Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide.
Pyridine nucleotides are critical during oxidative stress due to their roles in reductive reactions and energetics. The aim of the present study was to examine pyridine nucleotide changes in six brain regions of mice after an intracerebroventricular injection of the oxidative stress inducing agent, t-butyl hydroperoxide (t-BuOOH). A secondary aim was to investigate the correlation between NAD+ levels and DNA fragmentation. Here, we demonstrate that t-BuOOH induced a rapid oxidation of NADPH and a slow depletion of NAD+ in most brain regions. A slight increase in NADH also occurred in five brain regions. NAD+ depletion was associated with increased DNA fragmentation. This suggests the initiation of a death cascade involving poly(ADP-ribose) polymerase (PARP), NAD+, ATP depletion and consequent cell death in brain tissue. PARP activity was accelerated in some brain regions after 20 min of oxidative stress. To counteract oxidative stress induced toxicity, NAD+ levels were increased in the brain using an intraperitoneal injection of nicotinamide. A surplus of brain NAD+ prevented DNA fragmentation in some brain regions. Nicotinamide administration also resulted in higher brain NADH, NADP+ and NADPH levels in some regions. Their synthesis was further upregulated during oxidative stress. Nicotinamide as a precursor for NAD+ may provide a useful therapeutic strategy in the treatment of neurodegeneration.
Klaidman
L K
LK
Department of Molecular Pharmacology and Toxicology, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, PSC 508, Los Angeles, CA 90089-9121, USA.
Mukherjee
S K
SK
Adams
J D
JD
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D053938:DNA Fragmentation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009536:Niacinamide / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011685:Purine Nucleotides / Q000378:metabolism*; D020122:tert-Butylhydroperoxide / Q000633:toxicity
D018696:Neuroprotective Agents; D011685:Purine Nucleotides; D009243:NAD; D009536:Niacinamide; D009249:NADP; D000255:Adenosine Triphosphate; D020122:tert-Butylhydroperoxide; D011065:Poly(ADP-ribose) Polymerases