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).
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© 2015 Published by Elsevier Inc.