title: Methamphetamine induces heme oxygenase-1 expression in cortical neurons and glia to prevent its toxicity.
abstract: The impairment of cognitive and motor functions in humans and animals caused by methamphetamine (METH) administration underscores the importance of METH toxicity in cortical neurons. The heme oxygenase-1 (HO-1) exerts a cytoprotective effect against various neuronal injures; however, it remains unclear whether HO-1 is involved in METH-induced toxicity. We used primary cortical neuron/glia cocultures to explore the role of HO-1 in METH-induced toxicity. Exposure of cultured cells to various concentrations of METH (0.1, 0.5, 1, 3, 5, and 10 mM) led to cytotoxicity in a concentration-dependent manner. A METH concentration of 5 mM, which caused 50% of neuronal death and glial activation, was chosen for subsequent experiments. RT-PCR and Western blot analysis revealed that METH significantly induced HO-1 mRNA and protein expression, both preceded cell death. Double and triple immunofluorescence staining further identified HO-1-positive cells as activated astrocytes, microglia, and viable neurons, but not dying neurons. Inhibition of the p38 mitogen-activated protein kinase pathway significantly blocked HO-1 induction by METH and aggravated METH neurotoxicity. Inhibition of HO activity using tin protoporphyrine IX significantly reduced HO activity and exacerbated METH neurotoxicity. However, prior induction of HO-1 using cobalt protoporphyrine IX partially protected neurons from METH toxicity. Taken together, our results suggest that induction of HO-1 by METH via the p38 signaling pathway may be protective, albeit insufficient to completely protect cortical neurons from METH toxicity.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 114, ROC.
authors: Ya-Ni
authors: YN
authors: Huang
authors: Ching-Hsiang
authors: CH
authors: Wu
authors: Tzu-Chao
authors: TC
authors: Lin
authors: Jia-Yi
authors: JY
authors: Wang
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018920:Coculture Techniques; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008694:Methamphetamine / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D008694:Methamphetamine; D006419:Heme Oxygenase (Decyclizing)