A 2 × 2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning

TY - JOUR

T1 - A 2 × 2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning

T2 - Efficacy in a preclinical trial in murine thromboembolic stroke model

AU - Hoda, MD Nasrul

AU - Fagan, Susan C.

AU - Khan, Mohammad Badruzzaman

AU - Vaibhav, Kumar

AU - Chaudhary, Aizaz

AU - Wang, Lei

AU - Dhandapani, Krishnan Michael

AU - Waller, Jennifer L

AU - Hess, David C

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background: After the failure of so many drugs and therapies for acute ischemic stroke, innovative approaches are needed to develop new treatments. One promising strategy is to test combinations of agents in the pre-hospital setting prior to the administration of intravenous tissue plasminogen activator (IV-tPA) and/or the use of mechanical reperfusion devices in the hospital. Methods: We performed a 2 × 2 factorial design preclinical trial where we tested minocycline (MINO), remote ischemic perconditioning (RIPerC) and their combination treatment in a thromboembolic clot model of stroke in mice, without IV-tPA or later treated with IV-tPA at 4 hours post-stroke. Cerebral blood flow (CBF) was measured by laser speckle contrast imaging (LSCI), behavioral outcomes as neurological deficit score (NDS) and adhesive tape removal test, and infarct size measurement were performed at 48 hours post-stroke. Mice within the experimental sets were randomized for the different treatments, and all outcome measures were blinded. Results: RIPerC significantly improved CBF as measured by LSCI in both with and without tPA treated mice (P < 0.001). MINO and RIPerC treatment were effective alone at reducing infarct size (p < 0.0001) and improving short-term functional outcomes (p < 0.001) in the tPA and non-tPA treated animals. The combination treatment of MINO and RIPerC significantly reduced the infarct size greater than either intervention alone (p < 0.05). There were trends in favor of improving functional outcomes after combination treatment of MINO and RIPerC; however combination treatment group was not significantly different than the individual treatments of MINO and RIPerC. There was no "statistical" interaction between minocycline and RIPerC treatments indicating that the effects of RIPerC and MINO were additive and not synergistic on the outcome measures. Conclusion: In the future, combining these two safe and low cost interventions in the ambulance has the potential to "freeze" the penumbra and improve outcomes in stroke patients. This pre-clinical 2 × 2 design can be easily translated into a pre-hospital clinical trial.

AB - Background: After the failure of so many drugs and therapies for acute ischemic stroke, innovative approaches are needed to develop new treatments. One promising strategy is to test combinations of agents in the pre-hospital setting prior to the administration of intravenous tissue plasminogen activator (IV-tPA) and/or the use of mechanical reperfusion devices in the hospital. Methods: We performed a 2 × 2 factorial design preclinical trial where we tested minocycline (MINO), remote ischemic perconditioning (RIPerC) and their combination treatment in a thromboembolic clot model of stroke in mice, without IV-tPA or later treated with IV-tPA at 4 hours post-stroke. Cerebral blood flow (CBF) was measured by laser speckle contrast imaging (LSCI), behavioral outcomes as neurological deficit score (NDS) and adhesive tape removal test, and infarct size measurement were performed at 48 hours post-stroke. Mice within the experimental sets were randomized for the different treatments, and all outcome measures were blinded. Results: RIPerC significantly improved CBF as measured by LSCI in both with and without tPA treated mice (P < 0.001). MINO and RIPerC treatment were effective alone at reducing infarct size (p < 0.0001) and improving short-term functional outcomes (p < 0.001) in the tPA and non-tPA treated animals. The combination treatment of MINO and RIPerC significantly reduced the infarct size greater than either intervention alone (p < 0.05). There were trends in favor of improving functional outcomes after combination treatment of MINO and RIPerC; however combination treatment group was not significantly different than the individual treatments of MINO and RIPerC. There was no "statistical" interaction between minocycline and RIPerC treatments indicating that the effects of RIPerC and MINO were additive and not synergistic on the outcome measures. Conclusion: In the future, combining these two safe and low cost interventions in the ambulance has the potential to "freeze" the penumbra and improve outcomes in stroke patients. This pre-clinical 2 × 2 design can be easily translated into a pre-hospital clinical trial.

KW - Intravenous tPA

KW - Minocycline

KW - Neurovascular protection

KW - Remote ischemic perconditioning

KW - Thromboembolic stroke

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U2 - 10.1186/2040-7378-6-10

DO - 10.1186/2040-7378-6-10

M3 - Article

VL - 6

JO - Experimental and Translational Stroke Medicine

JF - Experimental and Translational Stroke Medicine

SN - 2040-7378

IS - 1

M1 - 10

ER -