Translating Drug-Induced Hibernation to Therapeutic Hypothermia

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 (T-a). Activation of adenosine A(1) receptors (A(1)ARs) 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 A(1)AR combined with a lower Ta would provide a means of managing core body temperature (T-b) below 37 degrees C for therapeutic purposes. We targeted the A(1)AR within the CNS by combining systemic delivery of the A1AR agonist N-6-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 T-a of 16 degrees C, induce and maintain the T-b between 29 and 31 degrees C for 24 h in both naive 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 A(1)AR activation in combination with a thermal gradient shows promise as a novel and effective pharmacological adjunct for inducing safe and reversible targeted temperature management.