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Restor Neurol Neurosci. 2018;36(1):45-57. doi: 10.3233/RNN-170781.

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

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Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA.
Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Psychology, University of Pittsburgh, Pittsburgh, PA, USA.



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.


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.


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.


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).


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.


Beam-walking; Morris water maze; behavior; controlled cortical impact (CCI); donepezil; functional recovery; hippocampus; learning and memory; traumatic brain injury

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