Neurological Basis of AMP-Dependent Thermoregulation and its Relevance to Central and Peripheral Hyperthermia

Abstract

Therapeutic hypothermia is of relevance to treatment of increased body temperature and brain injury, but drugs inducing selective, rapid, and safe cooling in humans are not available. Here, we show that injections of adenosine 5 0 -monophosphate (AMP), an endogenous nucleotide, promptly triggers hypothermia in mice by directly activating adenosine A1 receptors (A1R) within the preoptic area (POA) of the hypothalamus. Inhibition of constitutive degradation of brain extracellular AMP by targeting ecto 5 0 -nucleotidase, also suffices to prompt hypothermia in rodents. Accordingly, sensitivity of mice and rats to the hypothermic effect of AMP is inversely related to their hypothalamic 5 0 -nucleotidase activity. Single-cell electrophysiological recording indicates that AMP reduces spontaneous firing activity of temperature-insensitive neurons of the mouse POA, thereby retuning the hypothalamic thermoregulatory set point towards lower temperatures. Adenosine 5 0 -monophosphate also suppresses prostaglandin E2-induced fever in mice, having no effects on peripheral hyperthermia triggered by dioxymetamphetamine (ecstasy) overdose. Together, data disclose the role of AMP, 5 0 -nucleotidase, and A1R in hypothalamic thermoregulation, as well and their therapeutic relevance to treatment of febrile illness.

AMP-Dependent Hypothermia Affords Protection from Ischemic Brain Injury

“…7,8 Recently, we showed that AMP prompts hypothermia by activating adenosine (Ado) A1 receptors (A1Rs) on temperature-insensitive hypothalamic neurons of mice, thereby suppressing the thermoregulatory responses that maintain Tb. 9 We also show that AMP-dependent hypothermia reduces prostaglandin-induced fever in mice, having no effect on peripheral hyperthermia induced by dioxymethamphetamine (ecstasy) overdose. 9 Theoretically, AMPdependent cooling might be harnessed to therapeutic hypothermia of ischemic brain injury.…”

“…9 We also show that AMP-dependent hypothermia reduces prostaglandin-induced fever in mice, having no effect on peripheral hyperthermia induced by dioxymethamphetamine (ecstasy) overdose. 9 Theoretically, AMPdependent cooling might be harnessed to therapeutic hypothermia of ischemic brain injury. In rats undergoing middle cerebral artery occlusion (MCAo), however, AMP increases infarct size probably because of concomitant hypotension and hyperglycemia.…”

“…Data showing that hypothermia is counteracted by the A1R antagonist DPCPX confirm that AMP-dependent hypothermia is because of activation of A1Rs. 9 Accordingly, A1R negatively regulates central thermogenesis 12 and very recent evidence indicates that AMP is a bona fide A1R agonist. 13 Our findings also indicate that inhibition of ongoing degradation of AMP into Ado within the brain extracellular space by targeting ecto-5 0 -nucleotidase with AMPCP suffices to prompt Tb cooling in an A1R-dependent manner, and protects from experimental stroke.…”

“…Sensitivity of a given species to the hypothermic effects of AMP appears inversely related to the hypothalamic expression of the AMP-degrading enzyme 5 0 -ectonucleotidase. 9 Accordingly, hypothalamic 5 0 -ectonucleotidase activity is higher in rats than in mice, 9 and the former undergo AMP-dependent hypothermia only in the presence of 5 0 -ectonucleotidase inhibition 9 or high doses of AMP. 8 Therapeutic hypothermia induced by AMP could be harnessed to treatment of victims of stroke, cardiac arrest or neonatal hypoxia, and studies on sensitivity to AMP of gyrencephalic animals and humans might be worth pursuing.…”

Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

“…Following identification of the four receptors, Anderson et al (1994) used the available ligands to suggest that adenosine analogs cause hypothermia via adenosine A 1 receptor (A 1 AR) in the central nervous system. Further evidence for a role for A 1 AR includes prevention of AMP hypothermia by an A 1 AR antagonist (Muzzi et al, 2013), loss of the hypothermic effect of N 6 -cyclohexyladenosine in A 1 AR null (Adora1 2/2 ) mice (Johansson et al, 2001), and induction of a hypothermic state with A 1 AR agonist (N 6 -cyclohexyladenosine) injection into the nucleus of the solitary tract (Tupone et al, 2013). These observations firmly established that A 1 AR activation can cause hypothermia (Fredholm et al, 2011).…”