Project Summary/Abstract Decades of neuroprotection clinical trials for large vessel occlusion (LVO) acute ischemic stroke (AIS) failed to translate clinically. While these clinical trials were conducted, two treatments were approved for LVO AIS: 1) tPA thrombolysis within 6 hrs; and 2) Endovascular Arterial Thrombectomy (EAT) within 24 hrs of stroke onset were developed with strict imaging guidelines and only 25% qualified for treatment. A tacit assumption in Neuroprotection is tissue to protect. Neuroprotection clinical trials in AIS did not qualify patients by imaging. In "A New Paradigm for Neuroprotection Clinical Trials in Acute Ischemic Stroke" (2) the new paradigm shifted to "freezing the penumbra and core" early after stroke with imaging to qualify for tPA and EVT which could qualify 200,000 AIS in the US and 12.7M globally. Shearit, LLC, promotes Lamiflo™ a 4000kDA drag reducing polymer (DRP) of polyethylene oxide (US Patent 9,763,975 B1, Sept. 19, 2017) for cerebrovascular disease. and cancer (U.S. Patent No. 10,792,304 issued October 6, 2020). Lamiflo™ is the only treatment for AIS enhancing flow by the physical dynamics blood and red blood cell (RBC) flow, not pharmacologically and does not rely on tissue or vascular viability. It converts turbulent to laminar flow occurring at blood vessel bifurcations, vascular calcifications. It reduces near vessel wall cell free layer, axial RBC flow, plasma skimming and increases capillary RBC density to improve tissue oxygenation. Increased microvascular flow increases capillary endothelial wall shear rate, (highest in capillaries). Low endothelial wall shear rate detected by the glycocalyx wreaks havoc on endothelial function--increased water permeability, leukocyte endothelial adhesion and transendothelial transport, decreased nitric oxide synthesis, and increased cytokine, chemokine and microglial activation. Specific Aim: Demonstrate that Lamiflo™ at plasma levels of 5, and 10 ppm injected i.v.at 1 hr after transient middle cerebral artery occlusion (tMCAO) decreases the ischemic penumbra and core volumes after 2.5 hrs of tMCAO by monofilament (MFO) and embolism thrombus occlusion (EBO) without increasing the rate of hemorrhagic transformation (HT) and with 20% improved neurobehavioral recovery. One year old Sprague Dawley (SD) male and female rats are treated with Lamiflo™ i.v. at 1 hr after tMCAO by: 1) monofilament occlusion (MFO) or 2) embolus occlusion (EBO) with revascularization at 2.5 hrs, by MFO filament withdrawal and rtPA infusion for EBO. Magnetic Resonance Imaging (MRI) at baseline, at 2.5 hrs before reperfusion to quantitate Lamiflo™ reduction of penumbra and core volumes (Aim #1); and at 10 days recovery for final core volumes (Aim #2). HT is quantitated by MRI susceptibility weighted imaging (SWI) and quantitative susceptibility mapping (QSM) after 10 days recovery and Perl's iron stain. These studies will show the efficacy of Lamiflo™in reducing the volume of core and penu...