Shielding the Brain: Nrf2-ARE Pathway as a Therapeutic Focus inEpilepsy

Abstract: Epilepsy is a common neurological condition marked by frequent seizures, which often accompanies cognitive and psychological difficulties. With an estimated 65 million sufferers worldwide, epilepsy imposes an enormous burden on individuals, families, and healthcare systems. Seizures are categorized into focal, generalized, and seizures with unknown onset. Of all the focal seizures, temporal lobe epilepsy (TLE) is distinctive as it develops in the temporal lobes and causes altered consciousness as well as emotional difficulties. About 30% of people with TLE continue to have symptoms that do not improve with antiepileptic medications, resulting in further physical and psychological issues. Oxidative stress (OS) plays a pivotal role in the pathophysiology of epilepsy, driven by an overproduction of reactive oxygen species (ROS). Mitochondrial dysfunction and the accumulation of ROS disrupt neuronal calcium homeostasis, increase synaptic excitability, and contribute to neuronal injury and death. Antioxidant enzymes like catalase and superoxide dismutase help to reduce damage caused by ROS; yet, prolonged OS promotes the development of epileptogenesis. Additionally, recent research highlights the transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2), a key regulator of cellular defense against OS. Activation of the Nrf2-antioxidant response elements (ARE) signaling pathway enhances antioxidant enzyme expression and protects neurons from ROS damage. Studies suggest that targeting Nrf2 could offer novel therapeutic strategies for epilepsy by reducing OS and improving neuronal survival. Exploring Nrf2-activating compounds holds promise for developing more effective antiepileptic therapies, addressing the unmet need for treatments that can modulate the oxidative environment within the brain.