Identifying New AMP-Activated Protein Kinase Inhibitors That Protect against Ischemic Brain Injury

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• AMP-activated protein kinase (AMPK) mediates zinc-induced neuronal death via Bim induction, dependent on liver kinase B1 (LKB1).
• AMPK is implicated in excitotoxicity and ischemic brain injury, with zinc neurotoxicity as a contributing factor.
• Inhibiting AMPK presents a potential therapeutic approach for stroke-related brain injury.

Purpose of the Study:

• To identify novel inhibitors of AMPK activity and zinc-induced neuronal death.
• To evaluate these inhibitors in cultured neurons and a rat model of ischemic stroke.

Main Methods:

• Structure-based virtual screening identified compounds predicted to bind AMPK α2.
• In vitro assays assessed AMPK α2 inhibitory activity and neuroprotective effects in cultured mouse cortical neurons.
• In vivo efficacy was tested using a rat model of middle cerebral artery occlusion (MCAO).

Main Results:

• 40 compounds demonstrated in vitro AMPK α2 inhibitory activity; 7 reduced zinc-induced neuronal death in cultures.
• Agents 2G11 and 1H10 significantly attenuated multiple forms of neuronal death (oxidative stress, excitotoxicity, apoptosis).
• Intracerebroventricular administration of 2G11 and 1H10 reduced brain infarct volumes in MCAO rats, unlike compound C.

Conclusions:

• Novel AMPK inhibitors, specifically 2G11 and 1H10, demonstrate significant neuroprotective effects.
• These compounds effectively reduce brain infarct volumes in a preclinical stroke model.
• 2G11 and 1H10 represent promising drug development candidates for treating ischemic stroke.