A sensory stimulation-based collateral therapeutic for ischemic stroke: new insights and limitations
Stroke is currently the leading cause of long-term disability and the fifth leading cause of death in the United States, and prevalence is on the rise due to increasing aging populations. Nearly 90% of strokes are ischemic, where there is a blockage of blood flow to the brain. Despite many clinical and pre-clinical attempts to develop novel treatments, there remains only one FDA-approved treatment for stroke, rtPA, which breaks down the clot, however only about 5% of patients are eligible to receive it. Numerous stage III clinical trials have failed, partially due to not taking major stroke risk factors into account during pre-clinical research. Given the poor prognosis and the fact that ‘time is brain’ when it comes to stroke damage prevention, there is a clear need to develop a rapid and long-lasting treatment to protect from impending ischemic stroke damage. Harnessing the brains endogenous mechanisms for protection via collateral therapeutics has become an important area of research and a potentially viable solution to prevent ischemic stroke damage. Our lab has discovered that when using a rat model of ischemic stroke (permanent middle cerebral artery occlusion), intermittent sensory stimulation treatment, when delivered within two hours of ischemic onset, completely protects the cortex from impending ischemic stroke damage. This protection is due in part to retrograde blood flow through collateral vessels and into the occluded middle cerebral artery. This collateral-based treatment is appealing as it is non-invasive and non-pharmacological, and has the potential to be delivered rapidly. This dissertation will present evidence of the translational capabilities of this treatment, and evidence demonstrating potential clinical limitations by testing it under conditions in which the brains vasculature has been altered, either due to anesthesia, stroke risk factors or the species used to model ischemic stroke. We found that the protective effects of this treatment are not dependent on the type of anesthesia utilized, and are long-lasting. Additionally, this treatment was tested in the presence of hypertension, the number one risk factor for ischemic stroke, and also in mice. The results suggest that this collateral-based sensory stimulation treatment does not prevent ischemic stroke damage in hypertensive conditions, in which the vasculature, including collateral vessels, are known to be impaired. Additionally, when a normotensive mouse model was tested, subjects were not protected. Although this strain reportedly has collaterals, they appear to be impaired under the ischemic conditions utilized in our lab. These mice may represent a human subpopulation that do not have fully developed or fully functional collateral vessels. If translational, this work serves to further characterize this treatment and potentially identifies groups of patients that may not exhibit complete protection from ischemic stroke, thus highlighting the importance of the collateral vasculature in the protection from ischemic stroke damage and emphasizing the need for further research on the collateral system to identify variables that can enhance its function.