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      Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats

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          Abstract

          Supplemental Digital Content is available in the text.

          Abstract

          Background and Purpose—

          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.

          Methods—

          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.

          Results—

          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.

          Conclusions—

          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.

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          Most cited references30

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          A semiautomated method for measuring brain infarct volume.

          An accurate, reproducible method for determining the infarct volumes of gray matter structures is presented for use with presently available image analysis systems. Areas of stained sections with optical densities above that of a threshold value are automatically recognized and measured. This eliminates the potential error and bias inherent in manually delineating infarcted regions. Moreover, the volume of surviving normal gray matter is determined rather than that of the infarct. This approach minimizes the error that is introduced by edema, which distorts and enlarges the infarcted tissue and surrounding white matter.
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            Central neural pathways for thermoregulation.

            Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction.
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              Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of a promising treatment modality--Part 2: Practical aspects and side effects.

              Induced hypothermia can be used to protect the brain from post-ischemic and traumatic neurological injury. Potential clinical applications and the available evidence are discussed in a separate paper. This review focuses on the practical aspects of cooling and physiological changes induced by hypothermia, as well as the potential side effects that may develop. These side effects can be serious and, if not properly dealt with, may negate some or all of hypothermia's potential benefits. However, many of these side effects can be prevented or modified by high-quality intensive care treatment, which should include careful monitoring of fluid balance, tight control of metabolic aspects such as glucose and electrolyte levels, prevention of infectious complications and various other interventions. The speed and duration of cooling and rate of re-warming are key factors in determining whether hypothermia will be effective; however, the risk of side effects also increases with longer duration. Realizing hypothermia's full therapeutic potential will therefore require meticulous attention to the prevention and/or early treatment of side effects, as well as a basic knowledge and understanding of the underlying physiological and pathophysiological mechanisms. These and other, related issues are dealt with in this review.
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                Author and article information

                Journal
                Stroke
                Stroke
                STR
                Stroke; a Journal of Cerebral Circulation
                Lippincott Williams & Wilkins
                0039-2499
                1524-4628
                July 2016
                27 June 2016
                : 47
                : 7
                : 1907-1913
                Affiliations
                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.).
                Author notes
                Correspondence to Shan Ping Yu, MD, PhD, 101 Woodruff Circle, Woodruff Memorial Research Bldg, Suite 620, Emory University School of Medicine, Atlanta, GA 30322. E-mail spyu@ 123456emory.edu
                Article
                00033
                10.1161/STROKEAHA.116.013061
                4927220
                27301934
                23f49461-0b9a-45f5-9f54-eb2cc45b7ad1
                © 2016 The Authors.

                Stroke is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.

                History
                : 8 February 2016
                : 21 April 2016
                : 3 May 2016
                Categories
                10178
                10181
                Original Contributions
                Basic Sciences
                Custom metadata
                TRUE

                cell death,hypothermia,middle cerebral artery,neurotensin receptor 1,shivering,stroke

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