Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood-brain barrier in mice.
OBJECTIVE
Cyclosporin A, a calcineurin inhibitor, produces neurotoxicity with relatively high frequency in organ-transplanted patients. The aim of the present study was to clarify whether acute liver failure (ALF) simulated to the transient liver dysfunction at an early phase after liver transplantation increases the susceptibility to cyclosporin A-induced neurotoxicity through the blood-brain barrier (BBB) dysfunction.


METHODS
The right internal, left lateral and left internal lobes in male ddy mice were surgically excised under sodium pentobarbital anesthesia. Effect of cyclosporin A on harmine-induced tremors was examined and BBB permeability to (3)[H]cyclosporin A was assessed in partially (70%) hepatectomized mice at postoperative days 1, 3 and 7.


RESULTS
Patrial hepatectomy aggravated harmine-induced tremors. Cyclosporin A (50mg/kg, i.p.) markedly augmented harmine-induced tremors in partially hepatectomized mice at postoperative day 1. Consistent with these behavioral findings, the brain uptake of (3)[H]cyclosporin A in mice injected with (3)[H]cyclosporin A into the jugular vein at postoperative day 1 was significantly increased by partial hepatectomy compared with sham operation.


CONCLUSIONS
Our results indicate that ALF increases BBB permeability to cyclosporin A by lowering the function of P-glycoprotein and tight junctions, consequently leading to augmentation of cyclosporin A-induced neurotoxicity. The possibility that cyclosporin A increases the risk of neurotoxicity including tremors at an early phase of liver transplantation must be considered.
Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Atsushi
A
Yamauchi
Shinya
S
Dohgu
Fuyuko
F
Takata
Takuya
T
Watanabe
Tsuyoshi
T
Nishioku
Junich
J
Matsumoto
Yuka
Y
Ohkubo
Hideki
H
Shuto
Yasufumi
Y
Kataoka
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects; D018929:Cell Culture Techniques; D002460:Cell Line; D016572:Cyclosporine / Q000009:adverse effects* / Q000493:pharmacokinetics; D006247:Harmine / Q000494:pharmacology; D006498:Hepatectomy / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D017114:Liver Failure, Acute / Q000097:blood / Q000209:etiology / Q000378:metabolism; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D020258:Neurotoxicity Syndromes / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D014202:Tremor / Q000139:chemically induced
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D006247:Harmine; D016572:Cyclosporine