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.
Neurochemistry Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
L
L
Yang
R T
RT
Matthews
J B
JB
Schulz
T
T
Klockgether
A W
AW
Liao
J C
JC
Martinou
J B
JB
Penney
B T
BT
Hyman
M F
MF
Beal
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