When hypothermia meets hypotension and hyperglycemia: the diverse effects of adenosine 5′-monophosphate on cerebral ischemia in rats

• Published in: Journal of cerebral blood flow and metabolism Vol. 29; no. 5; pp. 1022 - 1034
• Main Authors: Zhang, Feng, Wang, Suping, Luo, Yumin, Ji, Xunming, Nemoto, Edwin M, Chen, Jun
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-05-2009; Nature Publishing Group; Sage Publications Ltd
• Subjects: Adenosine Monophosphate - administration & dosage; Adenosine Monophosphate - adverse effects; Adenosine Monophosphate - therapeutic use; Animals; Biological and medical sciences; Blood Glucose - metabolism; Blood Pressure - drug effects; Body Temperature; Brain Ischemia - metabolism; Brain Ischemia - physiopathology; Brain Ischemia - therapy; Disease Models, Animal; Heart Rate - drug effects; Hyperglycemia - chemically induced; Hypotension - chemically induced; Hypothermia, Induced - methods; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - physiopathology; Infarction, Middle Cerebral Artery - therapy; Insulin - blood; Male; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Treatment Outcome; Vascular diseases and vascular malformations of the nervous system; AMPK; Compound C; insulin; hibernation; hypocalcemia; acidosis; Purine nucleoside; Hydroelectrolytic balance disorder; Calcium; Rat; Cardiovascular disease; Acid base balance disorder; Inorganic element; Vascular disease; Hyperglycemia; Hibernation; Hypocalcemia; Cerebrovascular disease; Adenosine; Nervous system diseases; Rodentia; cAMP-dependent protein kinase; Insulin; Cerebral disorder; Metabolic disorder; Vertebrata; Mammalia; Animal; Central nervous system disease; Brain ischemia; Acidosis; Hypothermia
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2009.28

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.