Persistent depletion of striatal dopamine and cortical norepinephrine in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydro-3-pyridinol (MPTP-3-OL), an analog of MPTP.
MPTP-3-ol injected s.c. once daily for 4 days resulted in a dose-dependent depletion of striatal dopamine and cortical norepinephrine one week after the last dose. MPTP-3-ol was approximately one-fourth as potent as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in causing these effects. MPTP-3-ol was oxidized by monoamine oxidase in mouse brain in vitro and resulted in MPP+ (1-methyl-4-phenylpyridinium) formation in brain in vivo, both at about one-fourth the rates with MPTP. The in vitro metabolism of MPTP-3-ol was inhibited by deprenyl, a selective inhibitor of monoamine oxidase type B, and deprenyl pretreatment also blocked the depletion of striatal dopamine and cortical norepinephrine in vivo. Pretreatment with EXP 561, an inhibitor of catecholamine uptake, also prevented the dopamine- and norepinephrine-depleting effects of MPTP-3-ol. Thus, substitution of a hydroxy group on the 3-position of MPTP retains its neurotoxic potential toward catecholamine neurons but reduces potency by decreasing the rate of oxidation via monoamine oxidase type B.
Hemrick-Luecke
S K
SK
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
Robertson
D W
DW
Krushinski
J H
JH
Fuller
R W
RW
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology
D002395:Catecholamines; C072770:1-methyl-4-phenyl-1,2,3,6-tetrahydro-3-pyridinol; D012642:Selegiline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D009638:Norepinephrine