Nrf2 is predominantly expressed in hippocampal neurons in a rat model of temporal lobe epilepsy

Abstract

Background Drug resistance is a particular problem in patients with temporal lobe epilepsy, where seizures originate mainly from the hippocampus. Many of these epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure. Such conditions are characterized by pathophysiological mechanisms including massive oxidative stress that synergistically mediate the secondary brain damage, contributing to the development of epilepsy. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has emerged in recent years as an attractive therapeutic approach targeting to upregulate the antioxidative defenses in the cell, to ameliorate the oxidative stress-induced damage. Thus, it is important to understand the characteristics of Nrf2 activation during epileptogenesis and epilepsy. Here, we studied the temporal, regional, and cell-type specific expression of Nrf2 in the brain, in a rat model of temporal lobe epilepsy. Results Early after status-epilepticus, Nrf2 is mainly activated in the hippocampus and maintained during the whole period of epileptogenesis. Only transient expression of Nrf2 was observed in the cortex. Nevertheless, the expression of several Nrf2 antioxidant target genes was increased within 24 h after status-epilepticus in both the cortex and the hippocampus. We demonstrated that after status-epilepticus in rats, Nrf2 is predominantly expressed in neurons in the CA1 and CA3 regions of the hippocampus, and only astrocytes in the CA1 increase their Nrf2 expression. Conclusions In conclusion, our data identify previously unrecognized spatial and cell-type dependent activation of Nrf2 during epilepsy development, highlighting the need for a time-controlled, and cell-type specific activation of the Nrf2 pathway for mediating anti-oxidant response after brain insult, to modify the development of epilepsy.

Repurposing dimethyl fumarate as an antiepileptogenic and disease-modifying treatment for drug-resistant epilepsy

“…In agreement with our previously published study [38], a positive non-significant trend to increase Nrf2 mRNA level was observed in the cortex (Fig. 1A), and significantly increased in the hippocampus 1 week after KA-SE (Fig.…”

“…Therefore, we have analyzed neuronal cell density in CA1 and CA3 subregions of the hippocampus of DMF therapy vs. vehicle treated rats. Moreover, in our recent work [38], we found that Nrf2 expression following KA-SE model was increased predominantly in neurons of the CA1 and CA3 regions of the hippocampus, and no significant increase was detected in the cortex.…”

“…Collectively, these findings suggest that DMF, an Nrf2 activator, can modify the course of acquired epilepsy in a post-SE rat model. We have previously shown that the protective response of Nrf2 signaling is endogenously activated in response to KA-induced SE [38] in a brain region-specific manner, with antioxidant systems being upregulated to a greater degree in the hippocampus than in the cortex. However, this study is the first to identify that exogenous treatment with DMF increases the activation of the Nrf2 pathway to higher levels than SE alone, which may explain the enhanced neuroprotection in the hippocampus of DMFtreated animals.…”

Evaluation of the Antioxidant Activity of Levetiracetam in a Temporal Lobe Epilepsy Model

“…Nrf2 is known as the master inductor of the expression of antioxidant and detoxification enzymes and genes involved in mitochondrial biogenesis and preservation. The authors concluded that the activation of Nrf2 mediated the antioxidant response after brain insult and that it could therefore modify the development of epilepsy [ 62 , 63 ] ( Figure 3 ). Based on the above, it is probable that the nonsignificant changes in the increment of lipoperoxidation and protein oxidation observed in epileptic rats were due to Nrf2 activation, which controls the redox changes in the hippocampus during TLE, and also to the modulating activities of GR and GPx, which prevent OS from reaching the oxidation of the protein and lipids.…”

Nrf2 is expressed more extensively in neurons than in astrocytes following an acute epileptic seizure in rats

“…All data acquisition and analysis were performed blindly. The sample size and number of rats utilized in this study were determined based on statistical needs, experimental necessities, and our previous studies (Saadi et al, 2022; Sandouka et al, 2023). No statistical method was employed to predetermine the sample size.…”