title: Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke.
abstract: The restoration of energy balance during ischemia is critical to cellular survival; however, relatively little is known concerning the regulation of neuronal metabolic pathways in response to central nervous system ischemia. AMP-activated protein kinase (AMPK), a master sensor of energy balance in peripheral tissues, is phosphorylated and activated when energy balance is low. We investigated whether AMPK might also modulate neuronal energy homeostasis during ischemia. We utilized two model systems of ischemia, middle cerebral artery occlusion in vivo and oxygen-glucose deprivation in vitro, to delineate changes in AMPK activity incurred from a metabolic stress. AMPK is highly expressed in cortical and hippocampal neurons under both normal and ischemic conditions. AMPK activity, as assessed by phosphorylation status, is increased following both middle cerebral artery occlusion and oxygen-glucose deprivation. Pharmacological inhibition of AMPK by either C75, a known modulator of neuronal ATP levels, or compound C reduced stroke damage. In contrast, activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside exacerbated damage. Mice deficient in neuronal nitric-oxide synthase demonstrated a decrease in both stroke damage and AMPK activation compared with wild type, suggesting a possible interaction between NO and AMPK activation in stroke. These data demonstrate a role for AMPK in the response of neurons during metabolic stress and suggest that in ischemia the activation of AMPK is deleterious. The ability to manipulate pharmacologically neuronal energy balance during ischemia represents an innovative approach to neuroprotection.
authors.affiliation: Department of Neurology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. lmccullough@uchc.edu
authors.forename: Louise D
authors.initials: LD
authors.lastname: McCullough
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zeng
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Landree
authors.forename: Jill
authors.initials: J
authors.lastname: McFadden
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology; D002540:Cerebral Cortex / Q000201:enzymology; D003250:Constriction; D004195:Disease Models, Animal; D004734:Energy Metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D005947:Glucose / Q000008:administration & dosage; D006624:Hippocampus / Q000201:enzymology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020768:Middle Cerebral Artery; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D010100:Oxygen / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000209:etiology
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; D064429:Fatty Acid Synthases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose; D015107:4-Butyrolactone; D010100:Oxygen