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Potential Cause of Depression Identified

Potential Cause of Depression Identified

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Published by smh9662
Identifying the causes of depression
Identifying the causes of depression

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Categories:Types, Research
Published by: smh9662 on May 02, 2013
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05/14/2014

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Potential Cause of Depression Identified
 
Findings Have 'Enormous Therapeutic Potential,' Researchers Say
Megan BrooksFeb 19, 2013A protein involved in synaptic structure has been identified as a potential cause of depression, afinding that according to researchers has "enormous therapeutic potential for the development of  biomarkers and novel therapeutic agents."Investigators at the Mount Sinai School of Medicine in New York City found decreasedexpression of Rac1 in the postmortem brains of people with major depressive disorder (MDD)and in mice subjected to chronic stress. They were able to control the depressive response inmice by manipulating the expression of Rac1.Dr. Scott Russo"Our study is among only a few in depression research in which 2 independent human cohortsand animal models validate each other. Rac1 has enormous therapeutic potential, and I look forward to investigating it further," study investigator Scott Russo, PhD, said in a statement.The research was  published online February 17 in
 Nature Medicine.
 
Looking for Drug Targets
 Rac1 is a small Rho GTPase protein involved in modulating synaptic structure."There is a hypothesis that depression and stress disorders are caused by a restructuring of braincircuitry," Dr. Russo explained in an interview with
 Medscape Medical News
.The scientists subjected mice to repeated bouts of social stress and then evaluated the animals for changes in gene expression in the nucleus accumbens (NAc), the brain's reward center.The researchers found that expression of Rac1 was significantly downregulated in the brains of mice for at least 35 days following the end of the chronic social stressor. Rac1 was not affected
 
 by only a single episode of stress, indicating that only prolonged stressors that induce depressionare capable of downregulating Rac1.The scientists note that chronic stress in the mice caused epigenetic changes in chromatin that ledto Rac1 downregulation.They were able to control the depressive response to chronic stress to some extent by chronicantidepressant treatment. Histone deacetylase (HDAC) inhibitors were "extremely effective in both normalizing the reduction in Rac1 and also promoting antidepressant responses," Dr. Russotold
 Medscape Medical News
."What we think is happening is that chronic stress leads to a lasting change in the ability of our genes to transcribe this
 RAC1
gene, and if you target the epigenome, you can reverse that loss of Rac1 and promote synapses and more normal healthy responses," he said.As in the mice, Rac1 expression was also strongly downregulated in the NAc in postmortem brains of patients with MDD, who displayed similar epigenetic changes. In most of theindividuals with MDD who were taking antidepressants at the time of death, Rac1 expressionwas not restored to the levels seen in control participants, "suggesting a need for more directRAC1-targeting strategies to achieve therapeutic effects," the authors write."Currently, there aren't any approved drugs or even experimental drugs that target Rac1 that aresafe and effective," Dr. Russo said. "It would be nice if we could team up with some chemists or  pharma and figure out if there are some safe and effective Rac activators."However, there are caveats to that, he said."It might be difficult to target Rac specifically, because it is involved in cell proliferation andrestructuring so it may be difficult to get a compound that doesn't cause cancer. It might be better to screen for targets that more generally regulate synaptic plasticity. Ketamine is a drug that doesthis, and there is huge interest in ketamine" in depression, Dr. Russo said.
Experts Weigh In
 Commenting on the findings for 
 Medscape Medical News
, David Dietz, PhD, assistant professor of pharmacology and toxicology, State University of New York at Buffalo, who was notinvolved in the research, said the study "is exquisitely well done. The researchers did anexcellent job of translating their findings in the rodent model to the human condition."Maria V. Tejada-Simon, PhD, who also was not involved in this research but who has studiedRac1, noted that her group has been "highlighting the importance of Rac1 in the brain in general,and in psychiatric diseases in particular, for a while now. Therefore, I am not surprised that Rac1has been found to be also associated to stress disorders and depression.""Mood disorders have been linked to changes in synaptic structure, and it is certain that smallGTPases such as Rac1 have a tremendous role as modulators of these processes. However, we

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