The positive outcome that hypothermia contributes to neuroprotection following brain ischemia has stimulated recent clinical interest in the development of techniques to induce a hypothermic and hypometabolic state. Despite, the increased use of therapeutic hypothermia, the available induction techniques, employing various cold-exposure approaches rather than pharmacological methods, could be of limited utility in reaching an appropriate hypothermic state due to the activation of the central thermoregulatory responses that counteract the fall in temperature by reducing heat loss (cutaneous vasoconstriction) and increasing thermogenesis through brown adipose tissue (BAT) and shivering. Hibernating animals can reduce their energy expenditure by suspending both shivering and non-shivering thermogenesis, even in the face of marked falls in skin and core temperatures. In these species, activation of A1 adenosine receptors in the brain is thought to play a key role in triggering the torpor state. In the current studies, we investigated: 1) the potential for the A1 adenosine receptor agonist, N6-cyclohexyladenosine (CHA), to induce hypothermia in the rat (a non-hibernating species); 2) the precise thermo-effector mechanisms contributing to the fall in body temperature; 3) the brain circuits involved in the adenosine agonist-induced hypothermia; and 4) the effect of CHA-induced hypothermia on the outcome of ischemic stroke. In inactin-anesthetized (85mg/kg i.v.), Wistar rats, icv administration of CHA (10μl, 1mM) decreased core, skin and BAT temperatures, reduced expired CO2, heart rate (HR), BAT sympathetic nerve activity (SNA) and shivering EMG activity. In awake rats in a 15°C ambient, a similar icv injection of CHA decreased BAT temperature and induced a torpor-like state, in contrast to icv injection of saline vehicle which had no effect on BAT temperature or observed behavioral state. In urethane/chloralose anaesthetized rats, direct nanoinjection of CHA (60nl, 1mM) in the nucleus of the solitary tract (NTS) produced reductions in cold-evoked BAT SNA, BAT temperature, expired CO2 and HR concomitant with an increase of mean arterial pressure. These effects were reversed by local nanoinjection of muscimol (60nl, 1mM) and prevented by pretreatment of the NTS with an A1 adenosine receptor antagonist. We conclude that A1 adenosine receptor stimulation in the NTS produce hypothermia and torpor-like effect in the rat through inhibition of BAT and shivering thermogenesis. This pharmacological approach could provide the basis for induction of a rapid, sustained and controlled hypothermia, improving current methods for inducing hypothermia for neuroprotection following brain ischemia. Supported by NIH grant NS40987.

A hypothermic and hypometabolic state produced by A1 adenosine receptor activation in the nucleus of the solitary tract: implication for stroke

TUPONE, DOMENICO;
2013

Abstract

The positive outcome that hypothermia contributes to neuroprotection following brain ischemia has stimulated recent clinical interest in the development of techniques to induce a hypothermic and hypometabolic state. Despite, the increased use of therapeutic hypothermia, the available induction techniques, employing various cold-exposure approaches rather than pharmacological methods, could be of limited utility in reaching an appropriate hypothermic state due to the activation of the central thermoregulatory responses that counteract the fall in temperature by reducing heat loss (cutaneous vasoconstriction) and increasing thermogenesis through brown adipose tissue (BAT) and shivering. Hibernating animals can reduce their energy expenditure by suspending both shivering and non-shivering thermogenesis, even in the face of marked falls in skin and core temperatures. In these species, activation of A1 adenosine receptors in the brain is thought to play a key role in triggering the torpor state. In the current studies, we investigated: 1) the potential for the A1 adenosine receptor agonist, N6-cyclohexyladenosine (CHA), to induce hypothermia in the rat (a non-hibernating species); 2) the precise thermo-effector mechanisms contributing to the fall in body temperature; 3) the brain circuits involved in the adenosine agonist-induced hypothermia; and 4) the effect of CHA-induced hypothermia on the outcome of ischemic stroke. In inactin-anesthetized (85mg/kg i.v.), Wistar rats, icv administration of CHA (10μl, 1mM) decreased core, skin and BAT temperatures, reduced expired CO2, heart rate (HR), BAT sympathetic nerve activity (SNA) and shivering EMG activity. In awake rats in a 15°C ambient, a similar icv injection of CHA decreased BAT temperature and induced a torpor-like state, in contrast to icv injection of saline vehicle which had no effect on BAT temperature or observed behavioral state. In urethane/chloralose anaesthetized rats, direct nanoinjection of CHA (60nl, 1mM) in the nucleus of the solitary tract (NTS) produced reductions in cold-evoked BAT SNA, BAT temperature, expired CO2 and HR concomitant with an increase of mean arterial pressure. These effects were reversed by local nanoinjection of muscimol (60nl, 1mM) and prevented by pretreatment of the NTS with an A1 adenosine receptor antagonist. We conclude that A1 adenosine receptor stimulation in the NTS produce hypothermia and torpor-like effect in the rat through inhibition of BAT and shivering thermogenesis. This pharmacological approach could provide the basis for induction of a rapid, sustained and controlled hypothermia, improving current methods for inducing hypothermia for neuroprotection following brain ischemia. Supported by NIH grant NS40987.
2013
Tupone, D; Madden; Morrison, Cj
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/586499
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