Systemic administration of donepezil attenuates the efficacy of environmental enrichment on neurobehavioral outcome after experimental traumatic brain injury.

BACKGROUND: The acetylcholinesterase inhibitor (AChEI) donepezil (DON) is recommended as a potential treatment for cognition after clinical traumatic brain injury (TBI) and therefore may be prescribed as an adjunct therapy during rehabilitation. However, a dose-response study evaluating DON after a controlled cortical impact (CCI) injury in rats did not reveal cognitive benefits. OBJECTIVE: The aim of this study was to determine the effect of DON on behavioral and histological outcome when combined with environmental enrichment (EE), a preclinical model of neurorehabilitation. It was hypothesized that the combined treatments would produce a synergistic effect yielding improved recovery over neurorehabilitation alone. METHODS: Isoflurane-anesthetized adult male rats received a CCI or sham injury and then were randomly assigned to EE or standard (STD) housing plus systemic injections of DON (0.25 mg/kg) or vehicle (VEH; 1.0 mL/kg saline) once daily for 19 days beginning 24 hr after injury. Function was assessed by established motor and cognitive tests on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 19. RESULTS: DON was ineffective when administered alone. In contrast, EE conferred significant motor and cognitive benefits, and reduced cortical lesion volume vs. STD (p < 0.05). Combining the therapies weakened the efficacy of rehabilitation as revealed by diminished motor and cognitive recovery in the TBI+EE+DON group vs. the TBI+EE+VEH group (p < 0.05). CONCLUSION: These data replicate previous findings showing that EE is beneficial and DON is ineffective after CCI and add to the literature a novel and unpredicted finding that supports neither the hypothesis nor the use of DON for TBI. Investigation of other AChEIs after CCI injury is necessary to gain further insight into the value of this therapeutic strategy.

Unmasking sex-based disparity in neuronal metabolism.

Both classic and emerging literature point to sex-based disparity in neuronal metabolism. While detectable under baseline conditions, this phenomenon appears to be exaggerated or sometimes unmasked in neurons by cellular stress. A complex sex-dependent response to nutrient deprivation, excitotoxicity, oxidative/nitrositive stress, oxygen-glucose deprivation, and chemical toxicity has been observed in neurons in vitro, as well as after various insults including ischemic or traumatic brain injury in vivo. Importantly, sex-based disparity in response to diverse therapeutics has been seen in neurons in culture, contemporary animal models of brain injury, and in human disease. These have clear implications for pharmacological design of therapeutics targeting central nervous system diseases involving both males and females, and preclinical testing of promising agents.