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Study Led by NICHD Section Chief Suggests Drugs That Activate the NF-α1/FGF2/Neurogenesis Pathway Can Offer New Approach to Depression Therapy

In an article published in the June 2015 issue of Molecular Psychiatry, a scientific team led by senior author Y.Peng Loh, Ph.D., Chief of the Section on Cellular Neurobiology, National Institute of Child Health and Development (NICHD), NIH, reported that neurotrophic factor-α1 [NF-α1, which is also known as carbozxypeptidase E (CPE)] can prevent stress-induced depression through enhancement of neurogenesis and that NF-α1 is activated by rosiglitazone, a drug known to have anti-depressive activity. Major depressive disorder is one of the most common psychiatric illnesses in the United States, and its development is linked to the experience of stressful conditions. Short­term stress, however, is unlikely to be harmful, but prolonged stress may contribute to depression by triggering the release of chemicals that, at sustained, high levels, can kill nerve cells. Recent research indicates that neurotrophic factors and growth factors—naturally occurring substances that promote cell growth—play a role in relieving depression. Scientists suspect they do so by stimulating the generation of new brain cells, a process called neurogenesis. To explore this possibility, Dr. Loh and her team subjected mice to short-term stress and found increased levels of NF-α1, fibroblast growth factor 2 (FGF2), and neurogenesis in the hippocampus, a brain region minvolved in depression. These mice displayed no signs of depression-like behaviors. However, after long-term restraint stress, levels of NF-α1 and FGF2 fell and the mice displayed depression-like behaviors. In a separate set of experiments, mice genetically engineered to lack NF‐α1 had reduced FGF2 and reduced neurogenesis in the hippocampus and showed depression-like behavior. Giving the mice FGF2 reversed the depression. Finally, the researchers found that rosiglitazone, a drug with known antidepressant activity, increased FGF2 levels in hippocampus cells in a dish. Mice given rosiglitazone showed increased levels of NF-α1 and of neurogenesis. From its new results, the Peng-led team concluded that “development of drugs that activate the NF-α1/FGF2/neurogenesis pathway can offer a new approach to depression therapy.”

Y. PENG LOH, PH.D., CHIEF, NICHD SECTION ON CELLULAR NEUROLOGY, NIH

Dr. Loh is internationally recognized for her contributions toward understanding the mechanisms underlying the enzymatic processing, intracellular trafficking, and sorting of pro-hormones and neuropeptides to secretory granules of the regulated secretory pathway.

She revolutionized the field by discovering many non-enzymatic roles of the pro-hormone processing enzyme carboxypeptidase E (CPE).

Recently, she identified secreted CPE (now named NF-1) as a new signaling molecule with important neurotrophic functions in mediating neuroprotection, preventing stress-induced depression, and in neural stem cell differentiation in the developing brain.

Additionally she has discovered a splice variant form of CPE (CPE-DN) that induces metastasis in cancer cells and is a powerful biomarker for predicting future metastasis in cancer patients.

Dr. Loh’s pioneering work has led to more than 200 publications and, together with her mentoring service to the NIH community, has earned her numerous awards including the FASEB Excellence in Science Award, the Public Health Service Superior Service Award, the Women in Endocrinology Mentor’s Award for Outstanding Research and Mentoring, and the NIH Director’s Award for Mentoring.

DR. LOH & EXOSOME STUDIES

Very recently, on October 18, 2015, Dr. Loh delivered a highly stimulating presentation at the American Society for Exosomes and Microvecles (ASEMV http://www.asemv.org/) 2015 Annual Meeting in Marco Island, Florida. Her talk was entitled “Carboxypeptidase E: A Prognostic Cancer Biomarker in Tumors and Circulating Exosomes.”

Note that BioQuick News covered this exciting meeting and is preparing a multi-story, detailed report of all the exciting work and advances that were discussed, including Dr. Loh’s work. That detailed report should appear in BioQuick News in approximately two weeks.

BioQuick’s detailed report of the 2014 ASEMV Annual Meeting can be viewed here: http://www.bioquicknews.com/node/1986.

[Molecular Psychiatry abstract] [Dr. Loh & Anita B. Roberts Lecture 2014] [Video of Dr. Loh Giving Anita B.Roberts Lecture, December 11, 2014"] [Dr. Loh--NIH Annual Report 2014]