Alleviated cerebral infarction in male mice lacking all nitric oxide synthase isoforms after middle cerebral artery occlusion

J Anesth. 2024 Feb;38(1):44-56. doi: 10.1007/s00540-023-03271-8. Epub 2023 Nov 1.

Abstract

Purpose: The role of the nitric oxide synthases (NOSs) system in cerebral infarction has been examined in pharmacological studies with non-selective NOSs inhibitors. However, due to the non-specificity of the non-selective NOSs inhibitors, its role remains to be fully elucidated. We addressed this issue in mice in which neuronal, inducible, and endothelial NOS isoforms were completely disrupted.

Methods and results: We newly generated mice lacking all three NOSs by crossbreeding each single NOS-/- mouse. In the male, cerebral infarct size at 24 h after middle cerebral artery occlusion (MCAO) was significantly smaller in the triple n/i/eNOSs-/- genotype as compared with wild-type genotype. Neurological deficit score and mortality rate were also significantly lower in the triple n/i/eNOSs-/- than in the WT genotype. In contrast, in the female, there was no significant difference in the cerebral infarct size in the two genotypes. In the male triple n/i/eNOSs-/- genotype, orchiectomy significantly increased the cerebral infarct size, and in the orchiectomized male triple n/i/eNOSs-/- genotype, treatment with testosterone significantly reduced it. Cyclopaedic and quantitative comparisons of mRNA expression levels in cerebral infarct lesions between the male wild-type and triple n/i/eNOSs-/- genotypes at 1 h after MCAO revealed significant involvements of decreased oxidative stress and mitigated mitochondrial dysfunction in the alleviated cerebral infarction in the male triple n/i/eNOSs-/- genotype.

Conclusions: These results provide the first evidence that the NOSs system exerts a deleterious effect against acute ischemic brain injury in the male.

Keywords: Cerebral infarction; Mice; Nitric oxide synthase; Sex difference; Testosterone.

MeSH terms

  • Animals
  • Female
  • Infarction, Middle Cerebral Artery*
  • Male
  • Mice
  • Mice, Knockout
  • Nitric Oxide
  • Nitric Oxide Synthase* / genetics
  • Nitric Oxide Synthase* / metabolism
  • Oxidative Stress
  • Protein Isoforms / metabolism

Substances

  • Nitric Oxide Synthase
  • Protein Isoforms
  • Nitric Oxide