Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
National Residents Clinical Skills Training Center, Medical School of Southeast University, Nanjing, China.
Free Radic Biol Med. 2022 Aug 1;188:45-61. doi: 10.1016/j.freeradbiomed.2022.06.221. Epub 2022 Jun 15.
Neuronal nitric oxide synthase (nNOS) plays a pivotal role in the pathological process of neuronal injury in the development of epilepsy. Our previous study has demonstrated that nitric oxide (NO) derived from nNOS in the epileptic brain is neurotoxic due to its reaction with the superoxide radical with the formation of peroxynitrite. Neuropeptide Y (NPY) is widely expressed in the mammalian brain, which has been implicated in energy homeostasis and neuroprotection. Recent studies suggest that nNOS may act as a mediator of NPY signaling. Here in this study, we sought to determine whether NPY expression is regulated by nNOS, and if so, whether the regulation of NPY by nNOS is associated with the neuronal injuries in the hippocampus of epileptic brain. Our results showed that pilocarpine-induced temporal lobe epilepsy (TLE) mice exhibited an increased level of nNOS expression and a decreased level of NPY expression along with hippocampal neuronal injuries and cognition deficit. Genetic deletion of nNOS gene, however, significantly upregulated hippocampal NPY expression and reduced TLE-induced hippocampal neuronal injuries and cognition decline. Knockdown of NPY abolished nNOS depletion-induced neuroprotection and cognitive improvement in the TLE mice, suggesting that inhibition of nNOS protects against hippocampal neuronal injuries by increasing neuropeptide Y expression in TLE mice. Targeting nNOS-NPY signaling pathway in the epileptic brain might provide clinical benefit by attenuating neuronal injuries and preventing cognitive deficits in epilepsy patients.
神经元型一氧化氮合酶（nNOS）在癫痫发展过程中神经元损伤的病理过程中起着关键作用。我们之前的研究表明，癫痫脑中来自 nNOS 的一氧化氮（NO）由于与超氧自由基反应形成过氧亚硝酸盐而具有神经毒性。神经肽 Y（NPY）广泛存在于哺乳动物的大脑中，它与能量平衡和神经保护有关。最近的研究表明，nNOS 可能是 NPY 信号的介导物。在这项研究中，我们试图确定 NPY 的表达是否受 nNOS 调节，如果是这样，nNOS 对 NPY 的调节是否与癫痫脑中海马神经元损伤有关。我们的结果表明，匹罗卡品诱导的颞叶癫痫（TLE）小鼠表现出 nNOS 表达水平增加和 NPY 表达水平降低，同时伴有海马神经元损伤和认知缺陷。然而，nNOS 基因缺失显著上调了海马 NPY 的表达，减少了 TLE 诱导的海马神经元损伤和认知下降。NPY 的敲低消除了 nNOS 耗竭诱导的 TLE 小鼠的神经保护和认知改善，表明抑制 nNOS 通过增加 TLE 小鼠中的神经肽 Y 表达来保护海马神经元免受损伤。针对癫痫脑中的 nNOS-NPY 信号通路可能通过减轻神经元损伤和预防癫痫患者的认知缺陷提供临床益处。
