Role of berberine nanoformulation in epilepsy: A novel therapeutic strategy.

The aim of the present study was to develop a novel formulation of berberine (BBR) and demonstrate its anti-seizure effect in pentylenetetrazole (PTZ) induced kindling model in rats. Nanoparticles of BBR were formulated using Poly Lactic-co-Glycolic Acid (PLGA) as a polymer. Emulsification and solvent evaporation technique was used. PTZ induced kindling model in male wistar rat was used to demonstrate the anti-seizure effect of nano-BBR. The particle size obtained for the final formulation was 242.8 ± 67.35 nm with a PDI of 0.140 ± 0.01. PLGA encapsulated BBR nanoparticles showed the % encapsulation efficiency of 87.33 ± 2.42 % and % drug loading of 48.47 ± 1.34 %. In-vitro drug release data showed sustained release of nano-BBR as compared to BBR. Kinetic study data showed increase in AUC of nano-BBR (35,429.46 h.ng/ml) as compared to BBR (28,211.07 h.ng/ml). Cmax for nano- BBR (2251.90 ng/ml) is approximately 1.6 times greater than BBR (1505.50 ng/ml). Nano- BBR has shown the significant effect on the seizure score. The PLGA encapsulated berberine nanoparticles were prepared by an innovative simple method and offers excellent potential as an antiepileptic agent.

SEW2871 reduces seizures via the sphingosine 1-phosphate receptor-1 pathway in the pentylenetetrazol and phenobarbitone kindling model of drug-refractory epilepsy.

Epilepsy is a prevalent neurological disorder characterized by neuronal hypersynchronous discharge in the brain, leading to central nervous system (CNS) dysfunction. Despite the availability of anti-epileptic drugs (AEDs), resistance to AEDs is the greatest challenge in treating epilepsy. The role of sphingosine-1-phosphate-receptor 1 (S1PR1) in drug-resistant epilepsy is unexplored. This study investigated the effects of SEW2871, a potent S1PR1 agonist, on a phenobarbitone (PHB)-resistant pentylenetetrazol (PTZ)-kindled Wistar rat model. We measured the messenger ribonucleic acid (mRNA) expression of multi-drug resistance 1 (MDR1) and multi-drug resistance protein 5 (MRP5) as indicators for drug resistance. Rats received PHB + PTZ for 62 days to develop a drug-resistant epilepsy model. From day 48, SEW2871 (0.25, 0.5, 0.75 mg/kg, intraperitoneally [i.p.]) was administered for 14 days. Seizure scoring, behaviour, oxidative markers like reduced glutathione, catalase, superoxide dismutase, inflammatory markers like interleukin 1 beta tumour necrosis factor alpha, interferon gamma and mRNA expression (MDR1 and MRP5) were assessed, and histopathological assessments were conducted. SEW2871 demonstrated dose-dependent improvements in seizure scoring and neurobehavioral parameters with a reduction in oxidative and inflammation-induced neuronal damage. The S1PR1 agonist also downregulated MDR1 and MRP5 gene expression and significantly decreased the number of dark-stained pyknotic nuclei and increased cell density with neuronal rearrangement in the rat brain hippocampus. These findings suggest that SEW2871 might ameliorate epileptic symptoms by modulating drug resistance through downregulation of MDR1 and MRP5 gene expression.

Pentylenetetrazole Induced Kindling Model of Refractory Epilepsy: A Proof-of-concept Study to Explore Dose and Time Range of Phenobarbital in Rats.

Introduction: Drug-resistant epilepsy is an unmet medical condition that impacts 30% of epileptic patients. Numerous antiseizure drugs have already been developed but they provide only symptomatic relief and do not target the underlying pathogenesis. Preclinical models provide opportunities to gain insights into obscure mechanisms of drug-resistant epilepsy. Current animal models possess lacunae that need rectification and validation to discover novel antiepileptic drugs. The present study aims to validate 3 different doses of phenobarbital at 2 different periods. Methods: Pentylenetetrazole was given at a sub-convulsive dose (30 mg/kg/day/intraperitoneal [IP]) for 28 days to develop kindling in male Wistar rats. Further, kindled rats were divided into the following four groups: Pentylenetetrazole control, pentylenetetrazole and phenobarbital (20 mg/kg), pentylenetetrazole and phenobarbital 40 mg/kg, and pentylenetetrazole and phenobarbital (60 mg/kg). They were assessed on days 14 and 28 post-kindling. Seizure scoring, oxidative stress, phenobarbital plasma levels, and histopathology of hippocampal neurons were analyzed. Results: The results showed that the combination of pentylenetetrazole and phenobarbital (40 and 60 mg/kg) remarkably decreased seizure score, elucidated higher antioxidant effect, and prevented neuronal injury on day 14, whereas increased seizure score, oxidative stress, and neuronal death was observed with chronic administration of pentylenetetrazole and phenobarbital in kindled rats at day 28. Moreover, phenobarbital levels in blood were significantly increased at day 28 of phenobarbital treatment compared to day 14. Conclusion: The adapted protocol with phenobarbital 40 mg/kg dose could be of great potential in screening antiseizure drugs in refractory epilepsy.