Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus

Int J Mol Sci. 2017 Jul 12;18(7):1502. doi: 10.3390/ijms18071502.


Mitochondrial dysfunction plays a central role in the neuropathology associated with status epilepticus (SE) and is implicated in the development of epilepsy. While excitotoxic mechanisms are well-known mediators affecting mitochondrial health following SE, whether hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) also contributes to SE-induced mitochondrial dysfunction remains to be examined. Here we first evaluated the temporal evolution of poly-ADP-ribosylated protein levels in hippocampus following kainic acid-induced SE as a marker for PARP-1 activity, and found that PARP-1 was hyperactive at 24 h following SE. We evaluated oxidative metabolism and found decreased NAD⁺ levels by enzymatic cycling, and impaired NAD⁺-dependent mitochondrial respiration as measured by polarography at 24 h following SE. Stereological estimation showed significant cell loss in the hippocampal CA₁ and CA₃ subregions 72 h following SE. PARP-1 inhibition using N-(6-Oxo-5,6-dihydro-phenanthridin-2-yl)- N,N-dimethylacetamide (PJ-34) in vivo administration was associated with preserved NAD⁺ levels and NAD⁺-dependent mitochondrial respiration, and improved CA₁ neuronal survival. These findings suggest that PARP-1 hyperactivation contributes to SE-associated mitochondrial dysfunction and CA₁ hippocampal damage. The deleterious effects of PARP-1 hyperactivation on mitochondrial respiration are in part mediated through intracellular NAD⁺ depletion. Therefore, modulating PARP-1 activity may represent a potential therapeutic target to preserve intracellular energetics and mitochondrial function following SE.

Keywords: hippocampus; mitochondria; neuronal damage; poly(ADP-ribose) polymerase-1; status epilepticus.

MeSH terms

  • Animals
  • Blotting, Western
  • Electroencephalography
  • Hippocampus / metabolism*
  • Hippocampus / pathology*
  • Mitochondria / metabolism*
  • Mitochondria / pathology*
  • Neurons / metabolism*
  • Neurons / pathology*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Status Epilepticus / metabolism*
  • Status Epilepticus / pathology*


  • Poly (ADP-Ribose) Polymerase-1