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UM Miller School and Miami VA Medical Center researchers have developed a synthetic antagonist of growth hormone-releasing hormone (GHRH) that holds promise for a new drug therapy to reverse or stop the progression of Alzheimer’s disease. “Beneficial effects of novel antagonists of GHRH in different models of Alzheimer’s disease,” led by Andrew V. Schally, Ph.D., M.D.h.c., D.Sc.h.c., the 1977 Nobel Prize winner for Physiology or Medicine, Distinguished Professor in the Department of Pathology and Professor in the Division of Hematology/Oncology at the Miller School of Medicine, were published in AgingSchally and his team examined the effects of a growth hormone-releasing hormone antagonist which was conceptualized, designed, and synthesized in their laboratory at the Miami VA.

Many factors have been blamed for the etiology of Alzheimer’s disease, the most frequent form of dementia, and one which costs the U.S. more than $300 billion per year. The causative factors are thought to activate a cascade which leads to neuronal death and severe cognitive decline.

Neuroendocrine mechanisms, such as the GHRH-GH-IGF-1 axis, appear to play an important role in how this disease develops. In this study, the team evaluated the growth hormone-releasing hormone (GHRH) antagonist, MIA-690, in vitro and in vivo using mouse models.

Schally said, “In vitro our GHRH antagonist revealed anti-oxidative and neuroprotective properties as well as substantial inhibition of the bewilderingly complex GHRH-growth-hormone-insulin-like growth factor axis.” In vivo, he said there were improved indicators of cognitive performance, inhibition of amyloid-β aggregation, and inhibition oftau filaments; all are hallmarks of Alzheimer’s disease.

“Our compounds cross the blood-brain barrier with alacrity,” said Block, “and appear to target different levels of the pathologic cascade which leads to clinical Alzheimer’s disease.”

Specifically, the antagonist, MIA-690, inhibits amyloid aggregation and proteo-toxicity, thereby restoring normal neural metabolism and cellular regeneration. Schally and Block add that the potential for clinical therapeutic application is tremendously exciting.

In addition to Schally, who is also Distinguished Medical Research Scientist in the Miami Department of Veterans Affairs, the research team included Ferenc G. Rick, M.D., former research assistant professor of pathology at the Miller School, and member of the Endocrine, Polypeptide and Cancer Institute at the Miami VA, and Norman Block, M.D., professor of pathology, urology, oncology and biomedical engineering and the L. Austin Weeks Family Professor of Urologic Research. The first author of the article is Miklos Jaszberenyi, M.D., Ph.D., a visiting professor from the University of Szeged, Hungary. The synthesis of the compounds was accomplished by Ren-Zhi Cai, Ph.D., assistant professor of pathology at the Miller School, and Marta Zarandi, Ph.D., D.Sc., visiting professor of pathology.

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