Nitric Oxide-induced Activation of the Type 1 Ryanodine Receptor Is Critical for Epileptic Seizure-induced Neuronal Cell Death

• Published in: EBioMedicine Vol. 11; no. C; pp. 253 - 261
• Main Authors: Mikami, Yoshinori, Kanemaru, Kazunori, Okubo, Yohei, Nakaune, Takuya, Suzuki, Junji, Shibata, Kazuki, Sugiyama, Hiroki, Koyama, Ryuta, Murayama, Takashi, Ito, Akihiro, Yamazawa, Toshiko, Ikegaya, Yuji, Sakurai, Takashi, Saito, Nobuhito, Kakizawa, Sho, Iino, Masamitsu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2016; Elsevier
• Subjects: Animals; Calcium; Calcium - metabolism; Calcium Channel Agonists - pharmacology; Cell Death - drug effects; Cells, Cultured; Disease Models, Animal; Epilepsy - metabolism; Epilepsy - pathology; Humans; Kainic Acid - pharmacology; Male; Mice; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Neurodegeneration; Neurons - drug effects; Neurons - metabolism; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Pyramidal Cells - drug effects; Pyramidal Cells - metabolism; Pyramidal Cells - pathology; Research Paper; Ryanodine receptor; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; Seizures; Calcium; Neurodegeneration; Nitric oxide; Ryanodine receptor; Seizures
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.08.020

Status epilepticus (SE) is a life-threatening emergency that can cause neurodegeneration with debilitating neurological disorders. However, the mechanism by which convulsive SE results in neurodegeneration is not fully understood. It has been shown that epileptic seizures produce markedly increased levels of nitric oxide (NO) in the brain, and that NO induces Ca2+ release from the endoplasmic reticulum via the type 1 ryanodine receptor (RyR1), which occurs through S-nitrosylation of the intracellular Ca2+ release channel. Here, we show that through genetic silencing of NO-induced activation of the RyR1 intracellular Ca2+ release channel, neurons were rescued from seizure-dependent cell death. Furthermore, dantrolene, an inhibitor of RyR1, was protective against neurodegeneration caused by SE. These results demonstrate that NO-induced Ca2+ release via RyR is involved in SE-induced neurodegeneration, and provide a rationale for the use of RyR1 inhibitors for the prevention of brain damage following SE. •NO-induced activation of RyR1 is critical for seizure-induced neuronal cell death.•Dantrolene is protective against neurodegeneration caused by epileptic seizures.•RyR1 is a therapeutic candidate to ameliorate the brain damage following seizures. Status epilepticus (SE) is a life-threatening condition that can cause neurodegeneration. Mikami et al. report that NO-induced activation of type 1 ryanodine receptors (RyR1) is involved in SE-induced neuron death. Furthermore, dantrolene, an inhibitor of RyR1, has been found to be protective against neurodegeneration caused by SE.