Effects of metformin in experimental stroke.
OBJECTIVE
Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an important sensor of energy balance. Stroke-induced AMPK activation is deleterious because both pharmacological inhibition and genetic deletion of AMPK are neuroprotective. Metformin is a known AMPK activator but reduces stroke incidence in clinical populations. We investigated the effect of acute and chronic metformin treatment on infarct volume and AMPK activation in experimental stroke.


METHODS
Male mice were subjected to middle cerebral artery occlusion after acute (3 days) or chronic (3 weeks) administration of metformin. Infarct volumes, AMPK activation, lactate accumulation, and behavioral outcomes were assessed. The roles of neuronal nitric oxide synthase and AMPK were examined using mice with targeted deletion of AMPK or neuronal nitric oxide synthase.


RESULTS
Acute metformin exacerbated stroke damage, enhanced AMPK activation, and led to metabolic dysfunction. This effect was lost in AMPK and neuronal nitric oxide synthase knockout mice. In contrast, chronic metformin given prestroke was neuroprotective, improved stroke-induced lactate generation, and ameliorated stroke-induced activation of AMPK. Similarly, the neuroprotective effect of chronic prestroke metformin was lost in neuronal nitric oxide synthase knockout mice.


CONCLUSIONS
AMPK is an important potential target for stroke treatment and prevention. These studies show that the timing, duration, and amount of AMPK activation are key factors in determining the ultimate downstream effects of AMPK on the ischemic brain.
Li
Jun
J
Department of Neurology, Farmington, CT 06030, USA.
Benashski
Sharon E
SE
Venna
Venugopal Reddy
VR
McCullough
Louise D
LD
D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000494:pharmacology; D015994:Incidence; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology; D007773:Lactates / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors
D007004:Hypoglycemic Agents; D007773:Lactates; D008687:Metformin; D019001:Nitric Oxide Synthase; D055372:AMP-Activated Protein Kinases