title: Preconditioning induces sustained neuroprotection by downregulation of adenosine 5'-monophosphate-activated protein kinase.
abstract: Ischemic preconditioning (IPC) induces endogenous neuroprotection from a subsequent ischemic injury. IPC involves downregulation of metabolic pathways. As adenosine 5'-monophosphate-activated protein kinase (AMPK) is a critical sensor of energy balance and plays a major role in cellular metabolism, its role in IPC was investigated. A brief 3-min middle cerebral artery occlusion (MCAO) was employed to induce IPC in male mice 72 h before 90-min MCAO. Levels of AMPK and phosphorylated AMPK (pAMPK), the active form of the kinase, were assessed after IPC. A pharmacological activator or inhibitor of AMPK was used to determine the dependence of IPC on AMPK signaling. Additionally, AMPK-α2 null mice were subjected to IPC, and subsequent infarct damage was assessed. IPC induced neuroprotection, enhanced heat shock protein-70 (HSP-70), and improved behavioral outcomes. These beneficial effects occurred in parallel with a significant inhibition of pAMPK protein expression. Although both pharmacological inhibition of AMPK or IPC led to neuroprotection, IPC offered no additional protective effects when co-administered with an AMPK inhibitor. Moreover, pharmacological activation of AMPK with metformin abolished the neuroprotective effects of IPC. AMPK-α2 null mice that lack the catalytic isoform of AMPK failed to demonstrate a preconditioning response. Regulation of AMPK plays an important role in IPC-mediated neuroprotection. AMPK may be a potential therapeutic target for the treatment of cerebral ischemia.
authors: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors: V R
authors: VR
authors: Venna
authors: J
authors: J
authors: Li
authors: S E
authors: SE
authors: Benashski
authors: S
authors: S
authors: Tarabishy
authors: L D
authors: LD
authors: McCullough
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D005452:Fluoresceins; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D007211:Indoles; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000517:prevention & control*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000209:etiology; D009460:Neurologic Examination; D009930:Organic Chemicals; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D005452:Fluoresceins; D050884:HSP72 Heat-Shock Proteins; D007211:Indoles; D009930:Organic Chemicals; C435731:fluoro jade; C007293:DAPI; D017853:Phosphotransferases (Alcohol Group Acceptor); C019617:adenylylsulfate kinase