Irina A. Pikuleva
Case Western Reserve University, USA
Title: Efavirenz as a potential anti-Alzheimer's disease medication
Biography
Biography: Irina A. Pikuleva
Abstract
Efavirenz is the anti-HIV medication given daily at a 600 mg dose to keep the viral load low. We found that in mice, a very low dose of efavirenz (100-times lower than that given to HIV patients) enhances the activity of the brain enzyme cytochrome P450 46A1 (CYP46A1), which converts cholesterol to 24-hydroxycholesterol. Cholesterol 24-hydroxylation is the major pathway of cholesterol elimination from the brain; CYP46A1 controls this pathway and thereby cholesterol turnover in the brain. 5XFAD mice, a model of rapid amyloidogenesis, were treated daily with a 0.1 mg/kg of body weight efavirenz dose, which was delivered in drinking water. The treatment started at 1 month of age and continued for 8 months. Efavirenz administration stably activated CYP46A1 and enhanced cholesterol turnover in the 5XFAD brain. 5XFAD mice also had a significant reduction in amyloid-b burden and microglia activation in the brain cortex and hippocampus. Mouse performance was improved in Morris Water Maze test, and the treated animals had a signifciant reduction in mortality rates. The data obtained suggest that efavirenz should be considered as an anti-Alzheimer's disease medication, and the pathway of the brain cholesterol removal as a therapeutic target for this disease. A clinical trial is in progress to evaluate efavirenz effects on people with mild cognitive impairment due to Alzheimer's disease.