Research article

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

Lin Xu^1,2 , Susan C Fagan³ , Jennifer L Waller⁴ , David Edwards⁵ , Cesar V Borlongan^1,2 , Jianqing Zheng¹ , William D Hill⁶ , Giora Feuerstein⁷ and David C Hess^1,2

¹Department of Neurology, Medical College of Georgia, Augusta GA, 30912, USA

²VA Medical Center, Augusta, GA 30904, USA

³University of Georgia School of Pharmacy, Augusta, GA 30912, USA

⁴Biostatistics and Bioinformatics, Medical College of Georgia, Augusta, GA 30912, USA

⁵Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48202, USA

⁶Department of Cell Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA

⁷Department of Cardiovascular Diseases, Merck Research Laboratories, West Point PA 19486, USA

author email corresponding author email

BMC Neurology 2004, 4:7doi:10.1186/1471-2377-4-7

Published:	26 April 2004

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.