Chronic administration of flumazenil increases life span and protects rats from age-related loss of cognitive functions: a benzodiazepine/GABAergic hypothesis of brain aging.

Under barrier condition and with ad lib access to food and water, 20 Fischer-344 rats were chronically treated for 10 months with the benzodiazepine (BDZ) antagonist, flumazenil (FL; 4 mg/kg/day in drinking water acidified to pH = 3.0), beginning at the age of 13 months, while the group of 20 control age-matched rats received plain acidified water. The life span of the first 8 deceased rats treated with FL was significantly longer than that of the first 8 deceased rats in the age-matched control group. In tests for spontaneous ambulation and exploratory behavior in the Holeboard apparatus, conducted during the 3rd and the 8th month of treatment, the FL group, relative to controls, had significantly higher scores for the ambulation and exploratory behavior. In tests for unrewarded spontaneous alternation in the T maze, conducted at days 7, 39, 42, and 47 through 54 after drug withdrawal, i.e., at the age of 24-25 months, the FL-exposed group, compared to age-matched controls, showed a significantly higher percent of alternating choices, a behavior that was statistically comparable to that of the "young" 6-month-old controls. In the Radial Maze tests conducted 2 months after drug withdrawal, the FL group made significantly less "working memory" errors and "reference memory" errors, relative to the age-matched 25-month-old control group, a performance that was comparable to that of the young 7-month-old control group. In conclusion, chronic FL significantly protected rats from age-related loss of cognitive functions. It is postulated that the age-related alterations in brain function may be attributable to the negative metabolic/trophic influences of the "endogenous" benzodiazepine (BDZ) ligands and/or those ingested with food. A BDZ/GABAergic hypothesis of brain aging has been formulated which assumes that age-related and abnormally strong BDZ/GABAergic influences promote neurodegeneration by suppressing trophic functions of the aminergic and peptidergic neurons through opening of chloride channels in soma membrane and axon terminals, causing excessive hyperpolarizing and depolarizing inhibition, respectively. The review of human clinical and animal data indicates that FL has nootropic actions by enhancing vigilance cognitive and habituation processes.