Neuroprotective effect of Nrf2 activator dimethyl fumarate, on the hippocampal neurons in chemical kindling model in rat.

BACKGROUND: Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor, which activates the anti-oxidative stress response pathway. In epilepsy, oxidative stress is one of the key factors in the progression of the disease. So, the neuroprotective role of dimethyl fumarate (DMF), a Nrf2 pathway activator was explored in pentylenetetrazole (PTZ) induced kindling model of epilepsy in rats. METHODS: Male Wistar rats were subjected to different doses of DMF (15, 30, 60 mg/kg) to evaluate the effect on the PTZ induced kindling in rats. Seizure scoring, the percentage of animals kindled, histopathological analysis of hippocampus and biochemical estimation were done to study the effect of DMF on PTZ induced oxidative stress in rats. KEY FINDINGS: The number of kindled animals in the DMF 60 mg/kg treatment group (25%) was less in comparison to corn oil + PTZ control group (62.5%). The histopathological analysis of the hippocampus revealed a significant (p = 0.003) decrease in neuronal damage in DMF 60 mg/kg group as compared to corn oil + PTZ control group. The DMF 60 mg/kg treatment improved the level of antioxidants: glutathione peroxidase (GPx), superoxide dismutase (SOD), reduced glutathione (GSH) and reduced the lipid peroxidation as compared to corn oil + PTZ group. CONCLUSIONS: DMF has demonstrated the neuroprotective effect in PTZ induced kindling model of epilepsy. This can prove advantageous in the development of new treatment strategies for epilepsy.

Targeting crosstalk between Nuclear factor (erythroid-derived 2)-like 2 and Nuclear factor kappa beta pathway by Nrf2 activator dimethyl fumarate in epileptogenesis.

Purpose/Aim: Epilepsy is a complex, chronic neurological disorder characterized by increased and abnormal synchronization of neuronal electrical activity, which is manifested as seizures. It is associated with many comorbid conditions such as depression, anxiety, sleep disorder, psychiatric disorder etc., which consequently causes higher mortality rate. The understanding of its cellular and molecular mechanism is partial, because of which it remains an ongoing health problem, despite the increasing availability of newer antiepileptic drugs. Although recurrent seizures are the clinical indication of epilepsy, the disease process (epileptogenesis) begins before the onset of the first seizure. This dormant phase before the onset of first seizure provides an opportune time window for modifying the epileptogenic process by intervening in its progression with an appropriate treatment. MATERIAL AND METHODS: Studies have shown that in epilepsy, there is a chronic state of oxidative stress and inflammation, which plays a key role in epileptic pathogenesis. Various antioxidant mechanisms maintain the redox balance in the body by either scavenging or regulating the generation of free radicals. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is a well-established antioxidant pathway in various diseases such as diabetes, renal disease, various neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, etc. Results: It has been observed that single-target therapies are inefficient in providing anticonvulsant and disease-modifying effects in epilepsy. CONCLUSIONS: So, preventing the progression of epilepsy by targeting Nrf2-activated antioxidant pathway along with the other established antiepileptic pathways can prove beneficial in epilepsy treatment.