Abstract T P77: Long-term Neuroprotection with Pharmacological Hypothermia by TRPV1 Agonism in Ischemic Stroke

Background: Therapeutic hypothermia is a promising strategy for neuroprotection following stroke. However, current widely available methods are not compatible with conscious patients and produce unwanted physiological stress. We have recently demonstrated that pharmacological hypothermia (PH) through transient receptor potential vanilloid 1 (TRPV1) channel agonism is effective and safe in the conscious mouse and provides significant neuroprotection following ischemic stroke at 24 hours reperfusion. We now evaluate whether this method of PH provides sustained neuroprotection through one month reperfusion. Methods: Three experimental groups were evaluated: sham operated (Sham), stroke with normothermia (Stroke/NT), and stroke with PH (Stroke/PH) (n=8, 10, 7). Stroke was induced by transient occlusion of left distal middle cerebral artery (MCA) plus left common carotid artery for two hours. For the Stroke/PH group, hypothermia (32-34°C) was induced by infusion of TRPV1 agonist (dihydrocapsaicin) for 8 hours; beginning 90 minutes after reperfusion. We evaluated several behavioral tests from pre-stroke up to 28 days reperfusion. Total cerebral infarct was then evaluated in Nissl-stained brain sections at 30 days reperfusion. Results: The foot fault test was the most sensitive in demonstrating extended functional deficit after stroke. With this test, Stroke/NT demonstrated prolonged deficiency (through 21 days reperfusion) compared to Sham. PH treatment (Stroke/PH) demonstrated significant improvement in function compared to Stroke/NT. Other tests demonstrated non-statistically significant performance reduction of Stroke/NT in swimming time, grip side preference, turning and climbing time. Histological analysis demonstrated significant ipsilateral necrosis and hemisphere shrinkage in Stroke/NT brains compared to Stroke/PH brains. Conclusions: In summary, we demonstrate long-term neuroprotection with TRPV1-mediated PH following stroke. These studies support the therapeutic potential of TRPV1 agonism for promoting hypothermia in the conscious stroke subject.