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

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

1
Departments of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
2
Departments of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
3
Departments of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
4
Departments of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Wolfram S. Kunz
Received: 29 May 2017 / Revised: 6 July 2017 / Accepted: 10 July 2017 / Published: 12 July 2017
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Abstract

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. View Full-Text
Keywords: hippocampus; mitochondria; neuronal damage; poly(ADP-ribose) polymerase-1; status epilepticus hippocampus; mitochondria; neuronal damage; poly(ADP-ribose) polymerase-1; status epilepticus
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MDPI and ACS Style

Lai, Y.-C.; Baker, J.S.; Donti, T.; Graham, B.H.; Craigen, W.J.; Anderson, A.E. Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus. Int. J. Mol. Sci. 2017, 18, 1502.

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