Disrupting nNOS-PSD95 Interaction Improves Neurological and Cognitive Recoveries after Traumatic Brain Injury

Wenrui Qu, Nai Kui Liu, Xiangbing Wu, Ying Wang, Yongzhi Xia, Yan Sun, Yvonne Lai, Rui Li, Anantha Shekhar, Xiao Ming Xu

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Excessive activation of N-methyl-D-aspartate receptors (NMDARs) and the resulting neuronal nitric oxide synthase (nNOS) activation plays a crucial role in the pathogenesis of traumatic brain injury (TBI). However, directly inhibiting NMDARs or nNOS produces adverse side effects because they play key physiological roles in the normal brain. Since interaction of nNOS-PSD95 is a key step in NMDAR-mediated excitotoxicity, we investigated whether disrupting nNOS-PSD95 interaction with ZL006, an inhibitor of nNOS-PSD95 interaction, attenuates NMDAR-mediated excitotoxicity. In cortical neuronal cultures, ZL006 treatment significantly reduced glutamate-induced neuronal death. In a mouse model of controlled cortical impact (CCI), administration of ZL006 (10 mg/kg, i.p.) at 30 min postinjury significantly inhibited nNOS-PSD95 interaction, reduced TUNEL- and phospho-p38-positive neurons in the motor cortex. ZL006 treatment also significantly reduced CCI-induced cortical expression of apoptotic markers active caspase-3, PARP-1, ratio of Bcl-2/Bax, and phosphorylated p38 MAPK (p-p38). Functionally, ZL006 treatment significantly improved neuroscores and sensorimotor performance, reduced somatosensory and motor deficits, reversed CCI-induced memory deficits, and attenuated cognitive impairment. Histologically, ZL006 treatment significantly reduced the brain lesion volume. These findings collectively suggest that blocking nNOS-PSD95 interaction represents an attractive strategy for ameliorating consequences of TBI and that its action is mediated via inhibiting neuronal apoptosis and p38 MAPK signaling.

Original languageEnglish (US)
Pages (from-to)3859-3871
Number of pages13
JournalCerebral cortex (New York, N.Y. : 1991)
Volume30
Issue number7
DOIs
StatePublished - Jun 1 2020

Keywords

  • N-methyl-D-aspartate receptors
  • PSD95
  • apoptosis
  • nNOS
  • neuroprotection
  • traumatic brain injury

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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