The Involvement of the Keap1-Nrf2 Pathway in Seizure-like Activity Model

Oxidative stress is a biochemical state of imbalance in the production of reactive oxygen species and antioxidant defenses. The brain is extremely intolerant to oxidative stress because of its high oxygen demand. Reactive oxygen species (ROS), the most important oxygen free radical, is closely related to the pathology and development of various neurodegenerative diseases. Excessive ROS production disrupts the balance between cellular oxidation and antioxidant defense systems, induces lipid peroxidation, DNA fragmentation, cellular integrity, and functional impairment, and ultimately leads to neuronal function disruption and apoptosis.

Epilepsy is still a major medical concern with no cure. Several studies have shown that oxidative stress plays an important role in epilepsy pathogenesis and may represent a target for the treatment of epilepsy. To overcome this physiological stress, cells are equipped with elaborate defense systems that allow them to maintain homeostasis in an ever-changing environment. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) plays a central role in the inducible cytoprotective response to oxidative insults. Recent studies have suggested that Nrf2 binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes under conditions of oxidative stress, which reduces oxidative damage and accumulation of toxic metabolites. Therefore, our research aim is to evaluate the role of the Keap1-Nrf2 pathway in seizure-like activity model and to further investigate the skin-brain axis.

​I am Rhoda Olowe- a PhD student whose avidity for providing a possible solution to epilepsy, drove into the study of epilepsy disease, following my experience with a colleague battling epilepsy. I am currently looking into the role of Sestrins and the mechanisms underlying their antioxidant effects in experimental epilepsy models, with the aim to provide novel insights into the protective role of sestrin in epilepsy as well as its regulatory pathways involving the P62 dependent autophagic degradation of Keap1, attenuation of mTORC1 activity and consequent activation of Nrf2. Understanding how these pathways individually and collectively operate to activate the cellular antioxidant events may provide novel therapeutic treatment strategies that can translate into patient's trials to prevent epileptogenesis.

In recent years, oxidative stress and excessive reactive oxygen species (ROS) production have been implicated in many neurological pathologies. Excessive ROS generation during and after seizures have been shown to play a crucial role in immediate and longer-term excitotoxic neuronal death in which it is produced by several sources. Previous studies have shown that mitochondria and ROS producing enzymes, such as NADPH oxidase (NOX), are the main intracellular sources of ROS.

Therefore, we here propose to investigate the temporal profile and cellular localization of the NOX isoforms in normal brain, as well as brains subjected to acute and prolonged (i.e. status epilepticus) models.

Evaluation of expression of Nrf2 in experimental epilepsy models.

Epilepsy is one of the most common and disabling neurological disorder affecting over 65M people worldwide. Currently the available medications are prescribed to treat the symptoms of the disease while the core of the illness remains perplexed dilemma.

Common sequelae occur following a brain insult that have been shown to contribute to neuronal death and the development of epilepsy are generation of reactive oxygen species (ROS) and induction of oxidative stress which is thought to be an important pathogenic factor if not the major reason in occurrence of epilepsy. 

Recently, numerous studies are focusing on the transcription factor nuclear factor erythroid 2 related factor 2 (Nrf2) signaling pathway as an important target in protecting against oxidative stress- induced damage in a wide range of diseases, including epilepsy, through increasing the antioxidant defenses of cells . Herein, our main goal is to study the antioxidant effect of Nrf2 pathway at different epilepsy models. And following pharmacological activation of it.

There are specific studies that need to be conducted before researchers move forward with human clinical trials. Pharmacokinetics (what happens to a drug from the time it is administered to the moment it is eliminated from the body) and pharmacodynamics (what a drug does to the body - biochemical, physiologic, and molecular effects) can play an important role in pre-clinical testing. Besides pharmacodynamics, we are also studying the pharmacokinetics properties (Absorption, Distribution, Metabolism, and Excretion) of different drugs that helps in adjusting dosage, enhancing efficacy, and decreasing toxicity. This PK/PD analysis combines the two pharmacologic disciplines of pharmacokinetics and pharmacodynamics to describe the dose–concentration–response time course that is especially useful for drug development.