Abstract
BackgroundMinocycline, 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.MethodsRats 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.ResultsMinocycline 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.ConclusionsThe 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.
Highlights
Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally
Before translation of experimental stroke results to clinical trials in stroke patients can occur, a better understanding of the effective intravenous doses and the therapeutic window of minocycline must be obtained. The purpose of this investigation was to determine whether doses of minocycline which result in serum levels compatible with human administration, are effective in experimental cerebral ischemia
Temporary middle cerebral artery occlusion (TMCAO) model Male Sprague-Dawley rats weighing 270 to 330 gm were used for our studies
Summary
Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. Minocycline is a tetracycline antibiotic with demonstrated anti-inflammatory [1,2,3], glutamate antagonist [3,4], and anti-apoptotic actions [5,6,7,8] in many models of brain injury [2,3,9,10,11] These properties, along with its superior human safety and blood-brain-barrier penetration make it an ideal candidate for clinical trials in stroke and other neurological diseases [12]. Before translation of experimental stroke results to clinical trials in stroke patients can occur, a better understanding of the effective intravenous doses and the therapeutic window of minocycline must be obtained The purpose of this investigation was to determine whether doses of minocycline which result in serum levels compatible with human administration, are effective in experimental cerebral ischemia. This study explored whether such dosing regimens of minocycline could confer neuroprotection at a therapeutic window of at least 4 hours after the onset of ischemia
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