NeuroMolecular Medicine

, Volume 11, Issue 1, pp 28–42 | Cite as

Nicotinamide Prevents NAD+ Depletion and Protects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+ Consumption by SIRT1 may Endanger Energetically Compromised Neurons

  • Dong Liu
  • Robert Gharavi
  • Michael Pitta
  • Marc Gleichmann
  • Mark P. Mattson
Original Paper

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 (<4 h) that preceded the appearance of propidium iodide- and TUNEL-positive cells (markers of necrotic cell death and DNA strand breakage, respectively) which became evident by 6 h. Nicotinamide, an NAD+ 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

Excitotoxicity Glutamate NMDA NAD+ NADH SIRT1 PARP-1 PAR Nicotinamide MCAO TUNEL 

Notes

Acknowledgments

We would like to thank Graeme I. Bell for providing us the mouse GLUT3 cDNA clone used for riboprobe preparation and in situ hybridization. This research was supported by the Intramural Research Program of the National Institute on Aging.

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Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Dong Liu
    • 1
  • Robert Gharavi
    • 1
  • Michael Pitta
    • 1
  • Marc Gleichmann
    • 1
  • Mark P. Mattson
    • 1
  1. 1.Laboratory of NeurosciencesNational Institute on Aging, Intramural Research ProgramBaltimoreUSA

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