title: 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.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yabuki
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Miyuki
authors.initials: M
authors.lastname: Shigano
authors.forename: Kota
authors.initials: K
authors.lastname: Kumagai
authors.forename: Masahiko
authors.initials: M
authors.lastname: Morita
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002956:Citrulline / Q000008:administration & dosage*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000150:complications / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis
chemical_list: D018696:Neuroprotective Agents; D002956:Citrulline; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse