{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T11:58:59Z","timestamp":1781265539467,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,10]]},"group-title":"Neuroscience","reference-count":90,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Purpose<\/jats:title>\n                  <jats:p>Mild hypothermia provides potent neuroprotection in experimental ischemic stroke, however, its implementation in awake stroke patients is hampered by the induction of intense shivering and inconsistent body temperature control. Pharmacological activation of peripheral\/peritoneal TRPV1 channels with non-pungent capsinoids offers a means to induce hypothermia while minimizing TRPV1 activation in the injury region. We tested whether capsinoid-mediated mild hypothermia, initiated within the post-stroke period, reduces brain injury and improves functional outcomes in aged mice.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Aged (18\u201320 months) male and female C57BL\/6 mice underwent either permanent distal middle cerebral artery (MCA) occlusion (pdMCAO) or 60-minute MCA occlusion\/reperfusion (MCAO\/R). At 2 or 4 hours after stroke, mice received intraperitoneal injections of vehicle or capsinoids (&gt;97% purity; 40 mg\/kg) every 90 minutes to induce mild hypothermia for 4.5\u20136 hours. Core temperature was monitored by wireless probe. After pdMCAO, infarct volume was quantified at post-stroke day 3 (PSD3) by TTC and brain atrophy at PSD30 by iodine-enhanced microCT; sensorimotor function (DigiGait, forelimb grip strength, foot fault) was assessed at PSD7 and PSD30. Survival was the primary measured outcome for MCAO\/R.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Capsinoids induced a rapid and sustained reduction in core temperature of 2\u20134\u00b0C, independent of sex. In the pdMCAO model, capsinoid-induced hypothermia reduced infarct volume by 48% at PSD3 and decreased chronic cortical tissue loss by 44% at PSD30. Capsinoid-treated mice showed significant improvements in gait, grip strength, and contralateral foot fault performance at PSD7 and PSD30. In the MCAO\/R model, survival was significantly higher in capsinoid-treated mice (80%) versus vehicle controls (33%) through PSD3.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Intraperitoneal capsinoid administration after stroke induces mild hypothermia in aged mice and confers robust acute neuroprotection and improved chronic functional outcome and survival. These preclinical findings add support for the use of capsinoids as a means to target peripheral thermoeffectors for promoting neuroprotective hypothermia in conscious stroke subjects.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.05.730536","type":"posted-content","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T21:10:33Z","timestamp":1781125833000},"source":"Crossref","is-referenced-by-count":0,"title":["Capsinoids (non-pungent TRPV1 agonists) promote mild hypothermia and improved outcome following stroke in aged mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2262-5573","authenticated-orcid":false,"given":"Alexander P.","family":"Andersohn","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sodam","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea N.","family":"Doan","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Cantrell","sequence":"additional","affiliation":[{"name":"Natural Products Utilization Research Unit, Agricultural Research Service, United States Department of Agriculture, University, MS, 38677, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Jarret","sequence":"additional","affiliation":[{"name":"Plant Genetic Resources Conservation Unit, Agricultural Research Service, United States Department of Agriculture, 1109 Experiment Street, Griffin, GA 30223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gab S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8476-4785","authenticated-orcid":false,"given":"Sean P.","family":"Marrelli","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas McGovern Medical School at Houston, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061204350824000_2026.06.05.730536v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1804492"},{"key":"2026061204350824000_2026.06.05.730536v1.2","doi-asserted-by":"publisher","DOI":"10.1161\/str.0000000000000513"},{"key":"2026061204350824000_2026.06.05.730536v1.3","doi-asserted-by":"publisher","DOI":"10.1136\/svn-2019-000262"},{"key":"2026061204350824000_2026.06.05.730536v1.4","doi-asserted-by":"publisher","DOI":"10.1093\/neuros\/nyz004"},{"key":"2026061204350824000_2026.06.05.730536v1.5","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.110.612358"},{"key":"2026061204350824000_2026.06.05.730536v1.6","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000257304.21967.ba"},{"key":"2026061204350824000_2026.06.05.730536v1.7","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.109.562827"},{"key":"2026061204350824000_2026.06.05.730536v1.8","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.111.630624"},{"issue":"10","key":"2026061204350824000_2026.06.05.730536v1.9","first-page":"1977","article-title":"\u201cThrombolytic therapy in acute occlusion of the intracranial internal carotid artery bifurcation,\u201d (in eng)","volume":"16","year":"1995","journal-title":"AJNR Am J Neuroradiol"},{"key":"2026061204350824000_2026.06.05.730536v1.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199512143332401"},{"key":"2026061204350824000_2026.06.05.730536v1.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1214300"},{"key":"2026061204350824000_2026.06.05.730536v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(16)00163-x"},{"key":"2026061204350824000_2026.06.05.730536v1.13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1213701"},{"key":"2026061204350824000_2026.06.05.730536v1.14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1212793"},{"key":"2026061204350824000_2026.06.05.730536v1.15","doi-asserted-by":"publisher","DOI":"10.1097\/01.sa.0000087691.31092.12"},{"key":"2026061204350824000_2026.06.05.730536v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2014.04.052"},{"key":"2026061204350824000_2026.06.05.730536v1.17","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000153410.87750.53"},{"key":"2026061204350824000_2026.06.05.730536v1.18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2044.2009.06237.x"},{"key":"2026061204350824000_2026.06.05.730536v1.19","doi-asserted-by":"publisher","DOI":"10.1186\/cc11235"},{"key":"2026061204350824000_2026.06.05.730536v1.20","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000079019.02601.90"},{"key":"2026061204350824000_2026.06.05.730536v1.21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa003289"},{"key":"2026061204350824000_2026.06.05.730536v1.22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012689"},{"key":"2026061204350824000_2026.06.05.730536v1.23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcps050929"},{"key":"2026061204350824000_2026.06.05.730536v1.24","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.7218"},{"key":"2026061204350824000_2026.06.05.730536v1.25","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16645112"},{"key":"2026061204350824000_2026.06.05.730536v1.26","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.110.595371"},{"key":"2026061204350824000_2026.06.05.730536v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3174"},{"key":"2026061204350824000_2026.06.05.730536v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.08.025"},{"key":"2026061204350824000_2026.06.05.730536v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2010.44"},{"key":"2026061204350824000_2026.06.05.730536v1.30","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm083"},{"key":"2026061204350824000_2026.06.05.730536v1.31","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00329.2013"},{"key":"2026061204350824000_2026.06.05.730536v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17548-y"},{"key":"2026061204350824000_2026.06.05.730536v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2021.109228"},{"key":"2026061204350824000_2026.06.05.730536v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2005.01.001"},{"key":"2026061204350824000_2026.06.05.730536v1.35","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-012-9688-y"},{"key":"2026061204350824000_2026.06.05.730536v1.36","doi-asserted-by":"publisher","DOI":"10.1111\/ijs.12151"},{"key":"2026061204350824000_2026.06.05.730536v1.37","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.116.014200"},{"key":"2026061204350824000_2026.06.05.730536v1.38","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.110.592295"},{"key":"2026061204350824000_2026.06.05.730536v1.39","doi-asserted-by":"publisher","DOI":"10.1097\/ccm.0000000000000229"},{"key":"2026061204350824000_2026.06.05.730536v1.40","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00296.2013"},{"key":"2026061204350824000_2026.06.05.730536v1.41","doi-asserted-by":"publisher","DOI":"10.1080\/23328940.2015.1024383"},{"key":"2026061204350824000_2026.06.05.730536v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/39807"},{"key":"2026061204350824000_2026.06.05.730536v1.43","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.80139"},{"key":"2026061204350824000_2026.06.05.730536v1.44","doi-asserted-by":"publisher","DOI":"10.1124\/pr.109.001263"},{"key":"2026061204350824000_2026.06.05.730536v1.45","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13038"},{"key":"2026061204350824000_2026.06.05.730536v1.46","doi-asserted-by":"crossref","unstructured":"A. P. Andersohn , T. Wu , A. N. Doan , C. L. Cantrell , R. L. Jarret , and S. P. Marrelli , \u201cPeritoneal delivery of capsinoids, nonpungent TRPV1 agonists, induces mild hypothermia in concious mice through TRPV1 activation of visceral vagal afferents.,\u201c vol. (Accepted, soon to be published), ed: Scientific Reports, 2025.","DOI":"10.1038\/s41598-025-21388-6"},{"key":"2026061204350824000_2026.06.05.730536v1.47","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2261-10-51"},{"key":"2026061204350824000_2026.06.05.730536v1.48","unstructured":"C. L. Cantrell and R. L. Jarret , \u201cMethods for extracting and purifying capsinoids such as capsiate and dihydrocapsiate from capsicum sp. fruit,\u201d Unites States Patent Appl. US16\/171,953, 2018."},{"key":"2026061204350824000_2026.06.05.730536v1.49","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.119.025955"},{"key":"2026061204350824000_2026.06.05.730536v1.50","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00465"},{"key":"2026061204350824000_2026.06.05.730536v1.51","doi-asserted-by":"publisher","DOI":"10.2217\/whe.11.22"},{"key":"2026061204350824000_2026.06.05.730536v1.52","doi-asserted-by":"publisher","DOI":"10.1017\/s1481803500012471"},{"key":"2026061204350824000_2026.06.05.730536v1.53","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.105.166550"},{"key":"2026061204350824000_2026.06.05.730536v1.54","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0900854"},{"key":"2026061204350824000_2026.06.05.730536v1.55","doi-asserted-by":"publisher","DOI":"10.1186\/1745-6215-12-S1-A8"},{"key":"2026061204350824000_2026.06.05.730536v1.56","doi-asserted-by":"publisher","DOI":"10.1111\/ijs.12294"},{"key":"2026061204350824000_2026.06.05.730536v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)02567-6"},{"key":"2026061204350824000_2026.06.05.730536v1.58","doi-asserted-by":"publisher","DOI":"10.1177\/1941874413519802"},{"key":"2026061204350824000_2026.06.05.730536v1.59","doi-asserted-by":"publisher","DOI":"10.21037\/tp-23-253"},{"key":"2026061204350824000_2026.06.05.730536v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2022.06.002"},{"key":"2026061204350824000_2026.06.05.730536v1.61","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.14972"},{"key":"2026061204350824000_2026.06.05.730536v1.62","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000129840.66938.75"},{"key":"2026061204350824000_2026.06.05.730536v1.63","doi-asserted-by":"publisher","DOI":"10.1186\/1471-227X-15-S1-A7"},{"key":"2026061204350824000_2026.06.05.730536v1.64","doi-asserted-by":"publisher","DOI":"10.1542\/hpeds.2023-007403"},{"key":"2026061204350824000_2026.06.05.730536v1.65","doi-asserted-by":"publisher","DOI":"10.4037\/ccn2011618"},{"key":"2026061204350824000_2026.06.05.730536v1.66","doi-asserted-by":"publisher","DOI":"10.1007\/s12028-010-9474-7"},{"key":"2026061204350824000_2026.06.05.730536v1.67","doi-asserted-by":"publisher","DOI":"10.1136\/neurintsurg-2014-011562"},{"key":"2026061204350824000_2026.06.05.730536v1.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.06.006"},{"key":"2026061204350824000_2026.06.05.730536v1.69","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e3181962ad5"},{"key":"2026061204350824000_2026.06.05.730536v1.70","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2015.10.027"},{"key":"2026061204350824000_2026.06.05.730536v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2018.07.001"},{"key":"2026061204350824000_2026.06.05.730536v1.72","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(03)00266-7"},{"key":"2026061204350824000_2026.06.05.730536v1.73","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(13)61953-4"},{"key":"2026061204350824000_2026.06.05.730536v1.74","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2926-0_32"},{"key":"2026061204350824000_2026.06.05.730536v1.75","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000485"},{"key":"2026061204350824000_2026.06.05.730536v1.76","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2007.01841.x"},{"key":"2026061204350824000_2026.06.05.730536v1.77","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2000.tb03026.x"},{"key":"2026061204350824000_2026.06.05.730536v1.78","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.5"},{"key":"2026061204350824000_2026.06.05.730536v1.79","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.113.001796"},{"key":"2026061204350824000_2026.06.05.730536v1.80","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113494"},{"key":"2026061204350824000_2026.06.05.730536v1.81","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107777"},{"key":"2026061204350824000_2026.06.05.730536v1.82","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.12.007"},{"key":"2026061204350824000_2026.06.05.730536v1.83","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000208"},{"key":"2026061204350824000_2026.06.05.730536v1.84","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2025.1670175"},{"key":"2026061204350824000_2026.06.05.730536v1.85","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.05.048"},{"key":"2026061204350824000_2026.06.05.730536v1.86","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.06.006"},{"key":"2026061204350824000_2026.06.05.730536v1.87","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2013.102"},{"key":"2026061204350824000_2026.06.05.730536v1.88","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600059"},{"key":"2026061204350824000_2026.06.05.730536v1.89","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2009.07.006"},{"key":"2026061204350824000_2026.06.05.730536v1.90","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.150725"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.05.730536","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T11:35:18Z","timestamp":1781264118000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.05.730536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":90,"URL":"https:\/\/doi.org\/10.64898\/2026.06.05.730536","relation":{},"subject":[],"published":{"date-parts":[[2026,6,10]]},"subtype":"preprint"}}