The effects of aging and neurodegeneration on apoptosis-associated DNA fragmentation and the benefits of nicotinamide.
In this work, the tertiary butylhydroperoxide- (t-BuOOH) treated mouse was used as a model to study the oxidative stress that is associated with various neurodegenerative diseases. DNA was found to be an early target of t-BuOOH attack. Necrosis was associated with extensive DNA fragmentation that occurred in almost all regions of the brain within 20 min following intracerebroventricular (icv) injection of 109.7 mg/kg t-BuOOH. Apoptosis was associated with high levels of DNA fragmentation that was observed at 48 h after icv administration of 21.9 mg/kg t-BuOOH. Susceptibility to DNA damage was found to be age-dependent, since 24-mo-old mice exhibited consistently higher and more pervasive DNA damage than 8 mo-old-mice. Extensive DNA damage was seen in various brain regions in patients with Alzheimer disease (AD) and with both Alzheimer and Parkinson disease (AD-PD). These results directly implicate DNA damage in neurodegeneration. The DNA fragmentation ob-served can lead to both apoptosis and necrosis, as suggested by gel electrophoresis. Nicotinamide, a precursor of NAD in the brain, was able to prevent DNA fragmentation induced by low-dose t-BuOOH, when coadministered with the toxin.
Mukherjee
S K
SK
School of Pharmacy, Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles 90033, USA.
Adams
J D
JD
D000368:Aged; D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001923:Brain Chemistry / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000503:physiopathology* / Q000517:prevention & control; D009536:Niacinamide / Q000494:pharmacology*; D010300:Parkinson Disease / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D009536:Niacinamide