FK506 abrogates delayed neuronal death via suppression of nitric oxide production in rats.
OBJECTIVE
The mechanism of the neuroprotective effect of FK506 in relation to nitric oxide (NO) production has not been clarified in vivo. We have investigated the effect of FK506 on ischemia-induced NO production in association with the pathogenesis of delayed neuronal death (DND) in rats.


METHODS
In vivo microdialysis was performed in the hippocampus of male Sprague-Dawley rats (250-350 g). Dialysate samples were collected every 3 min. In the ischemia group (n=16), global ischemia was induced for 21 min and reperfusion was achieved. In the FK506 treatment group (n=25), FK506 (1 mg/kg, i.v.) was administered 21 min prior to the onset of global ischemia. Sham operations were done (n=15). The levels of NO(2)(-) in the dialysate samples were determined by the Griess reaction. The animals were decapitated 7 days after ischemia. Coronal brain sections were stained with hematoxylin and eosin.


RESULTS
In the ischemia group, the NO(2)(-) level significantly increased during ischemia. In the FK506 treatment group, there was no significant change in the NO(2)(-) level during ischemia. In histological examinations, FK506 treatment showed a neuroprotective effect against DND.


CONCLUSIONS
The effect of FK506 inhibiting NO production contributes to the neuro-protective effect of FK506 on DND in the hippocampus.
Sasaki
Takahiro
T
Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. tsasaki@sc.itc.keio.ac.jp
Hamada
Junichi
J
Shibata
Mamoru
M
Gotoh
Jun
J
Araki
Nobuo
N
Fukuuchi
Yasuo
Y
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007770:L-Lactate Dehydrogenase; D008297:Male; D017551:Microdialysis / Q000379:methods; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000633:toxicity; D009603:Nitroso Compounds / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D013194:Staining and Labeling; D016559:Tacrolimus / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles
C093285:NOC 18; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D016559:Tacrolimus