# Multiple mechanisms of TRPV1-mediated brain protection following stroke

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $336,875

## Abstract

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, t...

## Key facts

- **NIH application ID:** 9861272
- **Project number:** 5R01NS096186-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Sean P Marrelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,875
- **Award type:** 5
- **Project period:** 2017-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861272

## Citation

> US National Institutes of Health, RePORTER application 9861272, Multiple mechanisms of TRPV1-mediated brain protection following stroke (5R01NS096186-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9861272. Licensed CC0.

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