Thrombolysis and endovascular thrombectomy (ET), remain the only two FDA-approved therapies for acute ischemic stroke. Despite the efficacy of ET, 50% of the patients remain disabled at 3 months. Adjunctive therapies to thrombolysis and ET are needed that provide “bridging neuroprotection” and improve collateral blood flow. Since presence of collaterals is a major predictor of outcome with ET, a promising new therapeutic avenue is development of “collateral therapeutics. Translation from the bench (rodent stroke models) to the bedside has been plagued by failure. The NINDS Stroke Preclinical Assessment Network (SPAN) has been an attempt to bridge this translational chasm using a multi-site preclinical randomized clinical trial (pRCT) network modeled after human clinical trials. The Medical College of Georgia/Augusta University was one of the 6 testing centers in SPAN 1. We were a high performing center as demonstrated by our consistent infarct size in the middle cerebral artery (MCA) occlusion model. SPAN 1 was successful and demonstrated feasibility with excellent protocol adherence, excellent data completion and low rates of animal loss in a large, multi-site preclinical network The Specific Aims for SPAN 2 include: Aim 1. Test up to 8 selected drugs/interventions in parallel, in collaboration with the Coordinating Center, NINDS and the other testing laboratories in the SPAN Network, in a multisite pRCT design to select the best cerebroprotective agent(s) for clinical trial in acute stroke. Aim 2. Assess short and long-term functional outcomes after experimental stroke, with a specific emphasis on neuroimaging and behavioral testing. Aim 3. As part of the SPAN Network, propose new ideas for sub-studies and manuscripts and develop a training pipeline for the next generation of preclinical stroke investigators. Expected impact: We will advance the most effective drug/intervention(s) into human clinical trial.