Abstract
Epilepsy is one of the most common chronic neurological disorders which provoke progressive neuronal degeneration. Endoplasmic reticulum (ER) stress has recently been recognized as pivotal etiological factors contributing to epilepsy-induced neuronal damage. However, the specific contribution of epilepsy made to ER stress remains largely elusive. Here we use pentylenetetrazole (PTZ) kindling, a chronic epilepsy model, to identify neuronal nitric oxide synthase (nNOS) as a signaling molecule triggering PTZ kindling epilepsy-induced ER stress and oxidative damage. By genetic deletion of nNOS gene, we further demonstrated that nNOS acts through peroxynitrite, an important member of reactive nitrogen species, to trigger hippocampal ER stress and oxidative damage in the PTZ-kindled mice. Our findings thus define a specific mechanism for chronic epilepsy-induced ER stress and oxidative damage, and identify a potential therapeutic target for neuroprotection in chronic epilepsy patients.
Highlights
Neuronal nitric oxide synthase is widely expressed in neurons of the brain, where it produces nitric oxide (NO) during the conversion of L-arginine to citrulline, with the participation of NADPH. nNOS is structurally coupled with NMDA receptor by a scaffolding protein (PSD-95), activation of nNOS depends on its association with PSD-95 and NMDA receptor-mediated calcium influx (Sattler et al, 1999)
Our previous study has demonstrated that hippocampal nNOS mRNA level, protein content and enzymatic activity were significantly increased after the mice were fully kindled (Zhu et al, 2016a)
We find that inhibition of nNOS by 7-NI significantly decreased the nNOS enzymatic activity (Figure 2B). nNOS is structurally coupled with NMDA receptor by PSD-95, raising the possibility that nNOS enzymatic activity is dependent on NMDA receptor activation
Summary
Neuronal nitric oxide synthase (nNOS) is widely expressed in neurons of the brain, where it produces nitric oxide (NO) during the conversion of L-arginine to citrulline, with the participation of NADPH. nNOS is structurally coupled with NMDA receptor by a scaffolding protein (PSD-95), activation of nNOS depends on its association with PSD-95 and NMDA receptor-mediated calcium influx (Sattler et al, 1999). Our previous study has demonstrated that PTZ kindling activated NMDA receptor (Zhu et al, 2015) and induced nNOS activity (Zhu et al, 2016a), suggesting nNOS is stimulated through NMDA receptor activation in the epileptic condition. It is reported that loss of interneurons in nNOS and Hippocampal ER Stress the hippocampus of epileptic brain disrupts the balance of excitation and inhibition and causes hyperexcitability (Hofmann et al, 2016). This neuronal hyperexcitability may result in neurodegeneration by generation of excessive reactive oxygen/nitrogen species and by impairing the endogenous antioxidant system
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