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Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent

Subramaniam Jayanthi1, Xiaolin Deng, Pierre-Antoine H Noailles

  • 1Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institute of Health, DHHS, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|February 11, 2004
PubMed

Insights

Methamphetamine (METH) triggers neuronal apoptosis by linking endoplasmic reticulum (ER) stress and mitochondrial pathways. This drug-induced cell death involves complex cross-talk, activating both caspase-dependent and -independent processes.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Toxicology

Background:

  • Methamphetamine (METH) is a neurotoxic illicit drug.
  • METH induces apoptosis in striatal glutamic acid decarboxylase (GAD)-containing neurons in rodents.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying METH-induced neuronal apoptosis.
  • To explore the interplay between endoplasmic reticulum (ER) stress and mitochondrial pathways in METH neurotoxicity.

Main Methods:

  • Rodent models were used to study METH effects.
  • Analysis of protease activation (calpain, caspases), ER stress markers (GRP78/BiP, CHOP), mitochondrial fraction changes (AIF, smac/DIABLO, cytochrome c), and caspase substrate proteolysis (DFF-45, lamin A, PARP).

Main Results:

  • METH rapidly activated calpain and caspase-12, indicating ER stress.
  • Increased expression of GRP78/BiP and CHOP confirmed ER stress involvement.
  • Mitochondrial proteins translocated to the cytoplasm, preceding apoptosome formation.
  • Caspase-3 and -6 were cleaved, with caspase-3 activation potentially initiated by caspase-12.
  • Nuclear caspase substrates were proteolyzed, signifying downstream apoptotic events.

Conclusions:

  • METH-induced neuronal apoptosis results from cross-talk between ER stress and mitochondrial death pathways.
  • Both caspase-dependent and -independent apoptotic pathways are activated by METH.
  • These findings elucidate key mechanisms of METH neurotoxicity.

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