Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades SUBRAMANIAM JAYANTHI, XIAOLIN DENG, PIERRE-ANTOINE H. NOAILLES, BRUCE LADENHEIM and JEAN LUD CADET 1 Molecular Neuropsychiatry Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, DHHS, Baltimore, Maryland, USA 1 Correspondence: Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institute of Health, DHHS, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA. E-mail: jcadet@intra.nida.nih.gov Methamphetamine (METH) is an illicit drug that causes neurodegenerative effects in humans. In rodents, METH induces apoptosis of striatal glutamic acid decarboxylase (GAD) -containing neurons. This paper provides evidence that METH-induced cell death occurs consequent to interactions of ER stress and mitochondrial death pathways. Specifically, injections of METH are followed by an almost immediate activation of proteases calpain and caspase-12, events consistent with drug-induced ER stress. Involvement of ER stress was further supported by observations of increases in the expression of GRP78/BiP and CHOP. Participation of the mitochondrial pathway was demonstrated by the transition of AIF, smac/DIABLO, and cytochrome c from mitochondrial into cytoplasmic fractions. These changes occur before the apoptosome-associated pro-caspase-9 cleavage. Effector caspases-3 and -6, but not -7, were cleaved with the initial time of caspase-3 activation occurring before caspase 9 cleavage; this suggests possible earlier cleavage of caspase-3 by caspase-12. These events preceded proteolysis of the caspase substrates DFF-45, lamin A, and PARP in nuclear fractions. These findings indicate that METH causes neuronal apoptosis in part via cross-talks between ER- and mitochondria-generated processes, which cause activation of both caspase-dependent and -independent pathways.—Jayanthi, S., Deng, X., Noailles, P.-A. H., Ladenheim, B., Cadet, J. L. Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades. Key Words: apoptosis-inducing factor • CHOP transcription factor • BiP/GRP78 • DNA fragmentation
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Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades
JAYANTHI, SUBRAMANIAM; DENG, XIAOLIN; NOAILLES, PIERRE-ANTOINE H.; LADENHEIM, BRUCE; CADET, JEAN LUD
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, Volume 18 (2): 238
Fed of American Socs for Experimental Biology – Feb 1, 2004
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