Effects of glutathione depletion by 2‐cyclohexen‐1‐one on excitatory amino acids‐induced enhancement of activator protein‐1 DNA binding in murine hippocampus

Abstract

We have investigated the role of glutathione in mechanisms associated with excitatory amino acid signaling to the nuclear transcription factor activator protein-1 (AP1) in the brain using mice depleted of endogenous glutathione by prior treatment with 2-cyclohexen-1-one (CHX). In the hippocampus of animals treated with CHX 2 h before, a signi®cant increase was seen in enhancement of AP1 DNA binding when determined 2 h after the injection of kainic acid (KA) at low doses. The sensitization to KA was not seen in animals injected with CHX 24 h before, in coincidence with the recovery of glutathione contents to the normal levels. By contrast, CHX did not signi®cantly affect the potentiation by NMDA of AP1 binding under any experimental conditions. Prior treatment with CHX resulted in facilitation of behavioral changes induced by KA without affecting those induced by NMDA. These results suggest that endogenous glutathione may be at least in part involved in molecular mechanisms underlying transcriptional control by KA, but not by NMDA, signals of cellular functions.

Role of oxidative stress in epileptic seizures

“…Melatonin also prevented the neurotoxic effects of ROS generated by KA receptor activation through an increase in intracellular GSH (Floreani et al, 1997). Therefore, GSH may protect neuronal cells against KA neurotoxicity through a mechanism associated with ROS scavenging (Kim et al, 2000a; Kitayama et al, 1999; Ogita et al, 2001; Yoneda et al, 2001). …”

“…A previous study showed that prolonged GSH depletion may lead to sensitization of the KA receptor to potentiate AP-1 DNA-binding activity in the murine hippocampus (Kitayama et al, 1999; Ogita et al, 2001; Yoneda et al, 2001), suggesting that endogenous GSH may be partly involved in the underlying molecular mechanisms of transcription control by KA (Kitayama et al, 1999; Ogita et al, 2001; Yoneda et al, 2001). Changes in AP-1 DNA-binding activity were qualitatively similar to those observed with NF-kB in the adult rat brain (Rong and Baudry, 1996).…”

Transcriptionally Less Active Prodynorphin Promoter Alleles are Associated with Temporal Lobe Epilepsy: A Case‐Control Study and Meta‐Analysis

“…Moreover, PDYN promoter has an AP-1 binding site. Taking into account that AP-1 might be central in transcriptional cascades that follow an induced seizure in epilepsy experimental models [16] and that dynorphins have an important role in neuronal homeostasis regulating the opening of K+ channels [4], it can be suggested that functional variants in PDYN could be plausibly involved in TLE epileptogenesis. Furthermore, dynorphins are extensively expressed in dentate gyrus' granular cells [17].…”