1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride neurotoxicity is attenuated in mice overexpressing Bcl-2.
The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that Bcl-2 protects against free radicals and that it increases mitochondrial calcium-buffering capacity. The neurotoxicity of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyride (MPTP) is thought to involve both mitochondrial dysfunction and free radical generation. We therefore investigated MPTP neurotoxicity in both Bcl-2 overexpressing mice and littermate controls. MPTP-induced depletion of dopamine and loss of [3H]mazindol binding were significantly attenuated in Bcl-2 overexpressing mice. Protection was more profound with an acute dosing regimen than with daily MPTP administration over 5 d. 1-Methyl-4-phenylpyridinium (MPP+) levels after MPTP administration were similar in Bcl-2 overexpressing mice and littermates. Bcl-2 blocked MPP+-induced activation of caspases. MPTP-induced increases in free 3-nitrotyrosine levels were blocked in Bcl-2 overexpressing mice. These results indicate that Bcl-2 overexpression protects against MPTP neurotoxicity by mechanisms that may involve both antioxidant activity and inhibition of apoptotic pathways.
Yang
L
L
Neurochemistry Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Matthews
R T
RT
Schulz
J B
JB
Klockgether
T
T
Liao
A W
AW
Martinou
J C
JC
Penney
J B
JB
Hyman
B T
BT
Beal
M F
MF
D015655:1-Methyl-4-phenylpyridinium / Q000032:analysis; D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects*; D053143:Caspase 2; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004298:Dopamine / Q000032:analysis; D015259:Dopamine Agents / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006719:Homovanillic Acid / Q000032:analysis; D007274:Injections, Intraperitoneal; D020267:MPTP Poisoning; D008297:Male; D008454:Mazindol; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011869:Radioligand Assay; D014316:Tritium; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D061945:Caspase Inhibitors; D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D005609:Free Radicals; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D014316:Tritium; D015102:3,4-Dihydroxyphenylacetic Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D008454:Mazindol; D053143:Caspase 2; D020169:Caspases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D006719:Homovanillic Acid