Inhibition of neuronal nitric oxide synthase protects against hippocampal neuronal injuries by increasing neuropeptide Y expression in temporal lobe epilepsy mice

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.

Keywords: Cognitive deficit; Hippocampus; NPY; Neuronal injuries; Temporal lobe epilepsy; nNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epilepsy* / metabolism
  • Epilepsy, Temporal Lobe* / chemically induced
  • Epilepsy, Temporal Lobe* / genetics
  • Epilepsy, Temporal Lobe* / metabolism
  • Hippocampus / metabolism
  • Mammals / metabolism
  • Mice
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Neuropeptide Y / pharmacology
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type I / genetics
  • Nitric Oxide Synthase Type I / metabolism


  • Neuropeptide Y
  • Nitric Oxide
  • Nitric Oxide Synthase Type I