June 1, 2010 Inhibitors of GSK-3 proteins are being developed as potential therapeutics for numerous conditions, including bipolar disorder, Alzheimer disease, and diabetes. However, a team of researchers, led by Thomas Force, at Thomas Jefferson University, Philadelphia, has generated data in mice that indicate that these drugs might have adverse effects on the heart, suggesting that the risk/benefit assessment of such drugs might need to be considered carefully.
In the study, mice lacking GSK-3-alpha were found to develop heart defects when they were analyzed at over 2 months of age. In particular, they had enlarged heart muscle cells and hearts, and their hearts showed an inability to contract optimally. Further, in a model of high blood pressure, which puts substantial stress on the heart, mice lacking GSK-3-alpha developed much more severe heart defects than did normal mice.
These and other data generated in the study lead the authors to conclude that in the absence of GSK-3-alpha, the mouse heart cannot respond effectively to high blood pressure and rapidly fails, raising concern that therapeutic GSK-3 inhibitors might have serious adverse effects.
The research appears in the Journal of Clinical Investigation.
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- Jibin Zhou, Hind Lal, Xiongwen Chen, Xiying Shang, Jianliang Song, Yingxin Li, Risto Kerkela, Bradley W. Doble, Katrina MacAulay, Morgan DeCaul, Walter J. Koch, John Farber, James Woodgett, Erhe Gao and Thomas Force. GSK-3-alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice. Journal of Clinical Investigation, 2010; DOI: 10.1172/JCI41407
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