Contribution of nitric oxide, superoxide anion, and peroxynitrite to activation of mitochondrial apoptotic signaling in hippocampal CA3 subfield following experimental temporal lobe status epilepticus

Abstract

Summary Purpose: One cellular consequence of status epilepticus is apoptosis in the hippocampal CA3 subfield. We evaluated the hypothesis that the repertoire of cellular events that underlie such elicited cell death entails mitochondrial dysfunction induced by an excessive production of nitric oxide synthase II (NOS II)‐derived NO, increased superoxide anion (O2−) production, and peroxynitrite formation. Methods: In Sprague‐Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure‐like electroencephalography (EEG) activity. The effects of pretreatments with various test agents on the induced O2− production, peroxynitrite formation, mitochondrial respiratory chain enzyme activities, cytochrome c/caspase‐3 signaling, and DNA fragmentation in bilateral CA3 subfields were examined. Results: Significantly and temporally correlated increase in O2− and peroxynitrite levels (3 to 24 h), depressed mitochondrial Complex I activity (3 h), enhanced translocation of cytochrome c to cytosol (day 1), and augmented activated caspase‐3 (day 7) and DNA fragmentation (day 7) were detected bilaterally in hippocampal CA3 subfields after the elicitation of sustained seizure. Pretreatment with microinjection into the bilateral hippocampal CA3 subfield of a water‐soluble formulation of coenzyme Q10; a selective NOS II inhibitor, S‐methylisothiourea; a superoxide dismutase mimetic, 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl; an active peroxynitrite decomposition catalyst, 5,10, 15,20‐tetrakis‐(N‐methyl‐4‐pyridyl)‐ porphyrinato iron (III); or a peroxynitrite scavenger, L‐cysteine significantly blunted these cellular events. Discussion: Prolonged seizures prompted NO‐, O2−‐, and peroxynitrite‐dependent reduction in mitochondrial respiratory enzyme Complex I activity, leading to cytochrome c/caspase‐3‐dependent apoptotic cell death in the hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus.

Caspase 3 involves in neuroplasticity, microglial activation and neurogenesis in the mice hippocampus after intracerebral injection of kainic acid

“…The different onset of caspase 3 activation in CA1, CA3 and DG-hilus may due to that CA3 is highly accessible to KA-mediated excitotoxicity [38]. A similar nuclear activation of caspase 3 in neurons has been described previously [49,50]. Those studies suggested that SE-mediated nuclear caspase 3 activation may activate caspase-activated DNase (CAD) results in DNA fragmentation and apoptosis [51].…”

Protective effects of peroxisome proliferator‐activated receptors γ coactivator‐1α against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia

“…For this purpose, 10-lm paraffin-embedded brain sections were deparaffinized in two exchanges of xylene for 5 min each, washed sequentially in 100%, 95%, and 70% ethanol, and stained with cresyl violet (Chen et al, 2006;Chuang et al, 2009). Pyramidal neurons were counted in a double-blind manner in the middle CA1 region of the hippocampus.…”

“…Western blot analysis for PGC-1a, UCP2, or SOD2 subunits was carried out on proteins extracted from total lysate or nuclear fractions of hippocampal samples Chen et al, 2006;Chuang et al, 2009). The primary antisera used included a rabbit polyclonal antisera against PGC-1a or SOD2 (Santa Cruz Biotechnology, Santa Cruz, CA), or goat polyclonal antiserum against UCP2 (Santa Cruz Biotechnology), or mouse monoclonal antiserum against atubulin (Santa Cruz Biotechnology).…”

Coenzyme Q10 Ameliorates Neurodegeneration, Mossy Fiber Sprouting, and Oxidative Stress in Intrahippocampal Kainate Model of Temporal Lobe Epilepsy in Rat

“…In addition, CoQ10 could protect hippocampal neurons against kainate neurotoxicity (Won et al 2011) and its local application is capable to blunt cellular events leading to apoptosis and cell death in hippocampal CA3 subfield following status epilepticus (Chuang et al 2009). On this foundation, this compound may be a good candidate for neuroprotection against kainateinduced excitotoxic insult.…”