Lowering ambient or core body temperature elevates striatal MPP+ levels and enhances toxicity to dopamine neurons in MPTP-treated mice.
The neuroprotective effects of lowering body temperature have been well documented in various models of neuronal injury. The present study investigated the effects a lower ambient or core body temperature would have on damage to striatal dopamine (DA) neurons produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice received systemic MPTP treatment at two different temperatures, 4 degrees C and 22 degrees C. MPTP-treated mice maintained at 4 degrees C demonstrated (1) a greater hypothermic response, (2) a significant reduction in striatal DA content and tyrosine hydroxylase (TH) activity, and (3) significantly greater striatal 1-methyl-4-phenylpyridinium (MPP+) levels, as compared to mice dosed with MPTP at room temperature. Parallel studies with methamphetamine (METH) were conducted since temperature appears to play a pivotal role in the mediation of damage to DA neurons by this CNS stimulant in rodents. As previously reported, METH-induced hyperthermia and the subsequent loss of striatal DA content were attenuated in animals dosed at 4 degrees C. We also evaluated the effects a hypothermic state induced by pharmacological agents would have on striatal neurochemistry and MPP+ levels following MPTP treatment. Concurrent administration of MK-801 or 8-OHDPAT increased the striatal MPP+ levels following MPTP treatment. However, only 8-OHDPAT potentiated the MPTP-induced decrements of striatal DA content and TH activity; MK-801 did not affect MPTP decreases in these striatal markers of dopaminergic damage. Altogether, these findings indicate that temperature has a profound effect on striatal MPP+ levels and MPTP-induced damage to DA neurons in mice.
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Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Albers
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Sonsalla
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics; D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics / Q000633:toxicity*; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020267:MPTP Poisoning; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism; D009474:Neurons / Q000737:chemistry / Q000201:enzymology; D009498:Neurotoxins / Q000493:pharmacokinetics; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D017366:Serotonin Receptor Agonists; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine