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Research ArticleArticle

Calcineurin Inhibitors FK506 and SDZ ASM 981 Alleviate the Outcome of Focal Cerebral Ischemic/Reperfusion Injury

D. Bochelen, M. Rudin and A. Sauter
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 653-659;
D. Bochelen
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M. Rudin
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A. Sauter
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Abstract

The neuroprotective properties of drugs binding to FKBP12, with and without subsequent inhibition of calcineurin, were investigated in rat models of ischemic embolic stroke. Drug effects on brain infarct volumes evoked by transient middle cerebral artery occlusion (MCAO) and by permanent MCAO were determined in vivo by T2-weighted magnetic resonance imaging and post mortem by triphenyltetrazolium chloride staining and histology. Drugs binding to FKBP12 and inhibiting calcineurin, such as FK506 and SDZ ASM 981, dose dependently reduced the infarct volumes, determined 48 h after MCAO by both magnetic resonance imaging and triphenyltetrazolium chloride staining but only in the transient MCAO model. In vivo potencies to reduce brain infarcts paralleled the in vitro potencies to inhibit calcineurin. Histological staining after 6 days of survival showed that the neuroprotective effects were permanent. Rapamycin, known to bind with similar affinity to FKBP12 but not to inhibit calcineurin, was not neuroprotective but abolished the neuroprotective effects of FK506 when coadministered. In the permanent MCAO models, FK506 showed no effect when injected before and little effect when injected after MCAO. Measurements of core temperatures after MCAO in controls and drug-treated rats do not support hypothermia being the mechanism responsible for neuroprotection. We conclude that drugs inhibiting calcineurin activity are neuroprotective in focal cerebral ischemia/reperfusion but not in permanent ischemia models, possibly by preventing reperfusion injury.

Footnotes

  • Send reprint requests to: D. Bochelen, S-386.7.37, Novartis Pharma A.G., CH-4002 Basel, Switzerland. E-mail:damien.bochelen{at}pharma.novartis.com

  • Abbreviations:
    MCA
    middle cerebral artery
    MCAO
    middle cerebral artery occlusion
    ANOVA
    analysis of variance
    ICA
    internal carotid artery
    MABP
    mean arterial blood pressure
    ECA
    external carotid artery
    MRI
    magnetic resonance imaging
    TTC
    triphenyltetrazolium chloride
    NOS
    nitric oxide synthase
    FKBPs
    FK506 binding protein
    • Received March 19, 1998.
    • Accepted September 2, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

Calcineurin Inhibitors FK506 and SDZ ASM 981 Alleviate the Outcome of Focal Cerebral Ischemic/Reperfusion Injury

D. Bochelen, M. Rudin and A. Sauter
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 653-659;

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Research ArticleArticle

Calcineurin Inhibitors FK506 and SDZ ASM 981 Alleviate the Outcome of Focal Cerebral Ischemic/Reperfusion Injury

D. Bochelen, M. Rudin and A. Sauter
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 653-659;
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