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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)28-42
Number of pages15
JournalNeuroMolecular Medicine
Volume11
Issue number1
DOIs
StatePublished - Mar 2009
Externally publishedYes

Fingerprint

Niacinamide
Brain Ischemia
NAD
Neurons
Stroke
Energy Metabolism
Poly Adenosine Diphosphate Ribose
Proteins
Mitochondrial Membrane Potential
N-Methylaspartate
Enzymes
Nervous System Diseases
N-Methyl-D-Aspartate Receptors
Glutamic Acid
Cell Survival
Alzheimer Disease
Polymers
Cell Death
Ischemia

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Medicine
  • Neurology

Cite this

Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral Ischemia : NAD+ consumption by sirt1 may endanger energetically compromised neurons. / Liu, Dong; Gharavi, Robert; Pitta, Michael; Gleichmann, Marc; Mattson, Mark P.

In: NeuroMolecular Medicine, Vol. 11, No. 1, 03.2009, p. 28-42.

Research output: Contribution to journalArticle

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