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.
Highlights
Status epilepticus (SE), defined as seizure activities lasting greater than 30 min [1], is associated with hippocampal neuronal damage and implicated in the development of hippocampal sclerosis and epilepsy [2,3,4]
In this study we investigated whether poly(ADP-ribose) polymerase-1 (PARP-1) activation was associated with the canonical intracellular NAD+ depletion-mitochondrial failure pathway and contributed to hippocampal neuronal damage in a model of chemoconvulsant-induced SE using kainic acid [32]
We evaluated PARP-1 activity in the hippocampus following SE by assessing the amount of poly-ADP-ribosylated proteins in the hippocampal whole cell homogenates using western blotting
Summary
Status epilepticus (SE), defined as seizure activities lasting greater than 30 min [1], is associated with hippocampal neuronal damage and implicated in the development of hippocampal sclerosis and epilepsy [2,3,4]. Several mechanisms contribute to SE-induced neuronal damage and cell death with mitochondrial dysfunction representing an important and well-known pathological feature [3,5,6,7,8]. SE can lead to activation of N-methyl-D-aspartate (NMDA) receptors, which in turn increases intra-mitochondrial Ca2+ accumulation, as well as oxidative and nitrosative stress These pathological processes contribute to impaired oxidative phosphorylation and loss of mitochondrial membrane potential and structural integrity [3,7,8,9,10,12]. In this study we investigated whether PARP-1 activation was associated with the canonical intracellular NAD+ depletion-mitochondrial failure pathway and contributed to hippocampal neuronal damage in a model of chemoconvulsant-induced SE using kainic acid [32]. PARP-1 activation was associated with decreased intracellular NAD+ levels, impaired NAD+-dependent mitochondrial respiration and hippocampal CA1 damage. PARP-1 did not affect the function of individual electron transport chain complexes, suggesting that the impairment in NAD+-dependent mitochondrial respiration likely reflects decreased availability of NAD+ as a cofactor
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