Oxidative changes in brain pyridine nucleotides and neuroprotection using nicotinamide

Pyridine nucleotides are critical during oxidative stress due to their role s in reductive reactions and energetics. The aim of the present study was t o 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 cor relation 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 fragmenta tion. This suggests the initiation of a death cascade involving poly(ADP-ri bose) 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 injectio n of nicotinamide. A surplus of brain NAD(+) prevented DNA fragmentation in some brain regions. Nicotinamide administration also resulted in higher br ain NADH, NADP(+) and NADPH levels in some regions. Their synthesis was fur ther upregulated during oxidative stress. Nicotinamide as a precursor for N AD(+) may provide a useful therapeutic strategy in the treatment of neurode generation. (C) 2001 Elsevier Science B.V. All rights reserved.