Elevation of neuronal MAO-B activity in a transgenic mouse model does not increase sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
To examine whether expressing high levels of monoamine oxidase (MAO-B) activity abberently in neurons results in increased sensitivity of dopaminergic neurons to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 8-week-old transgenic mice expressing high neuronal levels of MAO-B were compared with age-matched nontransgenic littermates following i.p. injections of 30 mg/kg body weight of the protoxin. Levels of striatal dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), as well as tyrosine hydroxylase (TH)-immunopositive cell numbers in the substantia nigra (SN) were compared 1 week later between transgenics and controls. No difference was found in any of these parameters, indicating that high neuronal MAO-B levels does not cause increased sensitivity to MPTP, and therefore neither conversion of MPTP to its active form, 1-methyl-4-phenyl pyridium (MPP+) by MAO-B nor MPP+ uptake by the dopaminergic transporter are likely to be the rate-limiting step in the toxicity of this compound.
Andersen
J K
JK
Neurology Service, Massachusetts Hospital, Charlestown.
Frim
D M
DM
Isacson
O
O
Beal
M F
MF
Breakefield
X O
XO
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine