MPTP- and MPP(+)-induced effects on body temperature exhibit age- and strain-dependence in mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is toxic toward the dopaminergic nigrostriatal system of a plethora of species including rodents, nonhuman primates and humans. The present study was designed to evaluate if systemic administration of MPTP or its metabolite, 1-methyl-4-phenylpyridinium ion (MPP+), has significant effects on body temperature (BT) and whether such effects might play a role in the neurotoxicity. A single intraperitoneal (i.p.) dose of either MPTP (50 mg/kg) or MPP+ (12.5 mg/kg) leads to a decrease in BT in both C57BL/6N (C57) and CD-1 mice. The hypothermia induced by MPTP can be blocked by pretreatment with deprenyl (30 mg/kg, i.p.), an MAO-B inhibitor. However, the hypothermia elicited by MPP+ is refractive to MAO-B inhibition. These findings suggest that MPP+ is responsible for the BT reduction and that the primary site of action lies outside the blood-brain barrier. An initial hyperthermic phase in the CD-1 mice, which leads to the induction of heat shock protein-72 (HSP-72) throughout the brain, differentiates their response to MPTP from that of C57 mice. This initial hyperthermia appears to be protective since its prevention by dosing at a low ambient temperature enhances striatal dopamine (DA) depletion in CD-1 mice. The temperature effects of both MPTP and MPP+ also display an age-dependence in the C57 strain of mice, with the magnitude of the effects correlating positively with age. However, profound hypothermia could be induced by MPP+ in the absence of striatal DA depletion. The latter finding suggests that while a positive correlation was found between age and the magnitude of the hypothermia, DA depletion and hypothermia are not causally related. The apparent protective effect of the initial hyperthermia in the CD-1 strain of mice, however, suggests that BT is an important parameter in the neurotoxicity of MPTP.
Neurochemistry Laboratory, National Center for Toxicological Research, Jefferson, AR 72079-9502, USA.
T E
TE
Freyaldenhoven
S F
SF
Ali
R W
RW
Hart
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D015259:Dopamine Agents / Q000633:toxicity*; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012642:Selegiline / Q000494:pharmacology; D013045:Species Specificity
D015259:Dopamine Agents; D012642:Selegiline; D015655:1-Methyl-4-phenylpyridinium