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Target of Bipolar Disorder Drug Linked to Cardiac Defects

Lack of protein targeted by lithium leads to congenital heart defects in mice

THURSDAY, Oct. 2 (HealthDay News) -- Deletion of one form of the protein targeted by lithium, which is used to treat bipolar disorder, causes congenital cardiac defects in developing mice, according to research published online Oct. 1 in the Journal of Clinical Investigation.

Risto Kerkela, M.D., Ph.D., from Thomas Jefferson University in Philadelphia, and colleagues generated mice lacking the alpha and beta forms of the glycogen synthase kinase-3 (GSK-3) gene.

The researchers found that while mice lacking the GSK-3α gene had no cardiac defects, they were unable to obtain live mice lacking the GSK-3β gene. Embryos lacking the latter gene had multiple cardiac defects, including a double outlet right ventricle and ventricular septal defects. They also had hypertrophic myopathy to the extent that the ventricular cavities were nearly destroyed, which was due to the hyperproliferation of cardiomyocytes without hypertrophy and associated with the increased expression of several proteins regulating proliferation.

"These studies, which we believe are the first in mammals to examine the role of GSK-3α and GSK-3β in the heart using loss-of-function approaches, implicate GSK-3β as a central regulator of embryonic cardiomyocyte proliferation and differentiation, as well as of outflow tract development," Kerkela and colleagues conclude. "Although controversy over the teratogenic effects of lithium remains, our studies suggest that caution should be exercised in the use of newer, more potent drugs targeting GSK-3 in women of childbearing age."

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