Nicotinamide Prevents NAD+ Depletion and Protects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+ Consumption by SIRT1 may Endanger Energetically Compromised Neurons
- 14 March 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in NeuroMolecular Medicine
- Vol. 11 (1), 28-42
- https://doi.org/10.1007/s12017-009-8058-1
Abstract
Neurons require large amounts of energy to support their survival and function, and are therefore susceptible to excitotoxicity, a form of cell death involving bioenergetic stress that may occur in several neurological disorders including stroke and Alzheimer’s disease. Here we studied the roles of NAD+ bioenergetic state, and the NAD+-dependent enzymes SIRT1 and PARP-1, in excitotoxic neuronal death in cultured neurons and in a mouse model of focal ischemic stroke. Excitotoxic activation of NMDA receptors induced a rapid decrease of cellular NAD(P)H levels and mitochondrial membrane potential. Decreased NAD+ levels and poly (ADP-ribose) polymer (PAR) accumulation in nuclei were relatively early events (+ precursor and an inhibitor of SIRT1 and PARP1, inhibited SIRT1 deacetylase activity without affecting SIRT1 protein levels. NAD+ levels were preserved and PAR accumulation and neuronal death induced by excitotoxic insults were attenuated in nicotinamide-treated cells. Treatment of neurons with the SIRT1 activator resveratrol did not protect them from glutamate/NMDA-induced NAD+ depletion and death. In a mouse model of focal cerebral ischemic stroke, NAD+ levels were decreased in both the contralateral and ipsilateral cortex 6 h after the onset of ischemia. Stroke resulted in dynamic changes of SIRT1 protein and activity levels which varied among brain regions. Administration of nicotinamide (200 mg/kg, i.p.) up to 1 h after the onset of ischemia elevated brain NAD+ levels and reduced ischemic infarct size. Our findings demonstrate that the NAD+ bioenergetic state is critical in determining whether neurons live or die in excitotoxic and ischemic conditions, and suggest a potential therapeutic benefit in stroke of agents that preserve cellular NAD+ levels. Our data further suggest that, SIRT1 is linked to bioenergetic state and stress responses in neurons, and that under conditions of reduced cellular energy levels SIRT1 enzyme activity may consume sufficient NAD+ to nullify any cell survival-promoting effects of its deacetylase action on protein substrates.Keywords
This publication has 79 references indexed in Scilit:
- Preventing NAD+ Depletion Protects Neurons against ExcitotoxicityAnnals of the New York Academy of Sciences, 2008
- Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-PhosphotauJournal of Neuroscience, 2008
- Mechanisms of impaired mitochondrial energy metabolism in acute and chronic neurodegenerative disordersJournal of Neuroscience Research, 2007
- NAD metabolism and sirtuins: Metabolic regulation of protein deacetylation in stress and toxicityThe AAPS Journal, 2006
- Control of AIF-mediated Cell Death by the Functional Interplay of SIRT1 and PARP-1 in Response to DNA DamageCell Cycle, 2006
- Small molecule regulation of Sir2 protein deacetylasesThe FEBS Journal, 2005
- Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 DeacetylaseScience, 2004
- Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespanNature, 2003
- Activation of Mitochondrial ATP-Dependent Potassium Channels Protects Neurons against Ischemia-Induced Death by a Mechanism Involving Suppression of Bax Translocation and Cytochrome c ReleaseJournal of Cerebral Blood Flow & Metabolism, 2002
- The Effect of MK-801 on Cortical Spreading Depression in the Penumbral Zone following Focal Ischaemia in the RatJournal of Cerebral Blood Flow & Metabolism, 1992