AMP-Dependent Hypothermia Affords Protection from Ischemic Brain Injury

Abstract

In light of the relevance of therapeutic hypothermia to stroke treatment, we investigated whether 5 0 -adenosine monophosphate (AMP)-dependent cooling affords protection from ischemic brain injury. We show that hypothermia by AMP is because of adenosine A1 receptor (A1R) activation and is not invariantly associated with hypotension. Inhibition of ecto-5 0 -nucleotidasedependent constitutive degradation of brain extracellular AMP by methylene-ADP (AMPCP) also suffices to prompt A1R-dependent hypothermia without hypotension. Both intraischemic and postischemic hypothermia by AMP or AMPCP reduce infarct volumes and mortality of mice subjected to transient middle cerebral artery occlusion. Data disclose that AMP-dependent hypothermia is of therapeutic relevance to treatment of brain ischemia.

Role of Adenosine Signaling on Pentylenetetrazole-Induced Seizures in Zebrafish

“…There is evidence that seizure protection conferred by the EHNA in genetically seizure-prone epilepsy-like (EL) mice and PTZ infusion confirm that the inhibition of adenosine metabolism by deamination is an effective antiseizure strategy. 41 In this study, we have shown that the inhibition of ADA activity modulates acute seizures in zebrafish. When pretreated with the ADA inhibitor, EHNA, animals showed longer latency to reach the tonic-clonic seizure status.…”

“…Therefore, considering the possible equal ability of AMP and adenosine to activate A 1 receptors, currently it is not possible to understand exactly whether AMP and/or adenosine activate A 1 receptors within the brain. [34][35][36]41 Therefore, further studies are necessary to elucidate this mechanism.…”

Pharmacological hypothermia: a potential for future stroke therapy?

“…123 the side effects associated with drug administration. 130 In addition, hypothermia is associated with a reduction in drug metabolism. 29 The effect of this reduction needs to be carefully studied to prevent toxicity.…”

“…Yet another study hypothesized that AMP-dependent hypothermia can still provide ischemic neuroprotection, but at doses that were not accompanied by detrimental effects such as hypotension and hyperglycemia. 130 In this study, the researchers used mice to demonstrate that AMP could still elicit a transient hypothermic response without hypotension starting at a lower dose of 50 mg/kg AMP up until 100 mg/kg, after which hypotension would then be observed. Interestingly, it was indicated that the sensitivity of a species to the hypothermic effects of AMP is inversely related to the hypothalamic expression of AMP-degrading enzyme ecto-5'-nucleotidase.…”

“…Interestingly, it was indicated that the sensitivity of a species to the hypothermic effects of AMP is inversely related to the hypothalamic expression of AMP-degrading enzyme ecto-5'-nucleotidase. 130 As rats express higher levels of ecto-5'-nucleotidase than mice, they can only experience AMP-induced hypothermia at extremely high doses or in the presence of ecto-5'-nucleotidase inhibitors. 130 Thus, whether AMP-induced hypothermia can offer adequate neuroprotection after experimental stroke at an appropriate dose still remains to be seen.…”