Implication of poly (ADP-ribose) polymerase (PARP) in neurodegeneration and brain energy metabolism. Decreases in mouse brain NAD+ and ATP caused by MPTP are prevented by the PARP inhibitor benzamide.
Poly(ADP-ribose) polymerase (PARP) is a DNA binding protein that uses nicotinamide adenine dinucleotide (NAD+) as a substrate. Evidence from in vitro studies on nonneuronal cells in culture have shown that when fully activated by free radical-induced DNA damage, PARP depletes cellular NAD+ and consequently adenosine triphosphate (ATP) levels within a matter of minutes, and that this depletion is associated with a cell death that can be prevented by PARP inhibitors. The present in vivo study utilized the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, a model of central nigrostriatal dopamine neurotoxicity that recapitulates certain features of Parkinson's disease (PD), and one in which we have previously shown PARP inhibitors to be protective, to examine whether MPTP acutely caused region- and time-dependent changes in levels of NAD+ and ATP in the brain in vivo and whether such effects were modified by treatments with neuroprotective doses of the PARP inhibitor benzamide. The results confirm that MPTP reduces striatal ATP levels, as previously reported by Chan et al., show that MPTP causes a regionally-selective (striatal and midbrain) loss of NAD+, and indicate that the PARP inhibitor benzamide can prevent these losses without interfering with MPTP-induced striatal dopamine release. These findings suggest an involvement of PARP in the control of brain energy metabolism during neurotoxic insult, provide further evidence in support of the participation of PARP in MPTP-induced neurotoxicity in vivo and suggest that PARP inhibitors might be beneficial in the treatment of PD.
Cosi
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Division of Neurobiology Y, Centre de Recherche Pierre Fabre, Castres, France. cristina.cosi@pierre-fabre.com
Marien
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000187:drug effects / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology
D001549:Benzamides; D015259:Dopamine Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; C037689:benzamide; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011065:Poly(ADP-ribose) Polymerases; C001746:3-methoxytyramine; D004298:Dopamine