Cellular NAD depletion and decline of SIRT1 activity play critical roles in PARP-1-mediated acute epileptic neuronal death in vitro

Brain Res. 2013 Oct 16:1535:14-23. doi: 10.1016/j.brainres.2013.08.038. Epub 2013 Aug 27.


Intense poly(ADP-ribose) polymerase-1 (PARP-1) activation was implicated as a major cause of caspase-independent cell death in the hippocampal neuronal culture (HNC) model of acute acquired epilepsy (AE). The molecular mechanisms are quite complicated. The linkage among neuronal death, cellular nicotinamide adenine dinucleotide (NAD) levels, apoptosis-inducing factor (AIF) translocation, SIRT1 expression and activity were investigated here. The results showed that PARP-1 over-activation caused by Mg²⁺-free stimuli led to cellular NAD depletion which could block AIF translocation from mitochondria to nucleus and attenuate neuronal death. Also, SIRT1 deacetylase activity was reduced by Mg²⁺-free treatment, accompanied by elevated ratio of neuronal death, which could be rescued by NAD repletion. These data demonstrated that cellular NAD depletion and decline of SIRT1 activity play critical roles in PARP-1-mediated epileptic neuronal death in the HNC model of acute AE.

Keywords: 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone; AE; AIF; Acquired epilepsy; Apoptosis-inducing factor; COXIV; Cytochrome oxidase subunit IV; DPQ; Epilepsy; HNC; Hippocampal neuronal culture; MPT; Mitochondrial permeability transition; NAD; Neuronal death; Nicotinamide adenine dinucleotide; PAR; PARP-1; Poly(ADP-ribose); Poly(ADP-ribose) polymerase-1; Poly(ADP-ribose)polymerase-1; SIRT1; SREDs; Spontaneous recurrent epileptiform discharges; TUNEL; Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; WCC; Whole-cell current-clamp.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Inducing Factor / metabolism
  • Cell Death*
  • Epilepsy / metabolism*
  • Epilepsy / pathology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • NAD / metabolism*
  • Neurons / metabolism*
  • Neurons / pathology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Rats
  • Sirtuin 1 / metabolism*


  • Apoptosis Inducing Factor
  • NAD
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Sirtuin 1