Central pathways mediating adenosine-induced hypothermia

Hypothermia is a potential protective treatment to reduce stroke damage following myocardial infarction, brain hemorrhage or brain ischemia. The protective potential accrues from the reduced cellular metabolism and oxygen demand that accompanies a lowered body temperature, allowing improved survival of tissue in the hypoxic environment of ischemia. Pharmacological blockade of thermogenesis could provide an effective adjunct to external cooling for the induction of a hypothermic, hypometabolic state. Hypothermia and a torpor-like state can be induced in rat, as in hibernating animals, by activation of central A1AR (Tupone, et. al., J Neurosci 33:14512–25, 2013). This state is characterized by a reduced metabolism, body temperature, and cardiovascular and cortical functions (e.g., lower EEG amplitude). We applied this pharmacological approach to induce hypothermia in rat models of stroke: 1) brain ischemic stroke using a middle cerebral artery occlusion (MCAO) and 2) subarachnoid hemorrhage (SAH), which is accompanied by neurogenic fever (NF), a centrally-generated hyperthermia that is resistant to standard antipyretic treatment. Deep hypothermia induced by central activation of A1AR, which blocked brown adipose tissue and shivering thermogenesis, contributed to a significantly reduced infarct size following MCAO and to a marked reduction in the NF hyperthermia following SAH. In conclusion, pharmacological activation of central A1AR combined with a cold ambient temperature induces a deep hypothermia and reduces overall metabolism, and thus represents a potentially useful approach in the treatment of stroke and NF. Supported by Collins Medical Trust Grant (DT), NIH R01NS40987 (SM), Merit Award Department of Veterans Affairs (JC).