title: Overexpression of Nrf2 protects cerebral cortical neurons from ethanol-induced apoptotic death.
abstract: Ethanol (ETOH) can cause apoptotic death of neurons by depleting GSH with an associated increase in oxidative stress. The current study illustrates a means to overcome this ETOH-induced neurotoxicity by enhancing GSH through boosting Nrf2, a transcription factor that controls GSH homeostasis. ETOH treatment caused a significant increase in Nrf2 protein, transcript expression, Nrf2-DNA binding activity, and expression of its transcriptional target, NQO1, in primary cortical neuron (PCNs). However, this increase in Nrf2 did not maintain GSH levels in response to ETOH, and apoptotic death still occurred. To elucidate this phenomenon, we silenced Nrf2 in neurons and found that ETOH-induced GSH depletion and the increase in superoxide levels were exacerbated. Furthermore, Nrf2 knockdown resulted in significantly increased (P < 0.05) caspase 3 activity and apoptosis. Adenovirus-mediated overexpression of Nrf2 prevented ETOH-induced depletion of GSH from the medium and high GSH subpopulations and prevented ETOH-related apoptotic death. These studies illustrate the importance of Nrf2-dependent maintenance of GSH homeostasis in cerebral cortical neurons in the defense against oxidative stress and apoptotic death elicited by ETOH exposure.
authors.affiliation: Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
authors.forename: Madhusudhanan
authors.initials: M
authors.lastname: Narasimhan
authors.forename: Lenin
authors.initials: L
authors.lastname: Mahimainathan
authors.forename: Mary Latha
authors.initials: ML
authors.lastname: Rathinam
authors.forename: Amanjot Kaur
authors.initials: AK
authors.lastname: Riar
authors.forename: George I
authors.initials: GI
authors.lastname: Henderson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018920:Coculture Techniques; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000172:deficiency; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D000431:Ethanol; D005978:Glutathione