Nrf2 defense pathway: Experimental evidence for its protective role in epilepsy.

OBJECTIVE

Epigenetic mechanisms involved in transcriptional regulation of multiple molecular pathways are potentially attractive therapeutic interventions for epilepsy, because single target therapies are unlikely to provide both anticonvulsant and disease-modifying effects.

METHODS

A selection of epilepsy-related gene expression data sets were retrieved using NextBio software and imported to Ingenuity Pathway Analysis for transcription factor enrichment analysis. Nuclear factor erythroid 2-related factor 2 (Nrf2)-a transcription factor that promotes the expression of numerous antioxidant, anti-inflammatory, and neuroprotective proteins-was identified as a candidate for confirmation of mRNA expression in hippocampal tissue from patients with temporal lobe epilepsy and in mice following pilocarpine-induced status epilepticus (SE). Human Nrf2 was overexpressed via an adeno-associated virus (AAV) vector after the onset of spontaneous recurrent seizures (SRS) in the animals. At the end of a 5-week continuous monitoring period for SRS, quantitative immunohistochemistry using neuronal (neuronal-specific nuclear protein), astrocytic (glial fibrillary acidic protein), and microglial (ionized calcium binding adaptor molecule 1) markers was performed.

RESULTS

A significant increase in Nrf2 mRNA expression was observed in human epileptic hippocampal tissue. Nrf2 expression levels increased progressively in mice, reaching a peak at 72 hours after SE, and then declined. Similar expression patterns were observed for 3 Nrf2-regulated genes: HO-1, NQO1, and mGST. Remarkably, mice injected with AAV Nrf2 displayed significantly fewer generalized seizures, with profound reduction in microglia activation. Hippocampal neurons were preserved, whereas the number of astrocytes was unchanged.

INTERPRETATION

These findings extend the potential of Nrf2-based therapies to epilepsy and add to the rapidly accumulating evidence from other neurodegenerative and inflammatory disease models.