Posttreatment with the immunosuppressant cyclosporin A in transient focal ischemia

被引:135
作者
Yoshimoto, T [1 ]
Siesjö, BK [1 ]
机构
[1] Queens Med Ctr, Inst Neurosci, Ctr Study Neurol Dis, Honolulu, HI 96813 USA
关键词
D O I
10.1016/S0006-8993(99)01733-3
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Cyclosporin A (CsA) reduces ischemic brain damage when administered in such a way that its penetration across the blood-brain barrier is enhanced. Since only pretreatment has previously been used in focal ischemia, the objective of the present study was to establish whether posttreatment is efficacious and to assess the window of therapeutic opportunity for CsA. To that end, CsA was given 5 min to 6 h after the start of reperfusion following 2 h transient ischemia, and infarct volume was assessed after 48 h by triphenyltetrazolium chloride staining. Attempts were made to circumvent the BBB to CsA by an intracerebral needle lesion, by an increase in the intravenous CsA dose, or by osmotic opening with intracarotid mannitol. The results were compared to those obtained with FK506. Intravenous CsA in a dose bf 10 mg/kg failed to reduce infarct volume, unless preceded by a needle lesion. That procedure, and an increase in CsA dose to 50 mg/kg, reduced infarct volume to about 50% of control, but the higher dose had toxic side effects. The coupled intracarotid infusion of mannitol and CsA (10 mg/kg) was more efficacious, without overt side effects. However, mannitol proved dispensable since CsA alone reduced infarct volume to 30% of control, with a therapeutic window of 3-6 h. When given after 5 min of reflow, CsA reduced infarct volume to 10% of control and was clearly more neuroprotective than FK506. Possibly, this is because CsA blocks the mitochondrial permeability transition pore which is opened under adverse conditions. (C) 1999 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:283 / 291
页数:9
相关论文
共 46 条
[1]   CYCLOSPORINE-ASSOCIATED CENTRAL NERVOUS-SYSTEM TOXICITY AFTER ALLOGENEIC BONE-MARROW TRANSPLANTATION [J].
ATKINSON, K ;
BIGGS, J ;
DARVENIZA, P ;
BOLAND, J ;
CONCANNON, A ;
DODDS, A .
TRANSPLANTATION, 1984, 38 (01) :34-37
[2]  
Barth RF, 1997, CANCER RES, V57, P1129
[3]   EVALUATION OF 2, 3, 5-TRIPHENYLTETRAZOLIUM CHLORIDE AS A STAIN FOR DETECTION AND QUANTIFICATION OF EXPERIMENTAL CEREBRAL INFARCTION IN RATS [J].
BEDERSON, JB ;
PITTS, LH ;
GERMANO, SM ;
NISHIMURA, MC ;
DAVIS, RL ;
BARTKOWSKI, HM .
STROKE, 1986, 17 (06) :1304-1308
[4]   RAT MIDDLE CEREBRAL-ARTERY OCCLUSION - EVALUATION OF THE MODEL AND DEVELOPMENT OF A NEUROLOGIC EXAMINATION [J].
BEDERSON, JB ;
PITTS, LH ;
TSUJI, M ;
NISHIMURA, MC ;
DAVIS, RL ;
BARTKOWSKI, H .
STROKE, 1986, 17 (03) :472-476
[5]   The permeability transition pore as a mitochondrial calcium release channel: A critical appraisal [J].
Bernardi, P ;
Petronilli, V .
JOURNAL OF BIOENERGETICS AND BIOMEMBRANES, 1996, 28 (02) :131-138
[6]  
BULLARD DE, 1985, CANCER RES, V45, P5240
[7]  
Butcher SP, 1997, J NEUROSCI, V17, P6939
[8]  
CHI OZ, 1996, J CEREB BLOOD FLOW M, V16, P323
[9]   IMMUNOSUPPRESSANT FK506 ENHANCES PHOSPHORYLATION OF NITRIC-OXIDE SYNTHASE AND PROTECTS AGAINST GLUTAMATE NEUROTOXICITY [J].
DAWSON, TM ;
STEINER, JP ;
DAWSON, VL ;
DINERMAN, JL ;
UHL, GR ;
SNYDER, SH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (21) :9808-9812
[10]   ON THE INVOLVEMENT OF A CYCLOSPORINE-A SENSITIVE MITOCHONDRIAL PORE IN MYOCARDIAL REPERFUSION INJURY [J].
DUCHEN, MR ;
MCGUINNESS, O ;
BROWN, LA ;
CROMPTON, M .
CARDIOVASCULAR RESEARCH, 1993, 27 (10) :1790-1794