Document Type



Life Sciences | Medicine and Health Sciences


Abstract Background and Purpose—Ischemic preconditioning (IPC) induces endogenous neuroprotection from a subsequent ischemic injury. IPC involves down-regulation 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.

Methods—A brief 3 minute middle cerebral artery occlusion (MCAO) was employed to induce IPC in male mice 72 hours prior to 90 minute MCAO. Levels of AMPK and pAMPK, the active form of the kinase, were assessed after IPC. A pharmacological activator or inhibitor of AMPK was utilized to determine the dependence of IPC on AMPK signaling. Additionally, AMPK-α2 null mice were subjected to IPC and subsequent infarct damage was assessed.

Results—IPC induced neuroprotection, enhanced HSP70 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.

Conclusions—Regulation of AMPK plays an important role in IPC mediated neuroprotection. AMPK may be a potential therapeutic target for the treatment of cerebral ischemia.


Neuroscience. Author manuscript; available in PMC 2013 January 10. Published in final edited form as: Neuroscience. 2012 January 10; 201: 280–287. Published online 2011 November 18. doi: 10.1016/j.neuroscience.2011.11.014 PMCID: PMC3258333 NIHMSID: NIHMS340086