Introduction: The MAVARIC Pre-Clinical trial was performed to demonstrate safety, efficacy and neuroprotection of a multi-drug treatment approach following ischemic stroke. Using previously described in vitro and in vivo ischemic stroke models, we demonstrated that combinational tandem administration of magnesium and verapamil is both safe and neuroprotective. Magnesium, a NMDA modulator, has a well-defined history in stroke, while verapamil, a calcium channel blocker, has demonstrated neuroprotective effects when administered intra-arterially following recanalization.
Methods: In vitro studies used primary cortical neurons undergoing oxygen glucose deprivation (OGD), with reperfusion and combinational therapy for 24 hours. Neuroprotection was determined using cell viability (Hoechst Assay) and dendrite extension (MAP-2). In vivo studies with 4-month-old male C57/Bl6 mice used tandem transient middle cerebral artery occlusion model with intra-arterial combinational therapy immediately following recanalization. Safety and efficacy outcome measures were heart rate (HR), pulse distention (PD) and survival.
Results: In vitro study results demonstrated a significant increase in cell viability and dendrite extension compared to control. Results from in vivo combinational therapy following focal ischemia showed no difference in overall HR, PD or survival compared to control
Conclusions: Thus, combinational therapy following focal ischemia is safe, effective and neuroprotective warranting further study.
Patient Care: Using clinically relevant doses of verapamil and magnesium following experimental ischemic stroke in a cell and animal model allows our study to translate from bench to bedside. The work presented provided pre-clinical support to a currently enrolling clinical trial.
Learning Objectives: 1. Pairing vessel recanalization with intra-arterial neuroprotective pharmacotherapy is feasible.
2. Combinational therapy is safe in the setting of acute large vessel occlusion in animal models.
3. Neuroprotective adjunctive therapy can improve infarct volume and outcome when paired with recanalization/reperfusion in preclinical models of acute stroke.