BACKGROUND: Status epilepticus is a common and potentially life-threatening neurological emergency with a high risk for cognitive and neurobiological impairment. Our aim was to evaluate the neuroprotective effects of centrally administered irisin and acute exhausting exercise against oxidative brain injury and memory dysfunction due to a pentylenetetrazole (PTZ)-induced single seizure. Male Sprague Dawley rats with intracerebroventricular (icv) cannulas were randomly divided into intraperitoneally (ip) saline-injected control and PTZ-injected (45 mg/kg) seizure groups. Both the control and PTZ groups were then treated with irisin (7.5 µg/kg, 2 µl, icv), saline (2 µl, icv) or were forced to an acute bout of strenuous exercise before the ip injection of saline (control) or PTZ. Seizures were evaluated using the Racine score. To evaluate memory performance, a passive avoidance test was performed before and after PTZ injection. Following euthanasia at the 24th hour of seizure induction, brain tissues were removed for histopathological examination and for evaluating oxidative damage, antioxidant capacity, and neurotransmitter levels.
RESULTS: Glutamate/GABA imbalance observed in PTZ rats was corrected by irisin administration (p < 0.001/p < 0.01), while irisin prevented the generation of reactive oxygen species and lipid peroxidation (p < 0.05 - 0.001) and replenished the antioxidant catalase and glutathione levels (p < 0.01-0.01) in the cerebral tissue, and reduced the histologically evident neuronal injury due to a single seizure (p < 0.05 - 0.01). Irisin also delayed the onset of seizures (p < 0.05) and improved memory dysfunction (p < 0.05), but did not affect the severity of seizures. The acute exhaustive swimming exercise completed before PTZ-seizure depressed glutamate level (p < 0.001), maintained the oxidant/antioxidant balance, alleviated neuronal injury (p < 0.05 - 0.01) and upregulated cerebral BDNF expression (p < 0.05).
CONCLUSIONS: In conclusion, acute high-intensity exercise or exogenously administered irisin provides neuroprotection by maintaining the balance of excitatory/inhibitory neurotransmitters and oxidant/antioxidant systems.

Pentylenetetrazole- (PTZ)-induced kindling is a broadly used experimental model to evaluate the impact of antiseizure drugs and their novel combination on seizure progression. The current study aimed to evaluate the anti-kindling effects of ivermectin (IVM) and rufinamide (RUFI) alone and their combination with vitamin E. The mice were administered 11 injections of PTZ (40 mg/kg) followed by assessment for anxiety-like behavior and cognitive abilities in a series of behavior tests with subsequent brain isolation for biochemical and histopathological evaluation. The outcomes showed a marked protection by IVM + RUFI (P<0.001) from kindling progression, anxiety-like behavior and cognitive deficit. However, additional supplementation with vitamin E worked superior to duo therapy as these mice were noted to be most fearless to visiting open, illuminated and elevated zones of open field, light/dark and elevated-plus maze (P<0.0001). Further, they showed marked remembrance of the familiar milieu in y-maze (P<0.01) and novel objection recognition (P<0.05) tests. Additionally, their recollection of aversive stimuli in passive avoidance and spatial memory in Morris water maze were evident (P<0.0001), in comparison to kindled mice. The IVM + RUFI duo therapy and its co-administration with vitamin E prevented kindling-triggered oxidative stress in brains and neuronal damage in hippocampus. We conclude that the benefits of the co-administration of vitamin E might be the results of antioxidant and anti-inflammatory effects of vitamin E which might be potentiating the antiseizure effects of RUFI and GABA-A modulating potential by ivermectin.

GABA modulators such as phenobarbital (PB) and sodium channel blockers such as phenytoin (PHT) have long been the mainstay of pharmacotherapy for the epilepsies. In the context of neonatal seizures, both PB and PHT display incomplete clinical efficacy. Moreover, in animal models, neonatal exposure to these medications result in neurodegeneration raising concerns about safety. Cenobamate, a more recently approved medication, displays unique pharmacology as it is both a positive allosteric modulator of GABA-A receptors, and a voltage-gated sodium channel blocker. While cenobamate is approved for adult use, its efficacy and safety profile against neonatal seizures is poorly understood. To address this gap, we assessed the efficacy and safety of cenobamate in immature rodents. Postnatal day (P)7 rat pups were pretreated with cenobamate and challenged with the chemoconvulsant pentylenetetrazole (PTZ) to screen for anti-seizure effects. In a separate experiment, P7 rats were treated with cenobamate, and brains were processed to assess induction of cell death. Cenobamate displays dose-dependent anti-seizure efficacy in neonatal rats. Unlike PHB and PHT, it does not induce neurotoxicity in P7 rats. Thus, cenobamate may be effective at treating neonatal seizures while avoiding unwanted neurotoxic side effects such as cell death.

Currently, pharmacotherapy provides successful seizure control in around 70% of patients with epilepsy; however, around 30% of cases are still resistant to available treatment. Therefore, effective anti-epileptic therapy still remains a challenge. In our study, we utilized two mouse lines selected for low (LA) and high (HA) endogenous opioid system activity to investigate the relationship between down- or upregulation of the opioid system and susceptibility to seizures. Pentylenetetrazole (PTZ) is a compound commonly used for kindling of generalized tonic-clonic convulsions in animal models. Our experiments revealed that in the LA mice, PTZ produced seizures of greater intensity and shorter latency than in HA mice. This observation suggests that proper opioid system tone is crucial for preventing the onset of generalized tonic-clonic seizures. Moreover, a combination of an opioid receptor antagonist-naloxone-and a GABA receptor agonist-diazepam (DZP)-facilitates a significant DZP-sparing effect. This is particularly important for the pharmacotherapy of neurological patients, since benzodiazepines display high addiction risk. In conclusion, our study shows a meaningful, protective role of the endogenous opioid system in the prevention of epileptic seizures and that disturbances in that balance may facilitate seizure occurrence.

BACKGROUND: Epilepsy is a paroxysmal abnormal hypersynchronous electrical discharge characterized by recurrent seizures. It affects more than 50 million people worldwide. Stress is the leading cause of neurodegeneration and can produce seizures that may lead to or aggravate epilepsy. Inflammation plays a vital role in epilepsy by modulating oxidative stress, and levels of neuroinflammatory cytokines including NF-κB, TNF-α, and IL-1β.
METHODS: Stress-induced changes in behavior were evaluated in mice by employing behavioral assessment tests such as an elevated plus maze, light-dark box, open field test, tail suspension test, Y-maze, novel object recognition test, and Morris water maze in pentylenetetrazole (PTZ) kindled mice. Behavioral changes in all these paradigms including seizure score, latency, and frequency showed an increase in symptoms in PTZ (35 mg/kg) induced seizures in stressed mice (RS-PTZ) as compared to PTZ, Stress, and normal animals.
RESULTS: The Enzyme-linked immunosorbent assay (ELISA) results confirmed increased in serum cortisol levels. Histological examinations showed neurodegenerative changes in the hippocampus and cortex regions. The spectrophotometric evaluation showed an increase in oxidative stress by decreasing antioxidant production i.e. reduced glutathione, glutathione -s- transferase, and catalase (CAT), and increasing oxidant levels such as maloaldehyde and nitric oxide. Immunohistochemistry results showed increased expression of NF-κB, TNF-α, and IL-1β in the cortex and hippocampus of mice brains.
CONCLUSIONS: Results from the study conclude that stress increases the likelihood of eliciting an epileptic attack by increasing the level of reactive oxygen species and neuroinflammation.

UNASSIGNED: Sumatriptan protects the brain from damage and enhance the anti-seizure effect of morphine. There is evidence that nitric oxide (NO) may mediate these effects of both drugs. In the present study, we investigated the effects of sumatriptan (0.1-20 mg/kg, intraperitoneal [i.p.]) and morphine (0.1-20 mg/kg, i.p.) alone or in combination on seizure thresholds in an in vivo model of seizure in mice. Using various NO synthase inhibitors as well as the NO precursor, we assessed possible involvement of NO signaling in these effects.
UNASSIGNED: Clonic seizures were induced in male Naval Medical Research Institute mice by intravenous administration of pentylenetetrazol (PTZ).
UNASSIGNED: Acute sumatriptan administration exerted anti-convulsive effects at 0.5 (p<0.01) and 1 mg/kg (p<0.05), but pro-convulsive effects at 20 mg/kg (p<0.05). Morphine had anti-convulsive effects at 0.5 (p<0.05) and 1 mg/kg (p<0.001), but exerted pro-convulsive effect at 20 mg/kg (p<0.05). Combination treatment with sub-effective doses of sumatriptan (0.1 mg/kg) and morphine (0.1 mg/kg) significantly (p<0.05) exerted an anti-convulsive effect. Co-administration of the NO precursor L-arginine (60 mg/kg) with sub-effective doses of sumatriptan and morphine significantly (p<0.05) increased seizure threshold compared with sumatriptan alone, but not sumatriptan+morphine group. While concomitant administration of either the non-selective NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (5 mg/kg) or the selective inducible NOS inhibitor aminoguanidine (50 mg/kg) with combined sub-effective doses of morphine and sumatriptan produced significant anticonvulsive effects, concomitant administration with the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg) inhibited this effect.
UNASSIGNED: Our data suggest a possible role for the NO signaling in the anticonvulsive effects of combined sumatriptan and morphine on the PTZ-induced clonic seizures in mice.

UNASSIGNED: Epilepsy is a common and heterogenous neurological disorder characterized by recurrent spontaneous seizures. Animal models like rats play a crucial role in finding of mechanism of epilepsy in different brain regions. i.e., cerebral cortex, cerebellum, hippocampus, and pons medulla. Glutamate is an important excitatory neurotransmitter in the central nervous system and also glutamate plays a vital role in neuronal development and memory. The process of neuronal death evolved by glutamate receptor activation, has been hypothesized in both acute and chronic degenerative disorders including epilepsy. Considering the multifactorial neurochemical and neurophysiological malfunctions consequent to epileptic seizures, a few antiepileptic drugs are designed, to mitigate the debilitating aspects of epilepsy.
UNASSIGNED: Rat model, pentylenetetrazole (PTZ), an anticonvulsant drug, was selected for the present study. Induction of epilepsy/convulsions was induced by an intraperitoneal injection of PTZ (60 mg/kg body weight) in saline. Biochemical assays performed through spectrophotometer.
UNASSIGNED: Glutamine and Glutamine synthetase levels were decreased in the epileptic rats brain regions i.e., hippocampus, cerebellum, cerebral cortex, and pons medulla; glutamate dehydrogenase and glutaminase levels were increased in all the regions of epilepsy induced rats. Highest values are recorded in hippocampus when compared to other brain regions.
UNASSIGNED: PTZ suppresses the function of Glutamine and Glutamine synthetase activities in selected brain regions of rat and enhances the activities of the glutaminase and glutamate dehydrogenase when compared to control rats.

The Ocimum species present active compounds with the potential to develop drugs for treating chronic disease conditions, such as anxiety and seizures. The present study aims to investigate the anticonvulsant and anxiolytic-like effect of the essential oil from O. basilicum Linn (OEFOb) leaves and its major constituent estragole (ES) in vivo on adult zebrafish (aZF) and in silico. The aZF were treated with OEFOb or ES or vehicle and submitted to the tests of toxicity, open-field, anxiety, and convulsion and validated the interactions of the estragole on the involvement of GABAergic and serotonergic receptors by molecular docking assay. The results showed that the oral administration of OEFOb and ES did not have a toxic effect on the aZF and showed anxiolytic-like effects with the involvement of GABAA, 5-HT1, 5-HT2A/2C and 5-HT3A/3B as well on anxiety induced by alcohol withdrawal. The OEFOb and ES showed anticonvulsant potential attenuating the seizures induced by pentylenetetrazole (PTZ) by modulation of the GABAA system. Both anxiolytic and anticonvulsant effects were corroborated by the potential of the interaction of ES by in silico assay. These study samples demonstrate the pharmacological evidence and potential for using these compounds to develop new anxiolytic and anticonvulsant drugs.

Glutamatergic neurotransmission and oxidative stress are involved in the pathophysiology of seizures. Some anticonvulsants exert their effects through modulation of these pathways. Trigonelline (TRG) has been shown to possess various pharmacological effects like neuroprotection. Therefore, this study was performed to determine TRG\'s anticonvulsant effects, focusing on its potential effects on N-methyl-D-aspartate (NMDA) receptors, a type of glutamate receptor, and oxidative stress state in the prefrontal cortex (PFC) in PTZ-induced seizure in mice. Seventy-two male mice were randomly divided into nine groups. The groups included mice that received normal saline, TRG at doses of 10, 50, and 100 mg/kg, diazepam, NMDA (an agonist), ketamine (an antagonist), the effective dose of TRG with NMDA, as well as sub-effective dose of TRG with ketamine, respectively. All agents were administrated intraperitoneally 60 min before induction of seizures by PTZ. Latency to seizure, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels in serum and PFC were measured. Furthermore, the gene expression of NR2A and NR2B, subunits of NMDA receptors, was measured in the PFC. TRG administration increased the latency to seizure onset and enhanced TAC while reducing MDA levels in both the PFC and serum. TRG also decreased the gene expression of NR2B in the PFC. Unexpectedly, the findings revealed that the concurrent administration of ketamine amplified, whereas NMDA mitigated, the impact of TRG on latency to seizure. Furthermore, NMDA diminished the positive effects of TRG on antioxidant capacity and oxidative stress, while ketamine amplified these beneficial effects, indicating a complex interaction between TRG and NMDA receptor modulation. In the gene expression of NMDA receptors, results showed that ketamine significantly decreased the gene expression of NR2B when co-administrated with a sub-effective dose of TRG. It was found that, at least partially, the anticonvulsant effect of TRG in PTZ-induced seizures in male mice was mediated by the attenuation of glutamatergic neurotransmission as well as the reduction of oxidative stress.

Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is widely used for crop protection in agriculture. In this study, we identified a novel function of VA as a potential anti-seizure medication in a zebrafish epilepsy model. Electroencephalogram (EEG) analysis demonstrated that VA reduced pentylenetetrazol (PTZ)-induced seizures in the brains of larval and adult zebrafish. Moreover, VA reduced PTZ-induced irregular movement in a behavioral assessment of adult zebrafish. The developmental toxicity test showed no observable anatomical alteration when the zebrafish larvae were treated with VA up to 10 µM within the effective range. The median lethal dose of VA in adult zebrafish was > 14,000 mg/kg. These results imply that VA does not demonstrate observable toxicity in zebrafish at concentrations effective for generating anti-seizure activity in the EEG and alleviating abnormal behavior in the PTZ-induced epileptic model. Furthermore, the effectiveness of VA was comparable to that of valproic acid. These results indicate that VA may have a potentially safer anti-seizure profile than valproic acid, thus offering promising prospects for its application in agriculture and medicine.