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Nicotinamide therapy protects against both necrosis and apoptosis in a stroke model
Jun Yang1, Lori K Klaidman, Mei Ling Chang
1Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, PSC 508, Los Angeles, CA 90089-9121, USA.
Background And Purpose:
Nicotinamide protects against brain damage in ischemia-reperfusion. However, the dosage and time of treatment require clarification. It is also not clear if nicotinamide can protect against both necrosis and apoptosis.
Methods:
Dose-response and time-effect studies were designed. Transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 min. Different doses of nicotinamide were injected upon reperfusion. In time-effect studies, 500 mg/kg nicotinamide was administered at different times after the onset of reperfusion. Neurological finding scores were recorded. Infarct volumes were measured.
Results:
In contrast to controls, neurological deficit scores and infarct volumes were greatly reduced by treatment with nicotinamide. The ED(50) of nicotinamide was 239+/-79 mg/kg (P=.95). It was found that nicotinamide injected during the first 6 h of reperfusion could effectively inhibit the development of brain damage. The optimal dose of nicotinamide was 500 mg/kg and gave a maximal response.
Conclusions:
Poly(ADP-ribose) polymerase (PARP) plays a key role in DNA repair in stroke. Excessive PARP activity consumes NAD leading to energy depletion and neuronal damage. As an inhibitor of PARP, nicotinamide promotes the supply of energy. The results suggest that early application of nicotinamide at a suitable dosage significantly ameliorates necrotic and apoptotic brain injury after focal ischemia-reperfusion.