Oral L-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection.

Abstract

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(-) (NO(2-) and NO(3-)) 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.

• Authors: Yasushi Yabuki, Norifumi Shioda, Yui Yamamoto, Miyuki Shigano, Kota Kumagai, Masahiko Morita, Kohji Fukunaga
• Journal: Brain research (Brain Res) Vol. 1520 Pg. 157-67 (Jul 03 2013) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 23685189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Neuroprotective Agents
• Citrulline
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse

Topics

• Administration, Oral
• Animals
• Cell Death (drug effects)
• Cerebrovascular Circulation (drug effects)
• Citrulline (administration & dosage)
• Disease Models, Animal
• Immunohistochemistry
• Ischemic Attack, Transient (complications, metabolism)
• Male
• Memory (drug effects)
• Memory Disorders (drug therapy, etiology, metabolism)
• Mice
• Mice, Inbred C57BL
• Microdialysis (methods)
• Neurons (drug effects)
• Neuroprotective Agents (administration & dosage)
• Nitric Oxide (analysis)
• Nitric Oxide Synthase Type III (biosynthesis)