title: Translating drug-induced hibernation to therapeutic hypothermia.
abstract: Therapeutic hypothermia (TH) improves prognosis after cardiac arrest; however, thermoregulatory responses such as shivering complicate cooling. Hibernators exhibit a profound and safe reversible hypothermia without any cardiovascular side effects by lowering the shivering threshold at low ambient temperatures (Ta). Activation of adenosine A1 receptors (A1ARs) in the central nervous system (CNS) induces hibernation in hibernating species and a hibernation-like state in rats, principally by attenuating thermogenesis. Thus, we tested the hypothesis that targeted activation of the central A1AR combined with a lower Ta would provide a means of managing core body temperature (Tb) below 37 °C for therapeutic purposes. We targeted the A1AR within the CNS by combining systemic delivery of the A1AR agonist (6)N-cyclohexyladenosine (CHA) with 8-(p-sulfophenyl)theophylline (8-SPT), a nonspecific adenosine receptor antagonist that does not readily cross the blood-brain barrier. Results show that CHA (1 mg/kg) and 8-SPT (25 mg/kg), administered intraperitoneally every 4 h for 20 h at a Ta of 16 °C, induce and maintain the Tb between 29 and 31 °C for 24 h in both naïve rats and rats subjected to asphyxial cardiac arrest for 8 min. Faster and more stable hypothermia was achieved by continuous infusion of CHA delivered subcutaneously via minipumps. Animals subjected to cardiac arrest and cooled by CHA survived better and showed less neuronal cell death than normothermic control animals. Central A1AR activation in combination with a thermal gradient shows promise as a novel and effective pharmacological adjunct for inducing safe and reversible targeted temperature management.
authors: †University of Alaska Fairbanks, 902 North Koyukuk Drive, Fairbanks, Alaska 99775-7000, United States.|‡University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Tulasi R
authors: TR
authors: Jinka
authors: †University of Alaska Fairbanks, 902 North Koyukuk Drive, Fairbanks, Alaska 99775-7000, United States.
authors: Velva M
authors: VM
authors: Combs
authors: †University of Alaska Fairbanks, 902 North Koyukuk Drive, Fairbanks, Alaska 99775-7000, United States.
authors: Kelly L
authors: KL
authors: Drew
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006323:Heart Arrest / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006605:Hibernation / Q000187:drug effects* / Q000502:physiology*; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013696:Temperature; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; C027513:N(6)-cyclohexyladenosine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D000241:Adenosine
keywords: 8-SPT; A1AR and global cerebral ischemia; Adenosine; CHA; cardiac arrest; hibernation; targeted temperature management