Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model

Abstract

Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development.

In vitro and in vivo assessment of the antioxidant potential of isoxazole derivatives

“…Twenty mice were divided into four groups randomly, with five mice in each. The first group was administered with our novel compound 2a (5 mg/kg), the second group with the same compound (10 mg/kg), the third group with Quercetin (10 mg/kg) as a positive control, and the fourth group with normal saline (20%) and propylene glycol 80% as a negative control group 26 .…”

Crosstalk between neuroinflammation and oxidative stress in epilepsy

“…This can diminish neuroinflammation and induce Nrf2 activation to express the ARE, which has proven efficacy in treating epilepsy patients. Indeed, Nrf2 activators such as sulforaphane and hydroxylated fullerene have restored GSH levels and shown antiepileptic and neuroprotective properties in numerous epilepsy models ( Wang et al, 2014 ; Carrasco-Pozo et al, 2015 ; Pauletti et al, 2019 ; Uddin et al, 2020 ; Cao H et al, 2021 ; Sandouka and Shekh-Ahmad, 2021 ). An antioxidant and metal chelator, curcumin, was able to reduce gliosis and cytokine levels in PTZ-induced epilepsy ( Kaur et al, 2015 ).…”

The microbiota‐gut‐brain axis and epilepsy from a multidisciplinary perspective: Clinical evidence and technological solutions for improvement of in vitro preclinical models

“…Several works studying epileptic activity modulation by external agents (e.g., molecules, toxins, antiepileptic drugs) couple in vivo and in vitro methods 78–82 . In particular, exploiting these latter for a deeper understanding of what is observed in vivo.…”

“…Several works studying epileptic activity modulation by external agents (e.g., molecules, toxins, antiepileptic drugs) couple in vivo and in vitro methods. [78][79][80][81][82] In particular, exploiting these latter for a deeper understanding of what is observed in vivo. The preparation of brain tissues, in vitro, and their manipulation for multiple biochemical and electrochemical analysis is more accessible to study in detail the neural networks and provide the possibility to perform mechanistic studies on the brain's molecular and cellular mechanisms which is not allowed by classic in vivo models due to their intrinsic complexity.…”