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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Resveratrol stimulates AMP kinase activity in neurons
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Departments of *Pathology and Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110
Edited by Richard H. Goodman, Oregon Health & Science University, Portland, OR, and approved March 6, 2007 (received for review November 13, 2006)
Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-
-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.
caloric restriction | neuronal energy | neuronal protection
Conflict of interest: J.M. and Washington University have a financial interest in Sirtris Pharmaceuticals. Sirtris Pharmaceuticals did not support this work.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0610068104/DC1.
To whom correspondence should be addressed. E-mail: jmilbrandt{at}wustl.edu
© 2007 by The National Academy of Sciences of the USA
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