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Restricted clinical efficacy of cyclosporin A on rat transient middle cerebral artery occlusion

Matsumoto, S; Isshiki, A; Watanabe, Y and Wieloch, Tadeusz LU (2002) In Life Sciences 72(4-5). p.591-600
Abstract
The immunosuppressant cyclosporin A (CsA) has been shown to have neuroprotective action. The inhibition of both calcineurin activation and mitochondrial permeability transition pore (mtPTP) opening are considered the primary neuroprotective mechanisms of CsA. Here we have evaluated the effect of CsA on significantly reducing infarct size induced by transient middle cerebral artery occlusion (MCAO) in rats, and examined variable therapeutic applications for brain infarction. Experimental rats were divided into 12 groups according to: CsA administration time (immediately after occlusion or immediately after reperfusion); dosage (between 10 and 50 mg/kg); route (i.v. or i.p.); and with or without needle insertion, which hypothetically... (More)
The immunosuppressant cyclosporin A (CsA) has been shown to have neuroprotective action. The inhibition of both calcineurin activation and mitochondrial permeability transition pore (mtPTP) opening are considered the primary neuroprotective mechanisms of CsA. Here we have evaluated the effect of CsA on significantly reducing infarct size induced by transient middle cerebral artery occlusion (MCAO) in rats, and examined variable therapeutic applications for brain infarction. Experimental rats were divided into 12 groups according to: CsA administration time (immediately after occlusion or immediately after reperfusion); dosage (between 10 and 50 mg/kg); route (i.v. or i.p.); and with or without needle insertion, which hypothetically disrupts the blood brain barrier (BBB). Neuroprotective effects of CsA were hardly noticeable when administered immediately after occlusion or by i.v. injection. By needle insertion, CsA administration significantly reduced infarct size, although vehicle treatment also reduced infarct size compared with nontreatment animals, i.e. no needle insertion. These results suggest that needle insertion allows endogenous neuroprotective substances to pass into the brain. Furthermore, single dosages over 30 mg/kg CsA were excessive and negated potential neuroprotective effects. However, two i.p. administrations of 20 mg/kg CsA immediately and 24 hrs after reperfusion significantly ameliorated the infarct size compared to the vehicle-treated group. We conclude that CsA exhibits significant neuroprotective activity, although its therapeutic application for stroke may be limited by very strict and precise management requirements. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
mtPTP, cyclosporin A, focal cerebral ischemia, neuroprotection
in
Life Sciences
volume
72
issue
4-5
pages
591 - 600
publisher
Elsevier
external identifiers
  • wos:000180261300027
  • pmid:12467900
  • scopus:0037146882
ISSN
1879-0631
DOI
10.1016/S0024-3205(02)02267-1
language
English
LU publication?
yes
id
3226e79c-b799-4852-b816-7cfbc4d924f4 (old id 320260)
date added to LUP
2007-11-02 11:30:55
date last changed
2017-01-01 05:02:11
@article{3226e79c-b799-4852-b816-7cfbc4d924f4,
  abstract     = {The immunosuppressant cyclosporin A (CsA) has been shown to have neuroprotective action. The inhibition of both calcineurin activation and mitochondrial permeability transition pore (mtPTP) opening are considered the primary neuroprotective mechanisms of CsA. Here we have evaluated the effect of CsA on significantly reducing infarct size induced by transient middle cerebral artery occlusion (MCAO) in rats, and examined variable therapeutic applications for brain infarction. Experimental rats were divided into 12 groups according to: CsA administration time (immediately after occlusion or immediately after reperfusion); dosage (between 10 and 50 mg/kg); route (i.v. or i.p.); and with or without needle insertion, which hypothetically disrupts the blood brain barrier (BBB). Neuroprotective effects of CsA were hardly noticeable when administered immediately after occlusion or by i.v. injection. By needle insertion, CsA administration significantly reduced infarct size, although vehicle treatment also reduced infarct size compared with nontreatment animals, i.e. no needle insertion. These results suggest that needle insertion allows endogenous neuroprotective substances to pass into the brain. Furthermore, single dosages over 30 mg/kg CsA were excessive and negated potential neuroprotective effects. However, two i.p. administrations of 20 mg/kg CsA immediately and 24 hrs after reperfusion significantly ameliorated the infarct size compared to the vehicle-treated group. We conclude that CsA exhibits significant neuroprotective activity, although its therapeutic application for stroke may be limited by very strict and precise management requirements.},
  author       = {Matsumoto, S and Isshiki, A and Watanabe, Y and Wieloch, Tadeusz},
  issn         = {1879-0631},
  keyword      = {mtPTP,cyclosporin A,focal cerebral ischemia,neuroprotection},
  language     = {eng},
  number       = {4-5},
  pages        = {591--600},
  publisher    = {Elsevier},
  series       = {Life Sciences},
  title        = {Restricted clinical efficacy of cyclosporin A on rat transient middle cerebral artery occlusion},
  url          = {http://dx.doi.org/10.1016/S0024-3205(02)02267-1},
  volume       = {72},
  year         = {2002},
}