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Frontiers in Endocrinology 2020Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been...
Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline- pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3beta-methylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebo-controlled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.
Topics: Allosteric Regulation; Animals; Anticonvulsants; Epilepsy; GABA-A Receptor Agonists; Humans; Neurosteroids; Seizures; Treatment Outcome
PubMed: 33117274
DOI: 10.3389/fendo.2020.541802 -
Antioxidants (Basel, Switzerland) Jul 2023Epilepsy is a neurological disorder characterized by epileptic seizures resulting from neuronal hyperexcitability, which may be related to failures in Na,K-ATPase... (Review)
Review
Antioxidant Therapy Reduces Oxidative Stress, Restores Na,K-ATPase Function and Induces Neuroprotection in Rodent Models of Seizure and Epilepsy: A Systematic Review and Meta-Analysis.
Epilepsy is a neurological disorder characterized by epileptic seizures resulting from neuronal hyperexcitability, which may be related to failures in Na,K-ATPase activity and oxidative stress participation. We conducted this study to investigate the impact of antioxidant therapy on oxidative stress, Na,K-ATPase activity, seizure factors, and mortality in rodent seizure/epilepsy models induced by pentylenetetrazol (PTZ), pilocarpine (PILO), and kainic acid (KA). After screening 561 records in the MEDLINE, EMBASE, Web of Science, Science Direct, and Scopus databases, 22 were included in the systematic review following the PRISMA guidelines. The meta-analysis included 14 studies and showed that in epileptic animals there was an increase in the oxidizing agents nitric oxide (NO) and malondialdehyde (MDA), with a reduction in endogenous antioxidants reduced glutathione (GSH) and superoxide dismutase (SO). The Na,K-ATPase activity was reduced in all areas evaluated. Antioxidant therapy reversed all of these parameters altered by seizure or epilepsy induction. In addition, there was a percentage decrease in the number of seizures and mortality, and a meta-analysis showed a longer seizure latency in animals using antioxidant therapy. Thus, this study suggests that the use of antioxidants promotes neuroprotective effects and mitigates the effects of epilepsy. The protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO) CRD42022356960.
PubMed: 37507936
DOI: 10.3390/antiox12071397 -
Frontiers in Neurology 2021Clinical and pre-clinical studies indicate a reduction in seizure frequency as well as a decrease in susceptibility to subsequently evoked seizures after physical...
Clinical and pre-clinical studies indicate a reduction in seizure frequency as well as a decrease in susceptibility to subsequently evoked seizures after physical exercise programs. In contrast to the influence of exercise after epilepsy previously established, various studies have been conducted attempting to investigate whether physical activity reduces brain susceptibility to seizures or prevents epilepsy. We report a systematic review and meta-analysis of different animal models that addressed the impact of previous physical exercise programs to reduce seizure susceptibility. We included animal model (rats and mice) studies before brain insult that reported physical exercise programs compared with other interventions (sham, control, or naïve). We excluded studies that investigated animal models after brain insult, associated with supplement nutrition or drugs, that did not address epilepsy or seizure susceptibility, studies, studies, studies in humans, or studies. Electronic searches were performed in the MEDLINE (PubMed), Web of Science (WOS), Scopus, PsycINFO, Scientific Electronic Library Online (SciELO) databases, and gray literature, without restrictions to the year or language of publication. We used SYRCLE's risk of bias tool and CAMARADES checklist for study quality. We performed a synthesis of results for different types of exercise and susceptibility to seizures by random-effects meta-analysis. Fifteen studies were included in the final analysis (543 animals), 13 of them used male animals, and Wistar rats were the most commonly studied species used in the studies (355 animals). The chemoconvulsants used in the selected studies were pentylenetetrazol, penicillin, kainic acid, pilocarpine, and homocysteine. We assessed the impact of study design characteristics and the reporting of mitigations to reduce the risk of bias. We calculated a standardized mean difference effect size for each comparison and performed a random-effects meta-analysis. The meta-analysis included behavioral analysis (latency to seizure onset, = 6 and intensity of motor signals, = 3) and electrophysiological analysis (spikes/min, = 4, and amplitude, = 6). The overall effect size observed in physical exercise compared to controls for latency to seizure onset was -130.98 [95% CI: -203.47, -58.49] (seconds) and the intensity of motor signals was -0.40 [95% CI: -1.19, 0.40] (on a scale from 0 to 5). The largest effects were observed in electrophysiological analysis for spikes/min with -26.96 [95% CI: -39.56, -14.36], and for spike amplitude (μV) with -282.64 [95% CI: -466.81, -98.47]. . A higher number of animal models should be employed for analyzing the influence of exerciseon seizure susceptibility. The high heterogeneity in our meta-analysis is attributable to various factors, including the number of animals used in each study and the limited number of similar studies. . Studies selected in this systematic review and meta-analysis suggest that previous physical exercise programs can reduce some of the main features related to seizure susceptibility [latency seizure onset, spikes/min, and spike amplitude (μV)] induced by the administration of different chemoconvulsants. PROSPERO, identifier CRD42021251949; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=251949.
PubMed: 34956052
DOI: 10.3389/fneur.2021.771123