Brain-derived neurotrophic factor rescues neuronal death induced by methamphetamine

Background. Methamphetamine (MA) induces degeneration of various regions of the brain, resulting in neuropsychiatric damage. Although the underlying mechanisms of MA-induced neurotoxicity have been studied, there are few reports to date regarding the factor(s) that can effectively prevent MA-induced neurotoxicity. Because brain-derived neurotrophic factor (BDNF) has been known to prevent many kinds of neuronal cell death, we investigated whether BDNF inhibits MA-induced neuronal death. Methods. Using primary cortical neurons, we examined the effect of BDNF on MA-induced neuronal death. In addition, using pharmacologic and molecular biological tools, we elucidated which pathways are involved in this effect. Results: Brain-derived neurotrophic factor dose-dependently blocked MA-induced neuronal death, and this effect was inhibited by phosphatidylinositol-3-kinase inhibitors. In addition, overexpression of activated Akt protects neurons against MA. Furthermore, expression of kinase-defective Akt blocked the effect of BDNF on MA-induced neuronal death. Conclusions: Brain-derived neurotrophic factor effectively blocks MA-induced neuronal death, and Akt activation is necessary and sufficient for this effect. (C) 2004 Society of Biological Psychiatry.