ABSTRACT
Title
AMP-dependent thermoregulation: a new hypothalamic relay of relevance to ischemic brain injury
Authors
M. Muzzi, F. Blasi, M. Pittelli, R. Felici, A. Masi, E. Coppi, C. Traini, A. Pugliese, F. Moroni and A. Chiarugi
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence Italy.
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence Italy.
Abstract
Hypothermia is one of the most effective treatment strategies to reduce ischemic brain injury.
Among chemicals able to induce hypothermia, AMP has been shown to prompt rapid reduction of body temperature in both rat and mouse [1]. Yet, mechanism underlying the hypothermic effects of AMP are completely unknown, and whether the nucleotide can be used to induce hypothermia-dependent stroke protection waits to be demonstrated. In the present work, we show that both peritoneal, cerebroventricular and hypothalamic AMP injections induced hypothermia dose-dependently in the mouse. Importantly, even the sole AMP accumulation due to central inhibition of nucleotide degradation into adenosine by the 5’-ectonucleotidase inhibitor AMPCP was able to trigger hypothermia in mice. In these
animals, measurement of oxygen consumption and skin temperature demonstrated that AMP-dependent hypothermia is due to reduced thermogenesis concomitant to increased heat loss due to vasodilatation. Of note, AMP-induced hypothermia was prevented by concomitant central injection of the adenosine A1 receptor selective antagonist DPCPX.
Electrophysiological recordings from CA1 hippocampal slices confirmed that AMP is an agonist at A1 receptors. Finally, we report that both AMP- and AMPCP-dependent hypothermia provide significant neuroprotection in a mouse model of 90 minutes transient middle cerebral artery occlusion (tMCAo). Neuroprotection was lost when AMP/AMPCP-treated animals were artificially kept at 38°C during the ischemic period. Remarkably, post-ischemic (1,5 hrs) AMP treatment also prompted significant reduction of ischemic brain injury. In conclusion, data demonstrate that i) AMP causes hypothermia by acting as an agonist of hypothalamic A1 receptors, ii) inhibition of hypothalamic degradation of AMP into adenosine also prompts hypothermia, and iii) AMP-dependent hypothermia reduces post-ischemic brain damage both adopting intra-ischemic or post-ischemic treatment regimens. Targeting hypothalamic A1 receptors by means of endogenous or exogenous agonists might represent an innovative strategy to hypothermia stroke therapy.
[1] Zhang J. et al. (2006) Constant darkness is a circadian metabolic signal in mammals. Nature 19;439(7074):340-3.
Among chemicals able to induce hypothermia, AMP has been shown to prompt rapid reduction of body temperature in both rat and mouse [1]. Yet, mechanism underlying the hypothermic effects of AMP are completely unknown, and whether the nucleotide can be used to induce hypothermia-dependent stroke protection waits to be demonstrated. In the present work, we show that both peritoneal, cerebroventricular and hypothalamic AMP injections induced hypothermia dose-dependently in the mouse. Importantly, even the sole AMP accumulation due to central inhibition of nucleotide degradation into adenosine by the 5’-ectonucleotidase inhibitor AMPCP was able to trigger hypothermia in mice. In these
animals, measurement of oxygen consumption and skin temperature demonstrated that AMP-dependent hypothermia is due to reduced thermogenesis concomitant to increased heat loss due to vasodilatation. Of note, AMP-induced hypothermia was prevented by concomitant central injection of the adenosine A1 receptor selective antagonist DPCPX.
Electrophysiological recordings from CA1 hippocampal slices confirmed that AMP is an agonist at A1 receptors. Finally, we report that both AMP- and AMPCP-dependent hypothermia provide significant neuroprotection in a mouse model of 90 minutes transient middle cerebral artery occlusion (tMCAo). Neuroprotection was lost when AMP/AMPCP-treated animals were artificially kept at 38°C during the ischemic period. Remarkably, post-ischemic (1,5 hrs) AMP treatment also prompted significant reduction of ischemic brain injury. In conclusion, data demonstrate that i) AMP causes hypothermia by acting as an agonist of hypothalamic A1 receptors, ii) inhibition of hypothalamic degradation of AMP into adenosine also prompts hypothermia, and iii) AMP-dependent hypothermia reduces post-ischemic brain damage both adopting intra-ischemic or post-ischemic treatment regimens. Targeting hypothalamic A1 receptors by means of endogenous or exogenous agonists might represent an innovative strategy to hypothermia stroke therapy.
[1] Zhang J. et al. (2006) Constant darkness is a circadian metabolic signal in mammals. Nature 19;439(7074):340-3.