Translating CNS control of hibernation to non-hibernating species

      Hibernation is energy conservation that is associated with a decrease in core body temperature (Tb). Therapeutic hypothermia is now standard of care therapy for cardiac arrest and neonatal hypoxic ischemic encephalopathy. However, cooling conscious stroke patients is more difficult. Therapeutic hibernation refines temperature management by suppressing thermoregulatory processes to decrease metabolic demand (VO2) that leads to a subsequent decrease in Tb. We showed previously that the arctic ground squirrel enters hibernation through activation of CNS adenosine A1 receptors (A1AR), in a manner consistent with the inhibition of thermogenesis. Torpor in hamsters and mice also depends on central A1AR activation. Here we stimulated A1AR with the A1AR agonist N6-cyclohexyladenosine (CHA) and targeted the CNS by co-administration of 8-(p-Sulfophenyl) theophylline (8-SPT), a nonspecific adenosine receptor antagonist that does not cross blood brain barrier. Ambient temperature (Ta) was varied between 16-29 °C. Drugs were administered to naïve rats or 70 min following 8 minutes of cardiac arrest (male Sprague–Dawley, 2 to 3 months old, 375-400 g). CHA (1 mg/kg) plus 8-SPT (25 mg/kg) every 4 h induced and maintained Tb between 29-31 °C for 24 h in both naïve and cardiac arrested rats. 8-SPT reversed bradycardia without affecting Tb. The survival of animals subjected to cardiac arrest and cooled by CHA was better than normothermic control animals. Inter-animal variability in the cooling response has also been observed, however dynamic control of surface temperature is sufficient to prevent overcooling. Central A1AR activation in combination with a thermal gradient shows promise as an effective means to induce reversible therapeutic hibernation.
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