Rat Model Of Seizures Research Articles

Acute and chronic convection-enhanced muscimol delivery into the rat subthalamic nucleus induces antiseizure effects associated with high responder rates

Intracerebral drug delivery is an emerging treatment strategy aiming to manage seizures in patients with systemic drug-resistant epilepsies. In rat seizure and epilepsy models, the GABAA receptor agonist muscimol has shown powerful antiseizure potential when injected acutely into the subthalamic nucleus (STN), known for its capacity to provide remote control of different seizure types. However, chronic intrasubthalamic muscimol delivery required for long-term seizure suppression has not yet been investigated. We tested the hypothesis that chronic convection-enhanced delivery (CED) of muscimol into the STN produces long-lasting antiseizure effects in the intravenous pentylenetetrazole seizure threshold test in female rats. Acute microinjection was included to verify efficacy of intrasubthalamic muscimol delivery in this seizure model and caused significant antiseizure effects at 30 and 60 ng per hemisphere with a dose-dependent increase of responders and efficacy and only mild adverse effects compared to controls. For the chronic study, muscimol was bilaterally infused into the STN over three weeks at daily doses of 60, 300, or 600 ng per hemisphere using an implantable pump and cannula system. Chronic intrasubthalamic CED of muscimol caused significant long-lasting antiseizure effects for up to three weeks at 300 and 600 ng daily. Drug responder rate increased dose-dependently, as did drug tolerance rates. Transient ataxia and body weight loss were the main adverse effects. Drug distribution was comparable (about 2–3 mm) between acute and chronic delivery. This is the first study providing proof-of-concept that not only acute, but also chronic, continuous CED of muscimol into the STN raises seizure thresholds.

The Anticonvulsant Activity of Mucoadhesive Buccal Films of Sodium Valproate in Pentylenetetrazole-Induced Seizure Rat Model

The Anticonvulsant Activity of Mucoadhesive Buccal Films of Sodium Valproate in Pentylenetetrazole-Induced Seizure Rat Model

Esculetin alleviates pentylenetetrazole-induced seizures, cognitive impairment and pro-inflammatory cytokines and suppresses penicillin-induced epileptiform activity in rats

AimsTo investigate the effects of different doses of esculetin on epileptiform activity, behavioral seizures, memory impairment, and cortical and hippocampal NF-κB, as a mediator of pro-inflammatory gene induction, and pro-inflammatory cytokines in penicillin- and pentylenetetrazole(PTZ)-induced seizure models in rats. Main methodsDifferent doses of esculetin (5, 10, and 20 mg/kg), and diazepam (5 mg/kg) as a positive control, were tested in penicillin- and pentylenetetrazole(PTZ)-induced seizure models. In the PTZ model, cognitive function, behavioral seizures, and cortical and hippocampal pro-inflammatory biomarkers and survival factor was evaluated. In the penicillin model, the frequency and amplitude of electrophysiological epileptiform activity were assessed. Key findingsIn the PTZ model, the 10 mg/kg esculetin displayed anticonvulsant effects by extending onset-times of myoclonic-jerk and generalized tonic-clonic seizure, and by diminishing seizure severity and duration of generalized tonic-clonic seizure. It also ameliorated PTZ-induced cognitive impairment, and cortical and hippocampal activin-A, IL-1β, IL-6 and NF-κB levels. In the penicillin model, the 10 mg/kg esculetin decreased the frequency of spikes without changing the amplitude of spikes. As a positive-control, diazepam reversed all changes induced by both PTZ and penicillin. SignificanceEsculetin exhibits anticonvulsant and memory-improving effects by alleviating the behavioral and electrophysiological characteristics of epileptic seizures. Additionally, esculetin exerts anti-neuroinflammatory actions in the PTZ-induced seizures model. Thus, esculetin may be a multi-targeted promising agent with anticonvulsant and anti-neuroinflammatory effects in the treatment of epilepsy.

The antiinflammatory and electrophysiological effects of fingolimod on penicillin-induced rats.

The fact that inflammation triggers epileptic seizures brings to mind the antiepileptic properties of anti-inflammatory drugs. To investigate the electrophysiological and anti-inflammatory effects of fingolimod on an experimental penicillin-induced acute epileptic seizure model in rats. Thirty-two male Wistar rats were divided into four groups: control (penicillin), positive control (penicillin + diazepam [5 mg/kg]), drug (penicillin + fingolimod [0.3 mg/kg]) and synergy group (penicillin + diazepam + fingolimod). The animals were anesthetized with urethane, and epileptiform activity was induced by intracortical injection of penicillin (500,000 IU). After electrophysiological recording for 125 minutes, IL-1β, TNF-α, and IL-6 were evaluated by ELISA in the serum of sacrificed animals. During the experiment, animal deaths occurred in the synergy group due to the synergistic negative chronotropic effect of diazepam and fingolimod. Although not statistically significant, fingolimod caused a slight decrease in spike-wave activity and spike amplitudes in the acute seizure model induced by penicillin (p > 0.05). Fingolimod decreased serum IL-1β (p < 0.05); fingolimod and diazepam together reduced IL-6 (p < 0.05), but no change was observed in serum TNF-α values. Even in acute use, the spike-wave and amplitude values of fingolimod decrease with diazepam, anticonvulsant and anti-inflammatory effects of fingolimod will be more prominent in chronic applications and central tissue evaluations. In addition, concomitant use of fingolimod and diazepam is considered to be contraindicated due to the synergistic negative inotropic effect.

The effect of oxytocin and an enriched environment on anxiety-like behaviour and corticosterone levels in a prenatally stressed febrile seizure rat model.

Febrile seizures (FS) are a neurological abnormality which occur following a fever that has resulted from a systemic infection and are characterised by convulsions. These convulsions occur due to abnormally increased signalling of interleukin-1 beta, resulting in increased neuronal hyper-excitability. Furthermore, exposure to prenatal stress has been shown to exacerbate seizure duration, elicit anxiety-like behaviour and corticosterone levels. Oxytocin is a neuropeptide with anxiolytic, social bonding, and stress regulation effects. Therefore, the aim of the study was to assess whether oxytocin can attenuate the anxiety-like behaviour and increased corticosterone in rat offspring exposed to prenatal stress and FS. Sprague Dawley rats were mated. On GND14, prenatal stress was induced on pregnant dams for 1hr/7 days. On PND 14, rat pups were injected with lipopolysaccharide (LPS, 200μg/kg, i.p.) followed 2.5h later by an i.p. injection of kainic acid (KA, 1.75mg/kg). Oxytocin (1mg/kg) was induced via different routes (intraperitoneal or intranasal) as well an enriched environment between PND 22-26. The enriched environment included larger cages (1560cm2) with only 4 pups per cage, compared to those groups not receiving enrichment (646cm2), as well as cardboard rolls and plastic toys. On PND 27-33 the light/dark box and elevated plus maze were used to assess anxiety-like behaviour. On PND 34 all rats were euthanized using a sharp guillotine, trunk blood and hypothalamic tissue were collected for neurochemical analysis (ELISA kit). Our findings confirmed that exposure to both prenatal stress and febrile seizures resulted anxiety-like behaviour and significantly higher plasma corticosterone concentrations compared to their counterparts. Environmental enrichment was significantly effective in attenuating the increased basal corticosterone levels and anxiety-like behaviour seen in the prenatally stressed FS rat. Although direct administration of oxytocin showed higher significance in reducing corticosterone plasma levels when compared to the enriched environment. Furthermore, hypothalamic oxytocin levels were not significant in rat exposed to environmental enrichment while oxytocin treatment showed a significant effect when compared to their counterparts. Therefore, oxytocin administration during early postnatal development shows great potential in reversing the effects of prenatal stress and its subsequent exacerbation of FS.

Molecular docking to investigate the inhibitory activity and the role of nitric oxide in anticonvulsant effects of vitamin D on pentylenetetrazole‑induced epileptic seizures in rats

Despite the great breakthroughs in the field of epilepsy studies, the present drugs are ineffective in one-third of the patients, as well as without providing a definite treatment. There is accumulating evidence suggesting the role of vitamin D in epilepsy. The aim of this study was to investigate the effect of vitamin D on seizure formation, post-seizure cognitive functions, and the possible role of nitric oxide and oxidative stress in this effect, in the PTZ-induced seizure rat model. Sixty male Wistar albino rats were used in this study. The rats were randomly divided into 11 groups each containing 6 animals: Group 1: Control; Group 2: Saline+PTZ (45 mg/kg); Group 3: Vitamin D (1.5 mg/kg)+PTZ; Group 4: L-Arginine (500 mg/kg)+PTZ; Group 5: L-NAME (60 mg/kg)+PTZ; Group 6: 7-Nitroindazole (40 mg/kg); Group 7: Aminoguanidine (100 mg/kg)+PTZ; Group 8: Vitamin D+L- Arginine+PTZ; Group 9: Vitamin D+L-NAME+PTZ; Group 10: Vitamin D+7-Nitroindazole+PTZ; Group 11: Vitamin D+Aminoguanidine+PTZ. Animal behavior was evaluated with open field and passive avoidance tests. Nitric oxide (NO), total oxidative status (TOS), and total antioxidant status (TAS) levels in the cortex and hippocampus brain regions were determined by ELISA method. The treatment of vitamin D in combination with NO inhibitors has a positive effect on the PTZ-induced seizures and ameliorate post-seizure learning deficits. Moreover, the combination of vitamin D with NO inhibitors reduced oxidative stress and NO levels after seizures in the cortex and hippocampus. Also, we employed molecular docking and density functional theory analysis to investigate the inhibitory activity, reactivity, and stability of Vitamin D with other NO inhibitors. Vitamin D supplementation could be effective as a supportive treatment drug in epileptic patients, according to the findings.

Spatial, temporal, and cell-type-specific expression of NADPH Oxidase isoforms following seizure models in rats.

The NADPH Oxidase (NOX) enzymes are key producers of reactive oxygen species (ROS) and consist of seven different isoforms, distributed across the tissues and cell types. The increasing level of ROS induces oxidative stress playing a crucial role in neuronal death and the development of epilepsy. Recently, NOX2 was reported as a primary source of ROS production, activated by NMDA receptor, a crucial marker of epilepsy development. Here, we demonstrate spatial, temporal, and cellular expression of NOX2 and NOX4 complexes in in-vitro and in-vivo seizure models. We showed that the expression of NOX2 and NOX4 was increased in the initial 24h following a brief seizure induced by pentylenetetrazol. Interestingly, while this elevated level returns to baseline 48h following seizure in the cortex, in the hippocampus these levels remain elevated up to one week following the seizure. Moreover, we showed that 1- and 2- weeks following status epilepticus (SE), expression of NOX2 and NOX4 remains significantly elevated both in the cortex and the hippocampus. Furthermore, in in-vitro seizure model, NOX2 and NOX4 isoforms were overexpressed in neurons and astrocytes following seizures. These results suggest that NOX2 and NOX4 in the brain have a transient response to seizures, and these responses temporally vary depending on, seizure duration, brain region (cortex or hippocampus), and cell types.

Anticonvulsant activity of oxaprozin in a rat model of pentylenetetrazole-induced seizure by targeting oxidative stress and SIRT1/PGC1α signaling.

The effect of oxaprozin (OXP) on an experimental model of seizures in rats was investigated in this study. Seizures in Wistar rats (200-250 g) were induced by pentylenetetrazole (PTZ, 60 mg/kg). The anticonvulsant effect of OXP (100, 200, and 400 mg/kg, intraperitoneally) was evaluated in a seizure model. After behavioral tests, the animals underwent deep anesthesia and were put down painlessly. Animal serum was isolated for antioxidant assays (nitric oxide (NO) and glutathione (GSH)). The animals' brains were also isolated to gauge the relative expression of genes in the oxidative stress pathway (sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α)). Intraperitoneal injection of OXP increased the mean latency of myoclonic jerks and generalized tonic-clonic seizure (GTCS) and decreased the number of myoclonic jerks and GTCS duration compared with the PTZ group. Biochemical tests showed that pretreatment with OXP was able to restore GSH serum levels and reverse the augmented NO serum levels caused by PTZ induction to the normal level. The quantitative polymerase chain reaction results also revealed that OXP counteracts the negative effects of PTZ by affecting the expression of the Sirt1 and Pgc1α genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal, anti-inflammatory OXP drug in a model of neural impairment caused by seizures via the mechanism of inhibition of the oxidative stress pathway.

Neferine, an Alkaloid from Lotus Seed Embryos, Exerts Antiseizure and Neuroprotective Effects in a Kainic Acid-Induced Seizure Model in Rats.

Current anti-seizure drugs fail to control approximately 30% of epilepsies. Therefore, there is a need to develop more effective anti-seizure drugs, and medicinal plants provide an attractive source for new compounds. This study aimed to evaluate the possible anti-seizure and neuroprotective effects of neferine, an alkaloid from the lotus seed embryos of Nelumbo nucifera, in a kainic acid (KA)-induced seizure rat model and its underlying mechanisms. Rats were intraperitoneally (i.p.) administrated neferine (10 and 50 mg/kg) 30 min before KA injection (15 mg/kg, i.p.). Neferine pretreatment increased seizure latency and reduced seizure scores, prevented glutamate elevation and neuronal loss, and increased presynaptic protein synaptophysin and postsynaptic density protein 95 expression in the hippocampi of rats with KA. Neferine pretreatment also decreased glial cell activation and proinflammatory cytokine (interleukin-1β, interleukin-6, tumor necrosis factor-α) expression in the hippocampi of rats with KA. In addition, NOD-like receptor 3 (NLRP3) inflammasome, caspase-1, and interleukin-18 expression levels were decreased in the hippocampi of seizure rats pretreated with neferine. These results indicated that neferine reduced seizure severity, exerted neuroprotective effects, and ameliorated neuroinflammation in the hippocampi of KA-treated rats, possibly by inhibiting NLRP3 inflammasome activation and decreasing inflammatory cytokine secretion. Our findings highlight the potential of neferine as a therapeutic option in the treatment of epilepsy.

Unraveling the Effects of GSK-3β Isoform Modulation against Limbic Seizures and in the 6 Hz Electrical Kindling Model for Epileptogenesis.

Two closely related glycogen synthase kinase-3 (GSK-3) isoforms have been identified in mammals: GSK-3α and GSK-3β. GSK-3β is the most prominent in the central nervous system and was previously shown to control neuronal excitability. We previously demonstrated that indirubin and its structural analogue and the nonselective GSK-3 inhibitor BIO-acetoxime exerted anticonvulsant effects in acute seizure models in zebrafish, mice, and rats. We here examined for the first time the anticonvulsant effect of TCS2002, a specific and potent inhibitor of GSK-3β, in two models for limbic seizures: the pilocarpine rat model for focal seizures and the acute 6 Hz corneal mouse model for refractory seizures. Next, we additionally used the 6 Hz kindling model to establish differences in seizure susceptibility and seizure progression in mice that either overexpress human GSK-3β (GSK-3β OE) or lack GSK-3β (GSK-3β-/-) in neurons. We demonstrate that TCS2002 exerts anticonvulsant actions against pilocarpine- and 6 Hz-evoked seizures. Compared to wild-type littermates, GSK-3β OE mice are less susceptible to seizures but are more rapidly kindled. Interestingly, compared to GSK-3β+/+ mice, neuronal GSK-3β-/- mice show increased susceptibility to 6 Hz-induced seizures. These contrasting observations suggest compensatory neurodevelopmental mechanisms that alter seizure susceptibility in GSK-3β OE and GSK-3β-/- mice. Although the pronounced anticonvulsant effects of selective and acute GSK-3β inhibition in the 6 Hz model identify GSK-3β as a potential drug target for pharmacoresistant seizures, our data on the sustained disruption of GSK-3β activity in the transgenic mice suggest a role for GSK-3 in kindling and warrants further research into the long-term effects of selective pharmacological GSK-3β inhibition.

NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats.

NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target NaV1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A-related epilepsy syndromes (SCN8A-RES), where gain-of-function (GoF) mutations lead to excess NaV1.6 sodium current, or other indications where NaV1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of NaV1.6 (IC500.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for NaV1.1, 134 X for NaV1.2, 276 X for NaV1.7, and >583 Xfor NaV1.3, NaV1.4, and NaV1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting NaV1.6 currents, including resurgent and persistent NaV1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where NaV1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of SCN8A-developmental epileptic encephalopathy (SCN8A-DEE) and adult focal-onset seizures.

Nonsteroidal Anti-inflammatory Drug Oxaprozin is Beneficial Against Seizure-induced Memory Impairment in an Experimental Model of Seizures in Rats: Impact On Oxidative Stress and Nrf2/HO-1 Signaling Pathway.

There is substantial evidence that anti-inflammatory agents and antioxidants have neuroprotective properties and may be useful in the treatment of neurodegenerative disorders. In this regard, the effects of oxaprozin (OXP) (a nonsteroidal anti-inflammatory drug) on the experimental model of seizure and memory impairment caused by seizures in rats were investigated in the present study. Seizures in male Wistar rats (200-250g, 8weeks) were induced by pentylenetetrazol (PTZ, 60mg/kg). The anticonvulsant effects of OXP (100, 200, and 400mg/kg, administered intraperitoneally) were evaluated in the seizure model. The effect on memory was assessed using the passive avoidance (PA) test. After behavioral tests, the animals underwent deep anesthesia and were euthanized painlessly. Animal serum was isolated for antioxidant assays (MDA and GPx). The animals' brains (hippocampus) were also isolated to gauge the relative expression of genes in the oxidative stress pathway (Nrf2/HO-1). Intraperitoneal injection of OXP decreased the mean score on the Racine scale compared to the PTZ group. Moreover, in the PA test, OXP caused a significant increase in retention latency (RL) and total time spent in the light compartment (TLC) compared to the PTZ group. Biochemical tests showed that OXP was able to significantly increase GPx serum levels and significantly reduce MDA serum levels compared to the PTZ group. Quantitative polymerase chain reaction (qPCR) results also revealed that OXP counteracted the negative effects of PTZ by significantly increasing the expression of the Nrf2 and Hmox1 genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal anti-inflammatory drug OXP in a model of memory impairment caused by seizures via inhibition of the oxidative stress pathway.

The Beneficial Effect of Probiotics Supplementation on Penicillin-Induced Focal Seizure in Rats.

The focal epilepsy is a chronic neurological brain disorder which affects millions of people in the world. There is emerging evidence that changes in the gut microbiota may have effects on epileptic seizures. In the present study, we examined the effect of probiotics on penicillin-induced focal seizure model in rats. Male Wistar Albino rats (n: 21) were randomly divided into three groups: control (no medication), penicillin and penicillin + probiotic. Probiotic VSL#3 (12.86 bn living bacteria/kg/day) was given by gavage for 30days. The seizures were induced by intracortical injection of penicillin G (500IU) into the cortex. An ECoG recordings were made for 180min after penicillin G application. The spike frequency and the amplitude were used to assess the severity of seizures. Tumor necrosis factor (TNF-α), nitric oxide (NO) and interleukin (IL-6) levels in the brain were studied biochemically. Our results indicated that probiotic supplementation improved focal seizures through increasing the latency (p < 0.001) and decreasing the spike frequency (p < 0.01) compared to the penicillin group. Penicillin-induced seizure in rats significantly enhanced TNF-α (p < 0.01), NO (p < 0.01) and IL-6 (p < 0.05) compared to the control. Probiotic supplementation significantly decreased IL-6 (p < 0.05), TNF-α (p < 0.01) and NO (p < 0.001) compared to the penicillin group. When the body weights were compared before and after the experiment, there was no difference between the control and penicillin groups, but it was observed that the body weight decreased after probiotic supplementation in the penicillin + probiotic group. Probiotic supplementation may have anti-seizure effect by reducing proinflammatory cytokine and NO levels in epileptic rat brain.

Involvement of nitric oxide pathway in the acute anticonvulsant effect of salmon calcitonin in rats

Epilepsy is a chronic neurological disease that is thought to affect up to 1% of the world’s population. Evidence suggests that salmon calcitonin (sCT) has positive effects on epileptic seizures and epileptogenesis. However, it remains unknown that whether nitric oxide (NO) pathway contributed to this antiepileptic effect of sCT. We have used the pentylenetetrazole (PTZ)-induced seizure rat model to identify the effect of sCT on seizure score, seizure-induced cognitive deficit, and the NO pathway in the brain. We found that sCT increases the first myoclonic jerk (FMJ), decreased Racine’s convulsion scale (RCS), and abates seizure-induced cognitive impairment. We further demonstrated that sCT attenuated the abnormal increase of NO in the brain. These results revealed that sCT exerts an antiepileptic effect by modulating the NO pathway in the brain.

Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats.

Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1β, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1β and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

Anticonvulsive Effects and Pharmacokinetic Profile of Cannabidiol (CBD) in the Pentylenetetrazol (PTZ) or N-Methyl-D-Aspartate (NMDA) Models of Seizures in Infantile Rats.

In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1–2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 h after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined.

Anticonvulsant activity of β-caryophyllene in association with pregabalin in a seizure model in rats

Epilepsy is a common chronic neurological disease. The hallmark of epilepsy is recurrent, unprovoked seizures. Unfortunately, drug resistance is frequent in patients with epilepsy, and therefore improved therapeutic strategies are needed. In the present study, we tested the effect of pregabalin in association with beta-caryophyllene, an FDA-approved food additive and naturally occurring agonist of cannabinoid receptor subtype 2 against pentylenetetrazol (PTZ)-induced seizures in rats. In addition, selected neurochemical parameters were evaluated in the cerebral cortex. Adult male Wistar rats received beta-caryophyllene (100 mg/kg), pregabalin (40 mg/kg) or their combination before PTZ (60 mg/kg). Appropriated vehicle-treated control groups were included for each treatment. Animals were monitored by video-EEG and the latency to myoclonic seizures, latency to tonic-clonic seizures, tonic-clonic seizure duration and overall seizure score were measured. Glial fibrillary acidic protein (GFAP) release, erythroid-related factor 2 (Nrf2), c-fos and 3-nitrotyrosine (3-NT) levels were evaluated in the frontal cortex. We found that beta-caryophyllene plus pregabalin increased the latency to PTZ-induced myoclonic and tonic-clonic seizures and decreased the tonic-clonic seizure duration and overall seizure score. Interestingly, lower levels of GFAP, c-Fos and 3-NT were observed in animals receiving beta-caryophyllene and pregabalin treatments. Our results suggest a possible synergic effect of beta-caryophyllene plus pregabalin against PTZ induced-seizures.

The bee venom active compound melittin protects against bicuculline-induced seizures and hippocampal astrocyte activation in rats

Epilepsy is a chronic neuropathology characterized by an abnormal hyperactivity of neurons that generate recurrent, spontaneous, paradoxical and synchronized nerve impulses, leading or not to seizures. This neurological disorder affects around 70 million individuals worldwide. Pharmacoresistance is observed in about 30% of the patients and long-term use of antiepileptics may induce serious side effects. Thus, there is an interest in the study of the therapeutic potential of bioactive substances isolated from natural products in the treatment of epilepsy. Arthropod venoms contain neurotoxins that have high affinity for molecular structures in the neural tissue such as receptors, transporters and ion channels both in glial and neuronal membranes. This study evaluated the potential neuroprotective effect of melittin (MEL), an active compound of bee venom, in the bicuculline-induced seizure model (BIC) in rats. Male Wistar rats (3 months, 250–300 g) were submitted to surgery for the implantation of a unilateral cannula in the lateral ventricle. After the recovery period, rats received a microinjection of saline solution or MEL (0.1 mg per animal). Firstly, rats were evaluated in the open field (20 min) and in the elevated plus maze (5 min) tests after received microinjection of saline or MEL. After, 30 min later animals received BIC (100 mg/ml) or saline, and their behaviors were analyzed for 20 min in the open field according to a seizure scale. At the end, rats were euthanized, brains collected and processed to glial fibrillary acidic protein (GFAP) immunohistochemistry evaluation. No changes were observed in MEL-treated rats in the open field and elevated plus maze. However, 90% of MEL-treated animals were protected against seizures induced by BIC. There was an increase in the latency for the onset of seizures, accompanied by a reduction of GFAP-immunoreactivity cells in the dentate gyrus and CA1. Thus, our study suggests that MEL has an anticonvulsant potential, and further studies are needed to elucidate the mechanisms involved in this action.

Modulatory Effect of Camellia Sinensis Extract on the Function of Hypothalamic-Pituitary-Testicular Axis in PTZ-Induced Epileptic Seizures in Rat Model

Modulatory Effect of Camellia Sinensis Extract on the Function of Hypothalamic-Pituitary-Testicular Axis in PTZ-Induced Epileptic Seizures in Rat Model

Assessment of Anticonvulsant Activities of Petroleum Ether Extract of Anacyclus pyrethrum Roots on Experimental Rats

Background: Epilepsy is one of the most common neurological conditions and a significant cause of morbidity and mortality.&#x0D; Objectives: The present study aimed to evaluate the anticonvulsant activity of the petroleum ether extract of the root of Anacyclus pyrethrum on Pentylenetetrazole (PTZ)-induced seizure model in Wistar rats.&#x0D; Methods: The composition of the petroleum ether extract of A. pyrethrum was first analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). Subsequently, the anticonvulsant activities of these extracts (70 and 140 mg/kg, intraperitoneal injection) were evaluated on PTZ-induced seizures in rats. The protection rate against induced seizures, latency, and duration of seizures, as well as neurological symptoms, were assessed and compared to those protected by phenobarbital.&#x0D; Results: GC/MS analysis of the petroleum ether extract showed that the main components were octadecadienoic acid, hexadecanoic acid, diheptylcyclopropene, naphthalene, and methyl stearate. The extract (70 and 140 mg/kg) was found to provide significant protection against PTZ-induced seizures. Moreover, compared to the negative control, the extracts increased the latency of induced-convulsion and reduced the duration of epilepsy. Interestingly, the extracts showed a reduction in neurological symptoms and the severity of seizures compared to the negative control. All of these outcomes manifested in a dose-dependent manner.&#x0D; Conclusion: The petroleum ether extract of A. pyrethrum may produce anticonvulsant effects by reducing the duration of seizures and delaying the latency of seizures induced by PTZ.