Combination of ellagic acid and trans-cinnamaldehyde alleviates aging-induced cognitive impairment via modulation of mitochondrial function and inflammatory and apoptotic mediators in the prefrontal cortex of aged rats.

Cognitive impairments are associated with advancing age. Trans-cinnamaldehyde (CIN) and ellagic acid (ELA) have multiplex activities to reduce various age-related cognitive disorders. In this study, we investigated the effects of these compounds separately or in combination on the cognitive outcomes, mitochondrial function, and inflammatory and apoptotic mediators in aged male Wistar rats. Thirty-two old (22 months old) and eight young (5 months old) rats were randomly allocated to five groups of young control, aged control, ELA-aged, CIN-aged, and ELA + CIN-aged. ELA (15 mg/kg, orally) and CIN (50 mg/kg, intraperitoneally) separately or in combination were administered for 1 month in aged animals. Spatial memory and cognitive activity were evaluated by the Barnes maze and novel object recognition tests. Mitochondrial function (its reactive oxygen species [ROS], mitochondrial membrane potential and ATP level), pro-inflammatory cytokines such as interleukin (IL)-1β and IL-6 and pro-apoptotic caspase 3 and Bax, and anti-apoptotic Bcl2 levels and their ratio were assessed in the prefrontal cortex. Behavioral results revealed that CIN separately or in combination with ELA significantly alleviates aging-induced memory impairment. Moreover, co-administration of agents effectively decreased inflammatory cytokines, cleaved-caspase 3, Bax and Bax/Bcl2 levels, mitochondrial ROS production, and mitochondrial membrane depolarization and increased Bcl2 and ATP level as compared with untreated aged control rats. Combination therapy was greater than those of individual treatments in all parameters. Therefore, combination therapy with CIN and ELA improved aging-induced cognitive impairment through anti-inflammatory, anti-apoptotic, and mitochondrial-boosting effects in aged rats.