1. ¹Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA
2. ²Department of Neurology and Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
3. ³Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China
4. ⁴Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Correspondence: Dr J Chen, Department of Neurology, University of Pittsburgh School of Medicine, S-507, Biomedical Science Tower, Pittsburgh, Pennsylvania, 15213, USA. E-mail: chenj2@upmc.edu

Received 25 November 2008; Revised 4 March 2009; Accepted 4 March 2009; Published online 25 March 2009.

Abstract

Mild hypothermia renders potent neuroprotection against acute brain injury. Recent reports show that adenosine 5'-monophosphate (AMP) plays a role in thermoregulation and induces hypothermia in mice. Therefore, this study sought to determine whether AMP induces hypothermia in rats and to study its collective effects on cerebral ischemia induced by 2-h middle cerebral artery occlusion. An intraperitoneal injection of AMP induced hypothermia dose-dependently. At the dose of 4 mmol/kg, AMP induced promising mild hypothermia for 2.5 h. Unexpectedly, the AMP-induced hypothermia failed to reduce infarct volume after brain ischemia; instead, it exaggerated the ischemic damage, indicated by an increased infarct volume, as well as increased incidences of hemorrhagic transformation, seizure, and animal death. Physiologic parameter monitoring revealed that AMP causes profound hypotension, leading to cerebral hypoperfusion. Furthermore, AMP administration resulted in severe hyperglycemia, metabolic acidosis, and hypocalcemia. In addition, western blots showed early dephosphorylation and degradation of AMP-activated kinase in the ischemic cortex in AMP-treated rats. Taken together, our findings suggest that AMP induces hypothermia in rats, probably by limiting cellular access to glucose. However, the potential neuroprotection of AMP-mediated hypothermia against ischemia was overwhelmed by the detrimental effects of hypotension and hyperglycemia, thus making AMP an unlikely agent for inducing hypothermia to protect the brain against ischemic injury.