Oral l-Citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection

Yasushi Yabuki, Norifumi Shioda, Yui Yamamoto, Miyuki Shigano, Kota Kumagai, Masahiko Morita, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)


l-citrulline (l-Cit) is known to increase nitric oxide (NO) production via the increase of l-arginine (l-Arg) concentration in the blood and improve endothelial dysfunction in cardiovascular diseases. However, little is known about the effects of l-Cit on cerebrovascular dysfunction. Here we showed that oral l-Cit administration prevents cerebrovascular injury following cerebral ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. After BCCAO ischemia, mice were treated with l-Cit (50, 75, or 100 mg/kg p.o.) for 10 days once a day. l-Cit administration not only prevented neuronal cell death but also prevented capillary loss in the hippocampal region following brain ischemia. The cerebrovascular protective effect of l-Cit was associated with the restoration of endothelial nitric oxide synthase (eNOS) expression in the hippocampus. In addition, we devised a novel protocol to analyze NOx- (NO2- and NO3-) productions following l-Arg infusion using in vivo microdialysis and revealed that decreased l-Arg-induced NOx- levels were improved in the hippocampus of BCCAO mice following repeated l-Cit administration. Finally, memory deficits following brain ischemia were improved by oral administration of l-Cit. In summary, l-Cit is a potential therapeutic agent that protects cerebrovascular injury and in turn prevents neuronal cell death. Thereby, oral l-Cit administration improves cognitive deficits following brain ischemia.

Original languageEnglish
Pages (from-to)157-167
Number of pages11
JournalBrain research
Publication statusPublished - 2013 Jul 3


  • Bilateral common carotid artery occlusion
  • Ca/calmodulin dependent protein kinase II
  • Endothelial nitric oxide synthase
  • Neuroprotection
  • Nitric oxide
  • l-citrulline

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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