James David Adams, Jr.
Molecular Pharmacology and Toxicology
Neuroprotection against oxygen radicals
Oxygen radicals are formed in the brain and are involved in stroke, Parkinsonís disease, Alzheimerís disease, aging and other neurodegenerative conditions. DNA is a primary target of oxygen radicals in the brain, which induce DNA fragmentation. Brain cells die due to DNA fragmentation by processes of necrosis and apoptosis. Necrosis is a rapid loss of viability associated with swelling of the cytoplasm and rupture of the nucleus and the cell membrane. Necrotic cells are removed from the brain by macrophages within a few days of cell death. Apoptosis is programmed cell death where a genetic program is activated that causes the cell DNA to fragment, the cytoplasm to condense and the nucleus to condense. Apoptotic cells rupture with the formation of apoptotic bodies, which contain the debris from the cell. Apoptotic bodies are phagocytized by neighboring cells and can be removed within a few hours of cell death.
Aging, stroke, Parkinsonís disease and Alzheimerís disease are associated with DNA fragmentation in the brain and necrotic and apoptotic cell death. Stroke, Parkinsonís disease and Alzheimerís disease are more prominent in older people. Aging makes the brain more susceptible to DNA damage induced by oxygen radicals. Therefore, my laboratory is involved in finding agents that prevent DNA damage and prevent cell death in aging individuals and in patients suffering from stroke, Parkinsonís disease and Alzheimerís disease.
Nicotinamide is a vitamin that quickly penetrates into the brain and is a precursor for NAD. DNA fragmentation leads to the activation of poly(ADP-ribose) polymerase, an enzyme required for induction of DNA repair. Poly(ADP-ribose) polymerase uses NAD as a substrate and transfers poly(ADP-ribose) units onto various enzymes from NAD. The formation of poly(ADP-ribosylated) enzymes results in the activation of some enzymes and the deactivation of other enzymes. This creates a new physiologic balance in the cell, where DNA repair is important. Excessive poly(ADP-ribose) polymerase activity depletes cellular NAD. The depletion of NAD leads to the depletion of another adenine containing compound, ATP. NAD depletion is important in both apoptosis and necrosis. Therefore, my laboratory is working on using nicotinamide as a precursor for NAD to prevent neurodegeneration.
- Mukherjee, S.K., Yasharel, R., Klaidman, L.K., Hutchin, T.P. and Adams, J.D. Apoptosis and DNA fragmentation as induced by tertiary butylhydroperoxide in the brain. Brain Res. Bull. 38, 595-604 (1995).
- Klaidman, L.K., Mukherjee, S.K., Hutchin, T.P. and Adams, J.D. Nicotinamide as a precursor for NAD prevents apoptosis in the mouse brain induced by tertiary-butylhydroperoxide. Neurosci. Lett. 206, 5-8 (1996).
- Adams, J.D. Agents used in neurodegenerative disorders. in Burgerís Medicinal Chemistry and Drug Discovery, vol. 3., Wolff, M.E. (ed.), John Wiley & Sons, New York, 1996, pp. 261-319.