Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats.

Hdl Handle:
http://hdl.handle.net/10675.2/131
Title:
Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats.
Authors:
Xu, Lin; Fagan, Susan C.; Waller, Jennifer L.; Edwards, David; Borlongan, Cesar V ( 0000-0002-2966-9782 ) ; Zheng, Jianqing; Hill, William D; Feuerstein, Giora; Hess, David C.
Abstract:
BACKGROUND: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens. METHODS: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats. RESULTS: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose. CONCLUSIONS: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4-5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.
Citation:
BMC Neurol. 2004 Apr 26; 4:7
Issue Date:
19-May-2004
URI:
http://hdl.handle.net/10675.2/131
DOI:
10.1186/1471-2377-4-7
PubMed ID:
15109399
PubMed Central ID:
PMC415551
Type:
Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.
ISSN:
1471-2377
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorXu, Linen_US
dc.contributor.authorFagan, Susan C.en_US
dc.contributor.authorWaller, Jennifer L.en_US
dc.contributor.authorEdwards, Daviden_US
dc.contributor.authorBorlongan, Cesar Ven_US
dc.contributor.authorZheng, Jianqingen_US
dc.contributor.authorHill, William Den_US
dc.contributor.authorFeuerstein, Gioraen_US
dc.contributor.authorHess, David C.en_US
dc.date.accessioned2010-09-24T22:03:25Z-
dc.date.available2010-09-24T22:03:25Z-
dc.date.issued2004-05-19en_US
dc.identifier.citationBMC Neurol. 2004 Apr 26; 4:7en_US
dc.identifier.issn1471-2377en_US
dc.identifier.pmid15109399en_US
dc.identifier.doi10.1186/1471-2377-4-7en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/131-
dc.description.abstractBACKGROUND: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens. METHODS: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats. RESULTS: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose. CONCLUSIONS: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4-5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.en_US
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshDisease Models, Animalen_US
dc.subject.meshDose-Response Relationship, Drugen_US
dc.subject.meshDrug Evaluation, Preclinicalen_US
dc.subject.meshInfarction, Middle Cerebral Artery / complications / drug therapyen_US
dc.subject.meshInjections, Intravenousen_US
dc.subject.meshIschemic Attack, Transient / complications / drug therapyen_US
dc.subject.meshMaleen_US
dc.subject.meshMinocycline / administration & dosage / pharmacokinetics / therapeutic useen_US
dc.subject.meshNeurologic Examination / drug effectsen_US
dc.subject.meshNeuroprotective Agents / administration & dosage / pharmacokinetics / therapeutic useen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshTime Factorsen_US
dc.subject.meshTreatment Outcomeen_US
dc.titleLow dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
dc.typeResearch Support, U.S. Gov't, Non-P.H.S.en_US
dc.typeResearch Support, U.S. Gov't, P.H.S.en_US
dc.identifier.pmcidPMC415551en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameDepartment of Biostatistics and Epidemiology-
dc.contributor.corporatenameDepartment of Cellular Biology and Anatomy-

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