Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats.
Therapeutic hypothermia is a promising strategy for treatment of acute stroke. Clinical translation of therapeutic hypothermia, however, has been hindered because of the lack of efficiency and adverse effects. We sought to enhance the clinical potential of therapeutic hypothermia by combining physical cooling (PC) with pharmacologically induced hypothermia after ischemic stroke.



Wistar rats were subjected to 90-minute middle cerebral artery occlusion by insertion of an intraluminal filament. Mild-to-moderate hypothermia was induced 120 minutes after the onset of stroke by PC alone, a neurotensin receptor 1 (NTR1) agonist HPI-201 (formally ABS-201) alone or the combination of both. The outcomes of stroke were evaluated at 3 and 21 days after stroke.



PC or HPI-201 each showed hypothermic effect and neuroprotection in stroke rats. The combination of PC and HPI-201 exhibited synergistic effects in cooling process, reduced infarct formation, cell death, and blood-brain barrier damages and improved functional recovery after stroke. Importantly, coapplied HPI-201 completely inhibited PC-associated shivering and tachycardia.



The centrally acting hypothermic drug HPI-201 greatly enhanced the efficiency and efficacy of conventional PC; this combined cooling therapy may facilitate clinical translation of hypothermic treatment for stroke.
From the Departments of Anesthesiology (J.H.L., L.W., X.G., S.W., Z.Z.W., S.P.Y.) and Neurology (L.W.), Emory University School of Medicine, Atlanta, GA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA (J.H.L., L.W., X.G., Z.Z.W., S.P.Y.); JT Pharmaceuticals, Mt. Pleasant, SC (T.A.D.); and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston (T.A.D.).
Jin Hwan
JH
Lee
From the Departments of Anesthesiology (J.H.L., L.W., X.G., S.W., Z.Z.W., S.P.Y.) and Neurology (L.W.), Emory University School of Medicine, Atlanta, GA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA (J.H.L., L.W., X.G., Z.Z.W., S.P.Y.); JT Pharmaceuticals, Mt. Pleasant, SC (T.A.D.); and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston (T.A.D.).
Ling
L
Wei
From the Departments of Anesthesiology (J.H.L., L.W., X.G., S.W., Z.Z.W., S.P.Y.) and Neurology (L.W.), Emory University School of Medicine, Atlanta, GA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA (J.H.L., L.W., X.G., Z.Z.W., S.P.Y.); JT Pharmaceuticals, Mt. Pleasant, SC (T.A.D.); and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston (T.A.D.).
Xiaohuan
X
Gu
From the Departments of Anesthesiology (J.H.L., L.W., X.G., S.W., Z.Z.W., S.P.Y.) and Neurology (L.W.), Emory University School of Medicine, Atlanta, GA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA (J.H.L., L.W., X.G., Z.Z.W., S.P.Y.); JT Pharmaceuticals, Mt. Pleasant, SC (T.A.D.); and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston (T.A.D.).
Soonmi
S
Won
From the Departments of Anesthesiology (J.H.L., L.W., X.G., S.W., Z.Z.W., S.P.Y.) and Neurology (L.W.), Emory University School of Medicine, Atlanta, GA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA (J.H.L., L.W., X.G., Z.Z.W., S.P.Y.); JT Pharmaceuticals, Mt. Pleasant, SC (T.A.D.); and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston (T.A.D.).
Zheng Zachory
ZZ
Wei
From the Departments of Anesthesiology (J.H.L., L.W., X.G., S.W., Z.Z.W., S.P.Y.) and Neurology (L.W.), Emory University School of Medicine, Atlanta, GA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA (J.H.L., L.W., X.G., Z.Z.W., S.P.Y.); JT Pharmaceuticals, Mt. Pleasant, SC (T.A.D.); and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston (T.A.D.).
Thomas A
TA
Dix
From the Departments of Anesthesiology (J.H.L., L.W., X.G., S.W., Z.Z.W., S.P.Y.) and Neurology (L.W.), Emory University School of Medicine, Atlanta, GA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA (J.H.L., L.W., X.G., Z.Z.W., S.P.Y.); JT Pharmaceuticals, Mt. Pleasant, SC (T.A.D.); and Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston (T.A.D.). spyu@emory.edu.
Shan Ping
SP
Yu
D000818:Animals; D016923:Cell Death; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D006339:Heart Rate / Q000187:drug effects; D007036:Hypothermia, Induced / Q000379:methods*; D007053:Ice; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000628:therapy*; D008297:Male; D009043:Motor Activity; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009842:Oligopeptides / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018028:Receptors, Neurotensin / Q000819:agonists; D020127:Recovery of Function
C575024:ABS-201; D007053:Ice; D018696:Neuroprotective Agents; D009842:Oligopeptides; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor
cell death; hypothermia; middle cerebral artery; neurotensin receptor 1; shivering; stroke