Heat shock proteins protect cultured fibroblasts from the cytotoxic effects of MPP+.
1-Methyl-4-phenylpyridinium (MPP+), the cytotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has been shown to be toxic to a variety of cell types in culture. The addition of media containing 1 mM MPP+ to cultures of Chinese hamster ovary (CHO) fibroblasts led to the gradual depletion of cellular ATP stores and subsequent cell death. A 12-min heat shock of the cells at 45 degrees C, 3 h prior to the addition of MPP(+)-containing media, significantly attenuated cell death. Heat shock pretreatment led to an increased synthesis of all the major heat shock proteins (HSPs) in CHO cells. Further, the addition of the protein synthesis inhibitor, cycloheximide, prevented the protective effect of heat shock pretreatment, indicating that this protection was dependent upon new protein synthesis. In additional experiments, a rat fibroblast cell line which has been stably transfected with, and constitutively expresses a cloned human HSP-70 gene, was found to be more resistant to the cytotoxic effects of MPP+ than the parental fibroblast cell line. These results indicate that HSPs are protective toward the deleterious effects of MPP+ and that their synthesis represents an important parameter in the neurotoxicity of MPTP.
Neurochemistry Laboratory, National Center for Toxicological Research, Jefferson, AR 72079-9502, USA.
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D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016466:CHO Cells / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003513:Cycloheximide / Q000494:pharmacology; D003603:Cytotoxins / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats
D003603:Cytotoxins; D015259:Dopamine Agents; D006360:Heat-Shock Proteins; D011500:Protein Synthesis Inhibitors; D000255:Adenosine Triphosphate; D003513:Cycloheximide; D015655:1-Methyl-4-phenylpyridinium