Alpha-lipoic acid (LA) is a universal antioxidant that has gained tremendous attention for its benefits in neurological disorders. However, its therapeutic utilization is often hindered by low aqueous solubility and heat sensitivity, further challenging its delivery. Hence, to overcome these limitations, we have developed a novel delivery system using electrospun nanofiber proliposomes for on-demand LA delivery, aimed at improving its anti-epileptic efficacy. The amphiphilic nanofibers were made from polyvinylpyrrolidone K90 (PVP K90), phosphatidylcholine (PC), and beta-sitosterol exhibited uniform morphology and facilitated quick self-assembly into LA-loaded liposomes upon hydration. The nanofibers derived liposomes exhibited similar to 143 nm in size with a low polydispersity index and demonstrated excellent physicochemical stability up to one month. The solid-state characterisation via FTIR, DSC, and XRD demonstrated the amorphization and incoporation of LA into the nanofibers. The in vitro release studies demonstrated biphasic release of LA from the liposomal nanofibrous matrix. Biocompatibility tests of developed formulations on zebrafish embryos demonstrated safety at concentrations up to 40 mu M (equivalent to LA). Importantly, LA-loaded liposomal nanofibers significantly mitigated seizure-like behaviours, delayed seizure onset, and downregulated the neuronal activation marker c-Fos in a pentylenetetrazol (PTZ)-induced zebrafish seizure model. These findings highlight the potential of amphiphilic electrospun nanofibers-based liposomes as a stable, biocompatible, and effective delivery system for LA, representing a promising therapeutic approach for epilepsy.

Presently there has been a growing interest in the development of dietary-based interventions as alternative therapies to combat chronic neurological conditions like epilepsy. Medium-chain triglycerides (MCT) are composed of three fatty acids attached to a glycerol backbone and have shown several beneficial effects in various neurological diseases. The present study investigated MCT supplementation's impact on seizure severity and associated neurobehavioral comorbidities in a pentylenetetrazole (PTZ) mouse kindling model. Mice were administered 35 mg/kg (i.p.) of PTZ every other day for kindling induction. The kindled mice were then subjected to MCT supplementation for over 25 days with seizure scoring at every 5th day following PTZ exposure. Behavioral analysis was initiated at the end of 25 days of the MCT supplementation. After that, lipid peroxidation assay, and, gene and protein expression studies were performed in the isolated hippocampus. MCT significantly decreased seizure severity scores compared to control. The treatment reduced immobility duration in the forced swim and tail suspension tests, indicating a reversal of seizures-associated depression-like behavior. A significant reduction in the percentage of spontaneous alternation was observed in the kindled control group in the T-maze test, which remained unchanged following MCT supplementation in the treated group. Furthermore, no change was observed in the locomotion and anxiety index of the kindled mice supplemented with MCT compared to the control group. In addition, the supplementation attenuated the altered hippocampal lipid peroxidation, and mRNA and protein levels of mTOR and Gsk-3β. The study concluded that MCT supplementation suppresses epileptic seizures and associated depression-like behavior in kindled mice via interacting mTOR and Gsk-3β signaling.

Epilepsy is a serious global health issue, with nearly one-third of patients suffering from its drug-resistant form. There is currently a strong focus on developing non-pharmacological therapies for epilepsy management. Studies have shown that certain essential fatty acids help to maintain the integrity of the blood-brain barrier (BBB) and prevent onset of epilepsy. Polyunsaturated fatty acids, particularly omega-3 fatty acids, alter lipid metabolism and modify neuronal functions in the brain, making them a promising dietary intervention for managing epilepsy. The current study examined the effectiveness of Linum usitatissimum L. seed oil (flaxseed oil) exposure during the early life stages of zebrafish in pentylenetetrazole (PTZ)-induced seizures model. The lethal concentration 50 % of the oil was found to be 426.09 mu g/mL. The oil incubation decreased PTZ-mediated hyperactive responses and increased the latency to clonus-like seizures. Furthermore, the expression of a cellular protooncogene (c-fos) was reduced following the oil incubation. Whole-mount in-situ protein expression studies showed downregulated c-Fos in the cephalic region of the oil-treated larvae subjected to PTZ. The oil incubation increased major facilitator superfamily domain containing 2A (mfsd2aa) expression, thus suggesting a maintained BBB. Furthermore, the expression of brain-derived neurotrophic factor (bdnf), neurotrophic receptor tyrosine kinase 2 (ntrk2b), and gamma-aminobutyric acid (GABAA) subunits (gabrg2 and gabrd) was found to be increased in the oil-treated group. The study provided initial evidence for the potential of flaxseed oil as a non pharmacological intervention for the management of childhood epilepsy, however, more safety and efficacy studies are required in higher mammals for its further development.

The use of zebrafish (Danio rerio) larva as an experimental model has gained a lot of interest in epilepsy research due to its multiple advantages over mammalian models. The present study investigated the time-dependent expression of c-fos, an immediate early gene, and a marker of neuronal activation, following pentylenetetrazole (PTZ)-induced seizures in zebrafish larvae at 7-day post-fertilization . The larvae were exposed to 8 mM PTZ for a 15-min period, transferred to fish system water, and processed for c-Fos expression analysis at 15, 30, 45, 60, and 90 min of the start of the experiment. c-fos mRNA and c-Fos protein levels were quantified, and Pearson correlation analysis was conducted to assess their relationship. PTZ exposure induced seizure-like behavior and resulted in a dynamic temporal expression of c-Fos, with both mRNA and protein achieving peak levels at 45 min and declining by 90 min. This approach applied a fixed exposure duration and defined post-exposure time points, which allowed a more accurate temporal profiling. The observed peak expression at 45 min suggested an optimal window for evaluating c-Fos expression in the PTZ-induced seizures model of zebrafish larva. These findings provided a valuable reference for selecting experimental endpoints in zebrafish larva seizure studies and enhanced the reliability of c-Fos as a marker of neuronal activation.

A high-fat diet with appropriate protein and low carbohydrate content, widely known as the ketogenic diet (KD), is considered as an effective non-pharmacotherapeutic treatment option for certain types of epilepsies. Several preclinical and clinical studies have been carried out to elucidate its mechanism of antiepileptic action. Ketone bodies produced after KD's breakdown interact with cellular excito-inhibitory processes and inhibit abnormal neuronal firing. The generated ketone bodies decrease glutamate release by inhibiting the vesicular glutamate transporter 1 and alter the transmembrane potential by hyperpolarization. Apart from their effect on the well-known pathogenic mechanisms of epilepsy, some recent studies have shown the interaction of KD metabolites with novel neuronal targets, particularly adenosine receptors, adenosine triphosphate-sensitive potassium channel, mammalian target of rapamycin, histone deacetylase, hydroxycarboxylic acid receptors, and the NLR family pyrin domain containing 3 inflammasomes to suppress seizures. The role of KD in augmenting gut microbiota as a potential mechanism for epileptic seizure suppression has been established. Furthermore, some recent findings also support the beneficial effect of KD against epilepsy-associated comorbidities. Despite several advantages of the KD in epilepsy management, its use is also associated with a wide range of side effects. Hypoglycemia, excessive ketosis, acidosis, renal stones, cardiomyopathies, and other metabolic disturbances are the primary adverse effects observed with the use of KD. However, in some recent studies, modified KD has been tested with lesser side effects and better tolerability. The present review discusses the molecular mechanism of KD and its role in managing epilepsy and its associated comorbidities.

Schizophrenia is a neurological disorder that alters the behavior and affects the quality of life of a patient. It is characterized by hallucinations, disorganized behavior, cognitive dysfunction, hyperlocomotion, and loss of the reward system. Schizophrenia constitutes three symptoms' domains, viz. positive, negative and cognitive. Typical and atypical antipsychotics do not fully resolve all the symptoms' domains thus paving the way to the genesis of the glutamatergic hypothesis, i.e. N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Positive modulation of NMDA receptors by enhancing co-agonist, glycine effect is proposed to produce a therapeutic effect in schizophrenia. Hence, sarcosine (N-methyl glycine), natural amino acid, and a glycine transporter inhibitor (GlyT-1) which also acts on NMDA receptors were used in the present study. The present study unravels the role of sarcosine in the attenuation of ketamine-induced three symptom domains in a rat model through modulation of oxidative stress, mitochondrial dysfunction, and neuroinflammatory pathways. The animal model of schizophrenia was established by injecting ketamine intraperitoneal (ip) at a 30 mg/kg dose for 10 consecutive days, after which sarcosine (300, 600 mg/kg, ip) as a treatment was given for 7 days followed by behavioral, biochemical, molecular, and histopathological analysis. It was revealed that sarcosine reversed ketamine-induced behavioral impairments. Moreover, sarcosine ameliorated oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation and showed protective effects in histopathological examination by hematoxylin and eosin staining. Hence, conclusively, sarcosine was regarded to attenuate the behavioural symptoms of schizophrenia by alleviating oxidative stress, neuroinflammation, and mitochondrial dysfunction established by the ketamine.

The coronavirus disease 19 (COVID-19) outbreak caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) had turned out to be highly pathogenic and transmittable. Researchers throughout the globe are still struggling to understand this strain's aggressiveness in search of putative therapies for its control. Crosstalk between oxidative stress and systemic inflammation seems to support the progression of the infection. Glycogen synthase kinase-3 (Gsk-3) is a conserved serine/threonine kinase that mainly participates in cell proliferation, development, stress, and inflammation in humans. Nucleocapsid protein of SARS-CoV-2 is an important structural protein responsible for viral replication and interferes with the host defence mechanism by the help of Gsk-3 protein. The viral infected cells show activated Gsk-3 protein that degrades the Nuclear factor erythroid 2-related factor (Nrf2) protein, resulting in excessive oxidative stress. Activated Gsk-3 also modulates CREB-DNA activity, phosphorylates NF-​κB, and degrades β-catenin, thus provokes systemic inflammation. Interaction between these two pathophysiological events, oxidative stress, and inflammation enhance mucous secretion, coagulation cascade, and hypoxia, which ultimately leads to multiple organs failure, resulting in the death of the infected patient. The present review aims to highlight the pathogenic role of Gsk-3 in viral replication, initiation of oxidative stress, and inflammation during SARS-CoV-2 infection. The review also summarizes the potential Gsk-3 pathway modulators as putative therapeutic interventions in combating the COVID-19 pandemic.