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Apoptosis and oxidative stress in the aging brain
J D Adams1, S K Mukherjee, L K Klaidman
1School of Pharmacy, University of Southern California, Los Angeles 90033, USA.
Annals of the New York Academy of Sciences
|June 15, 1996
Summary
Oxidative stress in the brain causes DNA fragmentation, leading to cell death via necrosis and apoptosis. This damage, particularly in older mice, can be prevented by nicotinamide, a vitamin that supports DNA repair.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- DNA is highly susceptible to damage from oxidative stress in the brain.
- Oxidative stress induces rapid DNA fragmentation, primarily through free radical attack and endonuclease activation.
Purpose of the Study:
- To investigate the mechanisms of DNA damage and cell death (necrosis and apoptosis) induced by oxidative stress in the brain.
- To explore the role of aging in susceptibility to oxidative stress-induced brain damage.
- To evaluate the protective effect of nicotinamide against oxidative stress-induced DNA damage and cell death.
Main Methods:
- Induction of oxidative stress using intracerebroventricular injection of t-butylhydroperoxide in mice of various ages (2, 8, and 24 months).
- Assessment of DNA fragmentation and cell death using histological staining (Cresyl violet) and electron microscopy.
- Evaluation of apoptosis using specific staining for apoptotic DNA fragments.
- Pretreatment with nicotinamide to assess its protective effects.
Main Results:
- Intracerebroventricular injection of t-butylhydroperoxide rapidly induced DNA fragmentation and cell death, manifesting as necrosis and apoptosis.
- Necrosis resulted from extensive DNA fragmentation, while lower doses induced delayed apoptosis.
- Older mice (24 months) showed increased DNA fragmentation, necrosis, and apoptosis compared to younger mice.
- Pretreatment with nicotinamide effectively prevented DNA fragmentation and apoptosis.
Conclusions:
- Oxidative stress in the brain triggers both necrosis and apoptosis, largely due to DNA fragmentation.
- Aging exacerbates oxidative stress-induced brain damage.
- Nicotinamide, a precursor to NAD+, protects against oxidative stress by supporting DNA repair mechanisms, specifically the poly(ADP-ribose) polymerase pathway.