Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats.
Fagan, Susan C.
Waller, Jennifer L.
Borlongan, Cesar V
Hill, William D
Hess, David C.
MetadataShow full item record
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.
CitationBMC Neurol. 2004 Apr 26; 4:7
- Administration of melatonin after onset of ischemia reduces the volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model.
- Authors: Pei Z, Pang SF, Cheung RT
- Issue date: 2003 Mar
- Neuroprotective effect of SolCD39, a novel platelet aggregation inhibitor, on transient middle cerebral artery occlusion in rats.
- Authors: Belayev L, Khoutorova L, Deisher TA, Belayev A, Busto R, Zhang Y, Zhao W, Ginsberg MD
- Issue date: 2003 Mar
- Fibroblast growth factor-18 reduced infarct volumes and behavioral deficits after transient occlusion of the middle cerebral artery in rats.
- Authors: Ellsworth JL, Garcia R, Yu J, Kindy MS
- Issue date: 2003 Jun
- Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat.
- Authors: Candelario-Jalil E, González-Falcón A, García-Cabrera M, León OS, Fiebich BL
- Issue date: 2004 May 8
- Delayed systemic administration of PACAP38 is neuroprotective in transient middle cerebral artery occlusion in the rat.
- Authors: Reglodi D, Somogyvari-Vigh A, Vigh S, Kozicz T, Arimura A
- Issue date: 2000 Jun