, C. giganteus has demonstrated its antiepileptic and anxiolytic activities in rat model and may be used as preventive measure for patients suffering from epilepsy seizures and anxiety.

Pergularia daemia hydro-ethanolic extract protects against pentylenetetrazole kindling-induced seizures, oxidative stress, and neuroinflammation in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Current antiepileptic drugs fail to control approximately 30% of epilepsies. Therefore, there is a need to develop more effective antiepileptic drugs, and medicinal plants provide an attractive source for new compounds. Pergularia daemia (Asclepiadaceae) is used in Cameroon traditional medicine to treat stroke, anemia, inflammation, and epilepsy. Recently, traditional healers claim that an hydro-ethanolic extract of the roots of P. daemia is more effective than an aqueous extract on refractory seizures. AIM OF THE STUDY: The antiepileptic effect of P. daemia hydro-ethanolic extract was investigated on the pentylenetetrazole kindling model of temporal lobe epilepsy in mice and possible mechanisms of action. MATERIALS AND METHODS: Mice were divided into 8 groups treated as follows: normal group received distilled water (10 ml/kg, p.o.), control group received distilled water (10 ml/kg, p.o.), ethanol group received ethanol (5%, p.o.), positive control received sodium valproate (300 mg/kg, p.o.), and test groups received P. daemia hydro-ethanolic (HE) extract (1.6, 4, 8 and 16 mg/kg, p.o.). All groups were kindled by 11 injections of pentylenetetrazole (PTZ) (35 mg/kg, i.p.), once every alternate day (48 ± 2 h), until the development of kindling, i.e., the occurrence of stage 5 seizures for two consecutive trials. One week later, i.e., 29th day, mice were challenged with a single and lower dose of PTZ (25 mg/kg, i.p.) that does not induce seizures in normal mice but causes seizures in mice prone to seizures and behavioral alterations. After completion of the kindling procedure, Morris water maze, passive avoidance, and open field tests were performed. Afterward, animals were euthanized, and hippocampi were removed for the estimation of the levels of GABA-transaminase (GABA-T), L-glutamate decarboxylase (L-GAD), and γ-aminobutyric acid (GABA). Oxidative stress and neuroinflammation markers also were quantified. Finally, histological analysis of the hippocampus was carried out. RESULTS: PTZ-kindling induced myoclonic jerks and generalized tonic-clonic seizures in control mice. However, the HE extract of P. daemia (4-16 mg/kg), compared to sodium valproate, significantly protected mice against myoclonic jerks and generalized tonic-clonic seizures. Also, the HE extract (1.6-16 mg/kg) significantly increased the seizure score. Furthermore, the HE extract of P. daemia significantly reduced seizure-induced cognitive impairments. PTZ-kindling induced significant alterations in GABA, GABA-T, and L-GAD contents as well as oxidative stress, and neuroinflammation, and the HE extract significantly reversed these effects, suggesting possible mechanisms. All these activities of the HE extract were confirmed by its protective effect against neuronal loss in the hippocampus. CONCLUSIONS: The HE extract of P. daemia protected mice against kindled seizures and cognitive impairments, and these effects were greater than those of sodium valproate, a widely used antiepileptic drug. These effects may be mediated by neuromodulatory, anti-oxidant, and anti-inflammatory activities, thus suggesting a neuroprotective effect. These findings help to explain the beneficial use of these HE extracts of P.daemia in traditional medicine to treat epilepsy in Cameroon.

Neuroprotective role of chrysin-loaded poly(lactic-co-glycolic acid) nanoparticle against kindling-induced epilepsy through Nrf2/ARE/HO-1 pathway.

Chrysin is the major bioactive compound of blue passionflower, an important medicinal plant used in traditional herbal formulations since ancient times. In the present study, we report that chrysin nanoparticles (chrysin NPs) protect Wistar rats against kindling-induced epilepsy. Nanoparticles of sizes less than 150 nm with a spherical shape were prepared using poly(d,l-lactic-co-glycolic acid) and polyvinyl alcohol, respectively, as polymer and stabilizer. Rats were injected with subconvulsive doses of pentylenetetrazole (PTZ) (35 mg/kg, intraperitoneal) every second day, with 22 injections in total, and on the same days, they received protective doses of the chrysin NPs (5 and 10 µg/mL, PO), respectively, 45 min before each PTZ injection. After the last PTZ injection, an average of thirteen seizure scores was recorded. Animals were killed by decapitation 24 h after a seizure. The cortex and hippocampus were removed and stored in liquid nitrogen for determining oxidative stress terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, histopathology, and reverse transcription-polymerase chain reaction for messenger RNA expression. The result showed chrysin NPs treatment has counteracted oxidative stress, reduced neuronal apoptosis, and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1. In conclusion, our findings demonstrate that the neuroprotective effect of chrysin NPs against kindling-induced epilepsy might be escorted by the alleviation of oxidative stress through the Nrf2/antioxidant response element/HO-1 pathway signal pathway.

Cognition and memory impairment attenuation via reduction of oxidative stress in acute and chronic mice models of epilepsy using antiepileptogenic Nux vomica.

Ethnopharmacological relevance Processed Nux vomica seed extracts and homeopathic medicinal preparations (HMPs) are widely used in traditional Indian and Chinese medicine for respiratory, digestive, neurological and behavioral disorders. Antioxidant property of Nux vomica is well known and recent investigation has highlighted the anticonvulsant potential of its homeopathic formulation. AIM OF THE STUDY: To explore the anticonvulsant and antiepileptogenic potential of Nux vomica HMPs (6CH, 12CH and 30CH potency) in pentylenetetrazole (PTZ) induced acute and chronic experimental seizure models in mice and investigate their effects on cognition, memory, motor activity and oxidative stress markers in kindled animals. MATERIALS AND METHODS: Acute seizures were induced in the animals through 70 mg/kg (i.p.) administration of PTZ followed by the evaluation of latency and duration of Generalized tonic-clonic seizures (GTCS). Subconvulsive PTZ doses (35 mg/kg, i.p.) induced kindling in 29 days, which was followed by assessment of cognition, memory and motor impairment through validated behavioral techniques. The status of oxidative stress was estimated through measurement of MDA, GSH and SOD. RESULTS: HMPs delayed the latency and reduced the duration of GTCS in acute model signifying possible regulation of GABAergic neurotransmission. Kindling was significantly hindered by the HMPs that justified the ameliorated cognition, memory and motor activity impairment. The HMPs attenuated lipid peroxidation by reducing MDA level and strengthened the antioxidant mechanism by enhancing the GSH and SOD levels in the kindled animals. CONCLUSIONS: Nux vomica HMPs showed anticonvulsant and antiepileptogenic potency in acute and chronic models of epilepsy. The test drugs attenuated behavioral impairment and reduced the oxidative stress against PTZ induced kindling owing to which they can be further explored for their cellular and molecular mechanism(s).

Probiotics and Nigella sativa extract supplementation improved behavioral and electrophysiological effects of PTZ-induced chemical kindling in rats.

INTRODUCTION: Epilepsy is a most common neurological disorder that has negative effects on cognition. In the present study, we investigated the protective effect of Nigella sativa (NS) and probiotics on seizure activity, cognitive performance, and synaptic plasticity in pentylenetetrazole (PTZ) kindling model of epilepsy. METHODS: One hundred and forty-four rats were divided into 2 experiments: In experiment 1, animals were grouped and treated as follows: 1) control (PTZ + saline), 2) NS treatment, 3) probiotic treatment, and 4) NS and probiotic treatment. Six weeks after the treatment, PTZ kindling were performed, and 48 h after kindling, spatial learning and memory were measured in Morris water maze (MWM) test. Animals in experiment 2 received the same treatment as experiment 1: in control nonkindled groups, control animals were treated with probiotics, NS, and probiotics + NS. Six weeks after the treatment, PTZ kindling were performed, and 48 h after kindling, field potentials were recorded from the dentate gyrus area of the hippocampus; synaptic transmission and long-term potentiation (LTP) was measured. RESULTS: The results showed that the probiotic and NS supplementation significantly reduces kindling development so that animals in PTZ + NS + probiotic did not show full kindling. In MWM test, the escape latency and traveled path in the kindled group were significantly higher than the control group. In PTZ + NS + probiotics, these parameters were significantly lower than those in the PTZ + saline group. Adding probiotic and NS supplementation significantly reduced population spike (PS)-LTP as compared with the PTZ + saline group. CONCLUSION: Probiotic and NS supplementation have some protection against seizure, seizure-induced cognitive impairment, and hippocampal LTP in kindled rats.

The current approach of the Epilepsy Therapy Screening Program contract site for identifying improved therapies for the treatment of pharmacoresistant seizures in epilepsy.

The Epilepsy Therapy Screening Program (ETSP), formerly known as the Anticonvulsant Screening Program (ASP), has played an important role in the preclinical evaluation of many of the antiseizure drugs (ASDs) that have been approved by the FDA and thus made available for the treatment of seizures. Recent changes to the animal models used at the contract site of the ETSP at the University of Utah have been implemented in an attempt to better model the unmet clinical needs of people with pharmacoresistant epilepsy and thus identify improved therapies. In this review, we describe the changes that have occurred over the last several years in the screening approach used at the contract site and, in particular, detail the pharmacology associated with several of the animal models and assays that are either new to the program or have been recently characterized in more depth. There is optimism that the refined approach used by the ETSP contract site, wherein etiologically relevant models that include those with spontaneous seizures are used, will identify novel, potentially disease modifying therapies for people with pharmacoresistant epilepsy and those at risk for developing epilepsy. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

Validated animal models for antiseizure drug (ASD) discovery: Advantages and potential pitfalls in ASD screening.

Since 1993, over 20 new anti-seizure drugs (ASDs) have been identified in well-established animal seizure and epilepsy models and subsequently demonstrated to be clinically effective in double-blinded, placebo-controlled clinical trials in patients with focal onset seizures. All clinically-available ASDs on the market today are effective in at least one of only three preclinical seizure and epilepsy models: the acute maximal electroshock (MES), the acute subcutaneous pentylenetetrazol (scPTZ) test, or the kindled rodent with chronic evoked seizures. Thus, it reasons that preclinical ASD discovery does not need significant revision to successfully identify ASDs for the symptomatic treatment of epilepsy. Unfortunately, a significant need still persists for more efficacious and better tolerated ASDs. This is particularly true for those patients whose seizures remain drug resistant. This review will focus on the continued utility of the acute MES and scPTZ tests, as well as the kindled rodent for current and future ASD discovery. These are the only "clinically validated" rodent models to date and been heavily used in the search for novel and more efficacious ASDs. This is to say that promising ASDs have been brought to the clinic on the basis of efficacy in these particular seizure and epilepsy models alone. This review also discusses some of the inherent advantages and limitations of these models relative to existing and emerging preclinical models. It then offers insight into future efforts to develop a preclinical model that will advance a truly transformative therapy for the symptomatic treatment of difficult to treat focal onset epilepsy. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

An interaction study of Ocimum sanctum L. and levetiracetam in pentylenetetrazole kindling model of epilepsy.

ETHNOPHARMACOLOGICAL RELEVANCE: Ocimum sanctum L. commonly known as tulsi (synonym of Ocimum tenuiflorum L.) is widely used in Ayurveda medicine and is having multitude neuromodulatory effect including the anticonvulsant effect in acute seizure models as per previous studies. In India, it is used for the treatment of epilepsy as traditional medicine. However, its role in chronic seizure model and interaction with newer antiepileptic drugs has not been investigated, which will enhance its translational value. AIM OF THE STUDY: Current study investigated the effect of Ocimum on chronic seizure model and its interaction with levetiracetam (LEV), a newer antiepileptic drug. MATERIALS AND METHODS: The adjuvant role of Ocimum sanctum hydroalcoholic extracts (OSHE) 1000 mg/kg along with LEV 300 mg/kg was studied in adult male Wistar rats with mean weight of 227.84 ± 21.68 g using pentylenetetrazole (30 mg/kg, i.p.) kindling (K) (with maximum 24 injections on alternate days and challenge on 7th-day). Along with seizure score, neurobehavioral, brain tissue oxidative stress and histopathology status were assessed. Pharmacokinetic interaction was assessed between LEV and OSHE after 14 days of drug treatment. RESULTS: K-LEV + OSHE had least seizure score during kindling and on the pentylenetetrazole-challenge test (p=0.031) than other kindling groups. Seizure protection was more in K-LEV + OSHE (85.72%) than others (K-LEV-42.86%, K-OSHE-42.86%, and K-Control-28.58%). Ocimum treated groups had better memory retention potential as evident from Morris water maze (MWM), passive avoidance test but not in an elevated plus maze test. Oxidative-stress was lower in Ocimum treated groups than K-Control group. As per histopathology, K-LEV + OSHE group had the least neuronal degeneration among kindling groups. There was no significant pharmacokinetic interaction between LEV and OSHE, except increased Tmax in LEV + OSHE group than LEV alone (p=0.009). CONCLUSIONS: Ocimum per se and combination with levetiracetam treatment exerted better seizure control, memory retention, oxidative stress reduction, and neuronal structure preservation than kindling control group. There was a very minimal drug interaction between Ocimum and LEV. So, Ocimum as an adjuvant to LEV may be shelpful in enhancing the antiepileptic effect and also in minimizing the adverse effects.

Evaluation of anticonvulsant and antiepileptogenic activity of Euphorbia nivulia in PTZ-induced kindling model of epilepsy in mice.

Epilepsy remains a major chronic neurological disorder with significantly higher refractory seizure rate. Based on the folk medicine literature, we explored the anticonvulsant and antiepileptogenic activity of aqueous ethanolic extracts of Fumaria indica, Euphorbia lactea, Euphorbia helioscopia, Neurada procumbens, and Euphorbia nivulia. The acute anticonvulsant activity of the extracts was determined at different concentrations in different groups of Swiss albino mice. Among all the materials tested, the ethanolic extracts of Euphorbia nivulia (eth-EN) alone was found to exhibit concentration-dependent anticonvulsant effects when evaluated against the acute convulsant dose of Pentylenetetrazole (PTZ, 90mg/kg, s.c.). eth-EN extract at 100mg/kg i.p concentration showed maximum protection against the PTZ induced mortality (P<0.05). eth-EN (100mg/kg) treated animals also showed significant reduction in the progression of epileptogenesis (P<0.05) when tested against the PTZ-induced (50mg/kg s.c.) chemical kindling model of epilepsy. The FT-IR spectra of this extract showed both known and unknown spectral peaks from which the presence of the functional groups; i.e. aromatics, diketones, alkenes, carbonyls, carboxylic acids and amide compounds were confirmed. The unknown peaks strongly suggested the presence of novel compounds that may be responsible for its anticonvulsant and antiepileptogenic activity.

Neuroprotective effect of astaxanthin on newborn rats exposed to prenatal maternal seizures.

Maternal epilepsy during pregnancy is associated with an increased incidence of brain damage and cognitive deficits in offspring. Oxidative stress is believed to play a critical role in this process. Astaxanthin, a natural carotenoid and dietary supplement, possesses potent antioxidant properties. This study was designed to investigate whether astaxanthin ameliorates the hippocampal damage in newborn rats induced by maternal epileptic seizures in utero and to explore the underlying mechanisms. Female Sprague-Dawley rats underwent chronic amygdalar kindling. After being fully kindled, all rats were allowed to mate, and electrical stimulation in the amygdala was performed every other day throughout the pregnancy. Astaxanthin was intraperitoneally injected at a dose of 30 mg/kg/d throughout pregnancy. Prenatal astaxanthin administration ameliorated neuronal lesions, decreased oxidative stress and induced the expression of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus of pups. Astaxanthin also ameliorated placental ischemic damage in epileptic mothers. Based on the results of the present study, we concluded that astaxanthin might serve as a therapeutic agent for preventing brain damage in offspring exposed to prenatal maternal seizures.

Intrahippocampal 5-HT1A receptor antagonist inhibits the improving effect of low-frequency stimulation on memory impairment in kindled rats.

In addition to its anticonvulsant effect, low frequency stimulation (LFS) improves learning and memory in kindled animals. In the present study, the role of 5-HT1A receptors in mediating LFS' improving effect on spatial learning and memory was investigated in amygdala-kindled rats. Amygdala kindling was conducted in a semi-rapid kindling stimulations (12 stimulations per day) in male Wistar rats. LFS (4 trains of 0.1 ms pulse duration at 1 Hz, 200 pulses, 50-150 µA, at 5 min intervals) was applied after termination of kindling stimulations. NAD-299 (a selective 5-HT1A receptor antagonist; 2.5 and 5 µg/µl) was microinjected into the hippocampal CA1 before applying LFS. The Morris water maze, and novel object recognition tests were conducted after the last kindling stimulation. Hippocampal samples were also prepared, and 5-HT1A receptor gene expression levels were assessed using quantitative RT-PCR. In kindled animals, LFS reduced impairments in spatial learning and memory in the Morris water maze and novel object recognition tests. Microinjection of NAD doses of 5 µg/µl reduced the effects of LFS on learning and memory. The gene expression level of 5-HT1A receptors increased significantly in the hippocampus of amygdala-kindled rats. However, LFS applied after kindling stimulations inhibited this effect. It seems that activation of 5-HT1A receptors in the CA1 field is necessary for LFS' improving effects on spatial learning and memory in kindled animals; although surprisingly, LFS application prevented the elevation in gene expression of 5-HT1A receptors in kindled animals.

TRPV1 mediates the anticonvulsant effects of acetaminophen in mice.

OBJECTIVE: Acetaminophen is one of the most commonly used analgesic and antipyretic drugs. It has been reported that acetaminophen has anticonvulsant effects in several animal models of seizure. An active metabolite of acetaminophen, AM404, inhibits the uptake of the endocannabinoid anandamide. However, the mechanism of the anticonvulsant effect of acetaminophen is unknown. METHODS: This study was performed to examine whether or not acetaminophen can protect against pentylenetetrazol-induced kindling in mice and to investigate the precise mechanisms of the anticonvulsant effect of acetaminophen using the fully kindled mouse models. RESULTS: Repeated administration of acetaminophen significantly delayed the progression of seizure severity induced by pentylenetetrazol. Additionally, acetaminophen showed a dose-dependent anticonvulsant activity against fully pentylenetetrazol-kindled seizures. AM404 also exhibited a dose-dependent anticonvulsant activity in fully kindled animals. The anticonvulsant activity of acetaminophen was antagonized by capsazepine and AMG9810, two transient receptor potential vanilloid-1 (TRPV1) antagonists. However, the transient receptor potential ankyrin 1 (TRPA1) antagonist HC030031 and CB1 receptor antagonist AM251 had no effect. CONCLUSION: These findings suggest that acetaminophen has an anticonvulsant effect in pentylenetetrazol-kindled mouse models and TRPV1 mediates the anticonvulsant action.

Neuroprotective mechanisms of sildenafil and selenium in PTZ-kindling model: Implications in epilepsy.

Epilepsy is one of the furthermost common neurodegenerative diseases affecting above 50 million individuals worldwide. The pathogenesis of epileptic seizures is not satisfactorily explored, and hence more effective anti-convulsive therapies are indispensable. Current study aimed to investigate the mechanisms of the potential neuroprotective effects of sildenafil/selenium on chemically-induced convulsions in mice. Kindling model was induced using pentylenetetrazol (PTZ; 35 mg/Kg, 11 doses, intraperitoneally, every other day). PTZ-insulted groups were treated intraperitoneally with sildenafil (20 mg/Kg), selenium (0.2 mg/Kg) or their combination; 30 min before PTZ administration. PTZ-kindled model showed a significant loss of neuronal cells concurrently with nitrative/oxidative stress and lipid peroxidation. This was associated with enhanced expression of inducible nitric oxide synthase (iNOS), hemeoxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) along with increased activity of thioredoxin reductase (TrxR) in hippocampal tissue. Individual treatment with sildenafil or selenium showed partial neuroprotection, simultaneously with lower hippocampal expression of 4-hydroneonenal (4-HNE), nitrotyrosine, iNOS and HO-1, yet without reaching normal levels. Sildenafil, but not selenium, enhanced the expression of VEGF and the endothelial cell marker CD34. The joint treatment with sildenafil and selenium preserved hippocampal neuronal count, improved kindling score, blunted lipid peroxides and nitrotyrosine levels, concomitantly with iNOS inhibition, normalization of TrxR activity and HO-1 expression, and evident neo-angiogenesis. Current study demonstrated the roles of several central signalling cascades in the sildenafil/selenium-evoked neuroprotection represented in, at least in part, amelioration of nitrative/oxidative stress alongside modulation of angiogenesis. Thus, sildenafil combined with selenium could be repurposed as a potential therapeutic regimen for delaying epilepsy progression.

Improving effect of mild foot electrical stimulation on pentylenetetrazole-induced impairment of learning and memory.

Epilepsy is a common neurological disorder that affects learning and memory. Recently it has been shown that mild foot electrical stimulation (MFES) can increase learning and memory in normal rats. Pentylenetetrazole (PTZ) kindling is a model of human epilepsy. As with human epilepsy, PTZ kindling impairs learning and memory in rats. The purpose of this study was to investigate the effect MFES on kindling-induced learning and memory deficits in rats. Forty-nine male Wistar rats weighting 200 to 250 g were divided into the following seven groups: PTZ only, phenytoin only, MFES only, PTZ plus phenytoin, PTZ plus MFES, phenytoin plus MFES, and saline (control), with the treatments administered for 26 days. Forty-eight hours after the last injection, the animals performed the Morris water maze (MWM) task, and spatial learning and memory were measured. The results indicated that although chronic administration of phenytoin inhibited the development of PTZ kindling, it did not exert a protective effect against kindling-induced spatial learning and memory impairment in rats. On the other hand, pretreatment of PTZ-kindled animals with MFES significantly improved spatial working and reference memory. The results point to potential novel beneficial effects of MFES on learning and memory impairment induced by PTZ kindling in rats.

Safranal carried by nanostructured lipid vehicles inhibits generalized epilepsy in mice.

Safranal, a main component of Crocus sativus, is suggested to have neuroprotective effects. The aim of this study was to investigate the effect of safranal and nanostructured lipid vehicle (NLV) carried safranal in acute and chronic experimental mice models of epilepsy. In PILO acute seizure model, safranal dose-dependently extended latency to generalized seizure, decreased the highest seizure stages and the number of generalized seizures. Moreover, NLV carried safranal further enhanced the anti-seizure effect, which is comparable to the action of sodium valproate. Meanwhile, NLV carried safranal reduced and delayed the electroencephalogram spectra power after pilocarpine injection. In histological aspect, safranal dose-dependently reduced the loss of neurons induced by seizure and NLV system further improved this protection at the same dose. In MES acute model, safranal markedly increased the electroconvulsive threshold, where NLV further improved its effect. In PTZ chronic seizure model, NLV carried safranal significantly delayed the kindling rate of progress and the time it took to reach generalized seizures as compared to NLV control group. In conclusion, this study indicates that safranal inhibits generalized seizure in acute and chronic epilepsy models in mice and NLV can enhance this effect. So, NLV carried safranal may have potential value in treatment of generalized epilepsy.

Effects of Leontice leontopetalum and Bongardia chrysogonum on oxidative stress and neuroprotection in PTZ kindling epilepsy in rats.

We investigated the effects of Leontice leontopetalum and Bongardia chrysogonum on apoptosis, gamma-aminobutyric acid (GABAA) receptor positive cell number, cyclin-B1 and bcl-2 levels and oxidative stress in pentylenetetrazol (PTZ) kindling in rats. Kindling was produced by subconvulsant doses of PTZ treatments in rats. Wistar albino rats were divided into 4 groups; Control, PTZ treated (PTZ), PTZ+L. leontopetalum extract treated (PTZ+LLE) and PTZ+B. chrysogonum extract treated (PTZ+BCE) groups. Extracts were given a dose (200 mg/kg) 2h before each PTZ injection. PTZ treatment significantly decreased the glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activities and bcl-2 levels and increased the total oxidant status (TOS), malondialdehyde (MDA), cyclin B1, oxidative stress index (OSI) and number of neurons that expressed GABAA receptors when compared to the control. LLE and BCE possessed antioxidant activity in the brain and ameliorated PTZ induced oxidative stress, decreased cyclin-B1, increased bcl-2 levels, and kept the GABAA receptor number similar to that of the control despite the PTZ application.

Manual acupuncture improves parameters associated with oxidative stress and inflammation in PTZ-induced kindling in mice.

The use of acupuncture in the treatment of central nervous system (CNS) disorders is an age-old practice. Although only a few studies have proved its efficacy, evidence has indicated the use of acupuncture to treat different types of seizures. Therefore, the present study aimed to evaluate the effect of manual acupuncture (MAC) using the chemical kindling model. The role of MAC in oxidative stress and inflammation after pentylenetetrazole (PTZ)-induced kindling was investigated by measuring reactive oxygen species (ROS) production, superoxide dismutase (SOD), and catalase (CAT) activities, nitrite content, and deoxyribonucleic acid (DNA) damage in cerebral cortex. Mice received PTZ (60mg/kgs.c.) once every three days for 16days, totaling six treatments. MAC was applied at acupoint GV20 daily during the entire experimental protocol. Diazepam (DZP) (2mg/kg) was used as positive control. Also, we evaluated the MAC effect associated with DZP (MAC/DZP) at a low dose (0.15mg/kg). The results demonstrated that MAC or MAC/DZP were not able to reduce significantly seizure occurrence or to increase the latency to the first seizure during treatment. MAC/DZP promoted a difference in the first latency to seizure only on the third day. PTZ-induced kindling caused significant neuronal injury, oxidative stress, increased DNA damage, nitric oxide production, and expression of the pro-inflammatory Tumor Necrosis Factor-α (TNF-α). These effects were reversed by treatment with MAC or MAC/DZP. These results indicated that the stimulation of acupoint GV20 by MAC showed no potential antiepileptogenic effect in the model used, although it greatly promoted neuronal protection, which may result from antioxidant and anti-inflammatory effects observed here.

Vitamin D enhances antiepileptic and cognitive effects of lamotrigine in pentylenetetrazole-kindled rats.

Despite long use of antiepileptic drugs, it remains a challenge to achieve seizure control while reducing adverse effects and preventing cognitive impairment. Several lines of evidence suggest a role of vitamin D in epilepsy. So this study aimed to investigate the effect of vitamin D on epileptogenesis, cognitive dysfunction and antiepileptic activity of lamotrigine, in a rat model of chemical kindling. Rats were kindled by pentylenetetrazole injections every other day over four weeks, together with daily oral treatment by either vehicle, vitamin D, lamotrigine or combination of vitamin D and lamotrigine. The non-treated kindled rats developed generalized seizures and had poor cognitive performance in water maze, associated with prooxidative status; elevated malondialdehyde and nitric oxide with lowered glutathione levels; in brain tissues. Treatment with either vitamin D, lamotrigine or both leads to significant reduction of seizure activity score, improvement of cognitive performance, and amelioration of the disturbed oxidative stress biomarkers. These findings indicate that, vitamin D has anti-epileptic, cognitive improving and antioxidant effects, on its own and enhance the effects of lamotrigine, in a chronic model of epileptic seizures. Thus, vitamin D supplementation may be a useful addition to antiepileptic drugs improving seizure control and cognitive function in patients with epilepsy.

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.