A compound derived from green tea greatly diminished the neurotoxicity of proteins secreted by the human immunodeficiency virus, suggesting a new approach to the prevention and treatment of HIV-associated dementia, also known as AIDS dementia complex. The disorder is the most severe form of HIV-related neuropsychiatric impairment.
University of South Florida neuroscientist Brian Giunta, MD, reported the findings May 1 at Experimental Biology 2007 in Washington, DC. His presentation was part of the scientific program of the American Society for Pharmacology and Experimental Therapeutics. The study was conducted using a new mouse model for HIV-related dementia developed by Dr. Giunta and Jun Tan, MD, PhD, director of the Neuroimmunology Laboratory at the Silver Child Development Center, USF Department of Psychiatry,
"These findings suggest that EGCG, the green tea-derived compound, may represent a new and natural compound for the prevention and treatment of this devastating disease," Dr. Giunta said.
"This is a very important finding in the prevention and treatment of HIV-related dementia, which is usually observed in the late stages of HIV disease," said Abdul S. Rao, MD, MA, DPhil, senior associate vice president for USF Health and vice dean for research and graduate affairs at the College of Medicine. "The neuroprotective effects of EGCG, the green-tea extract, may offer an alternative to existing mono or combination antiretroviral therapies that are known to have poor central nervous system penetration."
HIV-associated dementia, a debilitating cognitive, emotional, and physical disorder, affects 22 percent of HIV-infected adults and more than half of HIV-infected children. Symptoms often begin with slight changes in behavior, intellectual ability, memory, and muscle coordination. Some patients experience depression-like symptoms such as loss of appetite and motivation. Tasks requiring complex thinking and high concentration become difficult, and motor skills gradually deteriorate over time.
The highly active antiretroviral therapies used in developed nations appear to slow the development of brain damage in patients with HIV-related dementia, making it a protracted disorder rather than an acute one. Unfortunately, these therapies neither cure nor prevent development of HIV-associated dementia and several epidemiologic studies indicate they increase the prevalence of the dementia. Currently, no treatments specifically target this neuropsychiatric disorder.
HIV-associated dementia is believed to be caused by the direct effects of HIV upon the brain. The virus secretes proteins known as Tat and gp120, which have direct toxic effects on the neurons. The proteins also have indirect effects caused by the release of chemical messengers known as cytokines, which interact with the HIV proteins to cause death of the brain cells. High levels of these cytokines alone also are toxic to the brain.
When healthy mice were given doses of the HIV proteins Gp120 and/or Tat, in combination with a cytokine known as interferon-gamma, they developed brain damage closely resembling that seen in HIV-associated dementia in humans. Dr. Giunta said the finding may help explain the cognitive and behavioral changes in individuals infected with HIV.
Dr. Giunta then used epigallocatechin-3-gallate (EGCG), the major antioxidant derived from green tea, to break into this pathway of neurotoxicity. He was successful both in cell studies and in studies involving the new mouse model of the disease.
Cultured neurons from mice were exposed to EGCG before being given a cocktail of the two neurotoxic HIV proteins and the toxic cytokine. The green tea compound inhibited the ability of the cytokine to act with the HIV proteins to cause death and damage of the neurons. In further confirmation, the green tea compound also inhibited the neurotoxic properties of these HIV proteins in the presence of the cytokine in live mice.
Dr. Giunta's coauthors for the study presented at Experimental Biology 2007 were Demian Obregon; Hauyan Hou; Jin Zeng; Nan Sun; Veljko Nikolic, MS; Jared Ehrhart; Douglas Shytle, PhD; Francisco Fernandez, MD; and Dr. Tan. Previous USF studies have shown that EGCG prevented Alzheimer's-like damage in the brains of mice.
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