Efeito de senolíticos sobre parâmetros neuroquímicos em camundongos fêmeas C57BL6 durante o envelhecimento

Abstract

Aging is a physiological and multifactorial process that leads to a decrease in the functional capacities of the brain, causing a decline in cognitive performance, impairing quality of life. Cellular aging begins with the increase in cell senescence, when cells lose their ability to divide and proliferate, interrupting the cell cycle and activating apoptosis mechanisms. During this process, senescent cells secrete mediators that induce inflammation and tissue damage defined as a senescence- associated secretory phenotype. Recently, a new class of compounds that promote the removal of senescent cells from tissue and organs called senolytics has been discovered, the first ones being studied being dasatinib (D) and quercetin (Q). Thus, this study aimed to investigate the neuroprotective potential of senolytic compounds (D+Q) in mice during the aging process. Female mice C57BL6 were divided into two groups (n=16 per group): Group I - Control (Vehicle) and Group II - Treated (D+Q). Treatment or vehicle was administered by gavage (dasatinib: 5 mg/kg and quercetin: 50 mg/kg) for three consecutive days every two weeks starting at 30 days of age,with half of the animals euthanized at 6 months of age and the other half at 14 months of age. At the end of treatment, the whole brain was collected for analysis of oxidative stress parameters, levels of tumor necrosis factor alpha, and activity of acetylcholinesterase and Na+, K+-ATPase. The results showed an increase in reactive oxygen species (ROS) levels, thiols total content and lipid peroxidation followed by a reduction in nitrite levels and in the activity of superoxide dismutase, catalase and glutathione S-transferase enzymes in the brain of control animals during aging. Treatment with D+Q protected against increased ROS and reduced catalase activity. Acetylcholinesterase activity was increased, the Na+, K+-ATPase activity was reduced in 14-month-old animals, while D+Q treatment was able to avoid this reduction. These data indicate the important role of senolytic drugs in regulating the process of brain aging and support the need for future investigations of the role of cellular senescence in age-associated neuropathologies.