Combined l-citrulline and glutathione administration prevents neuronal cell death following transient brain ischemia.
We previously reported that oral l-citrulline (l-Cit) administration antagonizes neuronal cell death in hippocampus following transient brain ischemia and that oral glutathione (GSH) administration prevents neuronal death through antioxidant activity. Here, we tested potential synergy of combined l-Cit and GSH administration in protection against neuronal death following cerebral ischemia. One day after a 20-min bilateral common carotid artery occlusion (BCCAO), mice were orally administered l-Cit or GSH alone (at 40 or 100mg/kgp.o.) or both (at 40mg/kgp.o. each) daily for 10days. The combination, but not l-Cit or GSH alone at 40mg/kgp.o., significantly prevented neuronal death in the hippocampal CA1 region in BCCAO mice. Consistently, combined l-Cit and GSH administration improved memory-related behavioral deficits observed in BCCAO mice. Combination treatment also significantly rescued reduced endothelial nitric oxide synthase (eNOS) protein levels and antagonized eNOS S-glutathionylation seen following BCCAO ischemia. Recovery of eNOS activity was confirmed by in vivo NO production in hippocampus of BCCAO mice. Taken together, combined administration of l-Cit with GSH rescues eNOS function, thereby inhibiting delayed neuronal death in hippocampus.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Kazuya
K
Matsuo
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Yasushi
Y
Yabuki
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp.
Kohji
K
Fukunaga
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002956:Citrulline / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism
D018696:Neuroprotective Agents; D002956:Citrulline; D052250:Nitric Oxide Synthase Type III; D005978:Glutathione
Bilateral common carotid artery occlusion; Endothelial nitric oxide synthase; Nitric oxide; S-glutathionylation