Human In Vitro Models of Epilepsy Using Embryonic and Induced Pluripotent Stem Cells.

The challenges in making animal models of complex human epilepsy phenotypes with varied aetiology highlights the need to develop alternative disease models that can address the limitations of animal models by effectively recapitulating human pathophysiology. The advances in stem cell technology provide an opportunity to use human iPSCs to make disease-in-a-dish models. The focus of this review is to report the current information and progress in the generation of epileptic patient-specific iPSCs lines, isogenic control cell lines, and neuronal models. These in vitro models can be used to study the underlying pathological mechanisms of epilepsies, anti-seizure medication resistance, and can also be used for drug testing and drug screening with their isogenic control cell lines.

Alpha-lipoic acid analogues in the regulation of redox balance in epilepsy: A molecular docking and simulation study.

OBJECTIVE: Oxidative stress is one of the pathophysiological mechanisms implicated in drug-resistant epilepsy. Recurrent seizures and prolonged treatment with anti-seizure medicines (ASMs) can produce reactive oxygen species (ROS) resulting in neuronal cell damage, cell toxicity, and cell death. This damage may contribute to the loss of efficacy of anti-seizure medicines. Add-on therapy with antioxidants, neuroimmunophilins, and polyphenols may thus be beneficial in drug-resistant epilepsy. In vitro and in vivo studies have shown a significant improvement in drug efficacy and seizure suppression using co-treatment of anti-seizure medication with naturally available antioxidants including alpha-lipoic acid (α-lipoic acid) from walnut; however, the underlying mechanisms of action remain to be fully understood. METHODS: We undertook molecular docking and molecular dynamics simulations to determine whether alpha-lipoic acid and related analogues interacted with the human manganese superoxide dismutase (MnSOD) protein, a member of the oxidative metabolic pathway. The 3D structure of the compounds and the protein were retrieved from protein and chemical databases, binding sites were identified and ligand-protein interactions were performed. RESULTS: Alpha-lipoic acid and various analogues docked within a human MnSOD binding region. Docking results were validated by molecular dynamic simulation. The CMX-2043 analogue showed strong binding with MnSOD compared to alpha-lipoic acid and other analogues. SIGNIFICANCE: Our findings provide new insights into additional mechanisms of action, which may in part, account for the antioxidant properties associated with alpha-lipoic acid and related analogues. The results support further in vitro and in vivo evaluation of these compounds to better understand their potential as add-on therapy for ASM treatment in epilepsy.

Sex Differences in the Risk of Cutaneous Adverse Drug Reactions Induced by Antiseizure Medications: A Systematic Review and Meta-analysis.

BACKGROUND: Cutaneous adverse drug reactions (cADRs) are one of the most common, severe, and life-threatening types of adverse reactions following treatment with antiseizure medications (ASMs). Some studies have reported a higher incidence of ASM-induced cADRs in females than in males. OBJECTIVE: This study sought to perform a systematic review, meta-analysis, and meta-regression to compare the ASM cADR risks between females and males. METHODS: We searched the literature using three databases (EMBASE, PubMed, and Web of Science) between October 1998 and November 2018, later updated to October 2019. Studies were included in the meta-analysis if they met the following criteria: (1) observational studies that estimated the incidence of cADRs related to ASMs; (2) provided the risk or odds ratio (OR) for cADRs among female and male patients exposed to ASMs; and (3) provided information on patients' characteristics. We assessed the impact of study characteristics, publication bias, and measures to reduce bias, and performed a DerSimonian and Laird random effects meta-analysis. RESULTS: We included 28 studies in this review. Of these, seven studies were eligible for inclusion in the meta-analysis, involving a total of 223,209 patients. Overall, females were more likely to develop cADRs to ASMs than males (OR 1.76, 95% confidence interval [CI] 1.55-1.99). The largest differences were observed in patients prescribed lamotrigine (OR 2.17, 95% CI 1.53-3.08, p < 0.001) and carbamazepine (OR 1.63, 95% CI 1.02-2.60, p = 0.042). Also, the OR trended higher for phenytoin (OR 2.46, 95% CI 0.79-7.65, p = 0.12), followed by oxcarbazepine (OR 1.91, 95% CI 0.75-4.85, p = 0.18) and sodium valproate (OR 0.60, 95% CI 0.12-2.99, p = 0.53), but the difference did not reach statistical significance. In the remaining 21 studies, 13 reported numerically higher risk of cADRs among females compared to male patients, and in five of these, the difference was statistically significant. CONCLUSION: Our findings confirmed that females are more susceptible to cADRs induced by ASMs than males. More research is needed to understand the pathophysiological mechanisms for this difference. PROTOCOL REGISTRATION: PROSPERO (CRD42018111943).

Epigallocatechin Gallate as an anti-obesity therapeutic compound: an in silico approach for structure-based drug designing.

Epigallocatechin gallate is a polyphenol of tea plants. Other than tea its trace amounts are found in apple skin, onions and plums. It has anti-adipogenic and anti-oxidant potential. It was investigated that epigallocatechin gallate stopped the adipogenic differentiation of mice mesenchymal stem cells but its underlying mechanism is not well understood. Different proteins and transcription factors responsible for differentiation of adipocytes could be its targets. This study was designed to determine the potential target of epigallocatechin gallate in human. Human Peroxisome Proliferator-Activated Receptors (PPAR) gamma protein was selected as the potential target as it is a key transcription factor for differentiation of adipose cells. Docking analysis of PPAR gamma and epigallocatechin gallate demonstrated that epigallocatechin gallate binds with PPAR gamma at its active site and blocks its activity. This study helps in understanding the mode of action of epigallocatechin gallate that would help for anti-obesity drug development.

Potential of Stem Cells as Regenerative Medicine: From Preface to Advancements.

Regenerative medicine is an emerging field to find solutions to some of the most challenging medical problems of humans. Regenerative medicine has the potential to revolutionize the whole health care system, in dealing with conditions such as heart disease, emphysema, liver fibrosis, kidney disease, diabetes, and neurological disorders. Among the many challenges to bringing regenerative medicine to the clinic is the selection of the best cell types and reliable ways to expand the number of cells. Stem cells emerged as the best cell type for regeneration of different organs. This review covers the application of stem cells in different degenerative diseases.