Methamphetamine induces heme oxygenase-1 expression in cortical neurons and glia to prevent its toxicity

Journal Article · Sun Nov 01 00:00:00 EDT 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.06.021· OSTI ID:21344771

Huang, Y -N ^[1]; Wu, C -H ^[1]; Lin, T -C ^[2]

---

1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 114 (China)
2. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 114 (China)

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.

• OSTI ID: 21344771
• Journal Information: Toxicology and Applied Pharmacology, Vol. 240, Issue 3; Other Information: DOI: 10.1016/j.taap.2009.06.021; PII: S0041-008X(09)00270-1; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMPHETAMINES
ANIMALS
APOPTOSIS
HEME
INHIBITION
MEN
MESSENGER-RNA
NERVE CELLS
OXYGENASES
TOXICITY
AMINES
ANALEPTICS
ANIMAL CELLS
AUTONOMIC NERVOUS SYSTEM AGENTS
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM AGENTS
DRUGS
ENZYMES
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
MALES
MAMMALS
MAN
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXIDOREDUCTASES
PIGMENTS
PORPHYRINS
PRIMATES
PROTEINS
RNA
SOMATIC CELLS
SYMPATHOMIMETICS
VERTEBRATES