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

Lin Xu, Susan C. Fagan, Jennifer L Waller, David Edwards, Cesar V. Borlongan, Jianqing Zheng, William D Hill, Giora Feurstein, David C Hess

Research output: Contribution to journalArticle

125 Citations (Scopus)

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.

Original languageEnglish (US)
Article number7
JournalBMC Neurology
Volume4
DOIs
StatePublished - Apr 26 2004

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Minocycline
Middle Cerebral Artery Infarction
Reperfusion
Hemodynamics
Neuroprotective Agents
Tetracycline
Brain Ischemia
Animal Models
Pharmacokinetics
Stroke
Placebos
Staining and Labeling
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Clinical Neurology

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Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. / Xu, Lin; Fagan, Susan C.; Waller, Jennifer L; Edwards, David; Borlongan, Cesar V.; Zheng, Jianqing; Hill, William D; Feurstein, Giora; Hess, David C.

In: BMC Neurology, Vol. 4, 7, 26.04.2004.

Research output: Contribution to journalArticle

Xu, Lin ; Fagan, Susan C. ; Waller, Jennifer L ; Edwards, David ; Borlongan, Cesar V. ; Zheng, Jianqing ; Hill, William D ; Feurstein, Giora ; Hess, David C. / Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats. In: BMC Neurology. 2004 ; Vol. 4.
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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.",
author = "Lin Xu and Fagan, {Susan C.} and Waller, {Jennifer L} and David Edwards and Borlongan, {Cesar V.} and Jianqing Zheng and Hill, {William D} and Giora Feurstein and Hess, {David C}",
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AU - Xu, Lin

AU - Fagan, Susan C.

AU - Waller, Jennifer L

AU - Edwards, David

AU - Borlongan, Cesar V.

AU - Zheng, Jianqing

AU - Hill, William D

AU - Feurstein, Giora

AU - Hess, David C

PY - 2004/4/26

Y1 - 2004/4/26

N2 - 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.

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