Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor proteins that regulate the expression of genes. Drugs that activate PPARs – PPAR agonists – are used to treat diabetes and elevated blood lipids. Given previous rodent research, this study examined the effects of different classes of PPAR agonists on chronic alcohol intake and preference in mice with a genetic predisposition for heavy drinking, and then examined genome-wide association data for polymorphisms in PPAR genes in alcohol-dependent (AD) humans. Findings indicate potential for repurposing FDA-approved PPAR? or PPAR? agonists for the treatment of AD.
Results will be published in the January 2015 online-only issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.
“PPAR receptors are biochemical sensors found in many cells in the body,” explained R. Adron Harris, director of the Waggoner Center for Alcohol and Addiction Research? at The University of Texas as well as corresponding author for the study. “Their job is to monitor our levels of sugars, fats, and other sources of energy and adjust our body metabolism to keep the levels of these nutrients at correct levels. However, sometimes our bodies or our diets and lifestyles cause undesirably high levels of sugar, leading to diabetes, or fats leading to hyperlipidemia, which can often be corrected by activating PPAR receptors with drugs called PPAR agonists.”
Harris added that although PPAR agonists were initially developed to control blood levels of sugar and fat, they were later found to also act on the brain, thought to possibly guard against neurodegeneration, and are currently being tested as a remedy for Alzheimer’s Disease.
“Especially over the past five years, there has been an increasing awareness that the brain uses many of the same signaling molecules as those used by the immune system,” added Robert Hitzemann, professor and chair of the department of behavioral neuroscience at Oregon Health and Science University. “In some cases the brain may be using these molecules for immune-related functions, [such as] response to inflammation caused by brain injury. However, in other cases the brain may simply have ‘hijacked’ the molecules to serve a different function, [such as] communication among normal cells, including between neurons and glia. Scientists have been asking what happens to these neuro-immune genes in response to excessive [drinking, finding that they] are significantly affected. Many of the pathways affected are those that would be susceptible to regulation by PPARs.”
“Because of these brain effects, several research groups have asked if PPAR agonists might be useful in drug addiction,” said Harris. “Several of these drugs are currently being tested for opiate addiction in humans. And, because these drugs are already approved by the FDA for humans, the drugs could be used ‘off label’ for treatment of alcoholism or other addictions. This is the first study to combine human genetic studies of alcoholism with animal models of alcohol consumption to show a connection between PPAR receptors and drugs acting on these receptors with alcohol abuse.”
The University of Texas at Austin
Oregon Health and Science UniversityAlcoholism: Clinical & Experimental Research (ACER)