Stroke is a significant health problem with limited treatment options. In this application, we present a new model in which activation of transient receptor potential vanilloid 1 (TRPV1) channels provides neuroprotection following ischemia/reperfusion (I/R) through two independent yet additive mechanisms. First, we provide evidence that pharmacological activation of vascular TRPV1 channels during the reperfusion phase selectively restores cerebral perfusion to the damaged brain regions. The hypoperfusion which occurs in damaged brain during early reperfusion can be dramatically and quickly restored without affecting the flow in non-injured brain regions. We propose that reactive oxygen species (ROS) produced following stroke lead to increased TRPV1 channel sensitivity to agonists, and thus the increased cerebral blood flow response. Second, activation of TRPV1 channels in the thermoregulatory system produces a rapid and sustainable decrease in body temperature (mild hypothermia) that is neuroprotective. In this context, TRPV1 activation effectively lowers the body's temperature ?set point?, allowing for a more rapid and controlled level of therapeutic hypothermia to be achieved. We have already established that pharmacological activation of TRPV1 channels (?TRPV1 agonism?) is neuroprotective. While part of the neuroprotective effect is through induction of mild hypothermia, our new studies indicate that an additional protective effect may be through restoration of flow to hypoperfused brain regions. We now propose the overall hypothesis that TRPV1 agonism provides two arms of protection following stroke by 1) improving reperfusion in injured brain regions and 2) promoting protective hypothermia. We will study these mechanisms separately and then in combination to determine the additive benefit following stroke in adult and aged mice of both sexes.
In aim 1, we will demonstrate selective increase in cerebral blood flow within the ischemia/reperfusion territory with TRPV1 agonism. These studies include in vivo cerebral blood flow measurements in adult and aged mice of both sexes following stroke.
In aim 2, we will determine the role of ROS in potentiating endothelial TRPV1- mediated vasodilation and increased cerebral blood flow using isolated cerebral arteries and in vivo preparations. We will use a combination of pharmacological approaches, available knockout/transgenic mice, and a novel knockout mouse to demonstrate the specific role of endothelial TRPV1 channels and NOX-derived ROS in the mechanism.
In aim 3, we will demonstrate the long-term neuroprotective benefit of TRPV1 agonism following stroke. We will evaluate the vascular component alone (hypothermia-independent mechanism) as well as the combined vascular and hypothermic components (hypothermia-dependent mechanism). Aged mice of both sexes will be evaluated by behavioral testing, histology, and blood brain barrier function during the course of one month of reperfusion. All together, these studies should establish TRPV1 agonism as a multi-faceted approach to neuroprotection following stroke.
This project explores new methods in the treatment of stroke. In particular, these studies define the way capsaicin-like compounds can be used to produce protective whole body cooling (induced hypothermia) as well as increased blood flow in the injured region of the brain.
|Sancho, Maria; Samson, Nina C; Hald, Bjorn O et al. (2017) KIR channels tune electrical communication in cerebral arteries. J Cereb Blood Flow Metab 37:2171-2184|
|Cao, Zhijuan; Balasubramanian, Adithya; Pedersen, Steen E et al. (2017) TRPV1-mediated Pharmacological Hypothermia Promotes Improved Functional Recovery Following Ischemic Stroke. Sci Rep 7:17685|