Donepezil is ineffective in promoting motor and cognitive benefits after controlled cortical impact injury in male rats

Abstract

The acetylcholinesterase (AChE) inhibitor donepezil is used as a therapy for Alzheimer's disease and has been recommended as a treatment for enhancing attention and memory after traumatic brain injury (TBI). Although select clinical case studies support the use of donepezil for enhancing cognition, there is a paucity of experimental TBI studies assessing the potential efficacy of this pharmacotherapy. Hence, the aim of this pre-clinical study was to evaluate several doses of donepezil to determine its effect on functional outcome after TBI. Ninety anesthetized adult male rats received a controlled cortical impact (CCI; 2.8 mm cortical depth at 4 m/sec) or sham injury, and then were randomly assigned to six TBI and six sham groups (donepezil 0.25, 0.5, 1.0, 2.0, or 3.0 mg/kg, and saline vehicle 1.0 mL/kg). Treatments began 24 h after surgery and were administered i.p. once daily for 19 days. Function was assessed by motor (beam balance/walk) and cognitive (Morris water maze) tests on days 1-5 and 14-19, respectively. No significant differences were observed among the sham control groups in any evaluation, regardless of dose, and therefore the data were pooled. Furthermore, no significant differences were revealed among the TBI groups in acute neurological assessments (e.g., righting reflex), suggesting that all groups received the same level of injury severity. None of the five doses of donepezil improved motor or cognitive function relative to vehicle-treated controls. Moreover, the two highest doses significantly impaired beam-balance (3.0 mg/kg), beam-walk (2.0 mg/kg and 3.0 mg/kg), and cognitive performance (3.0 mg/kg) versus vehicle. These data indicate that chronic administration of donepezil is not only ineffective in promoting functional improvement after moderate CCI injury, but depending on the dose is actually detrimental to the recovery process. Further work is necessary to determine if other AChE inhibitors exert similar effects after TBI.

FIG. 1.

Mean (±SEM) time (sec) balancing on an elevated narrow beam prior to, and after, traumatic brain injury (TBI) or sham injury. All TBI+donepezil groups were significantly impaired relatively to the SHAM group (**p<0.0001). Additionally, beam balance ability improved similarly across 5 testing days in the TBI groups regardless of drug dose or vehicle administration, except for the TBI+donepezil (3.0 mg/kg) group, which performed significantly worse than the TBI+vehicle group, as well as other TBI+donepezil groups (*p<0.0005 vs.TBI+vehicle and TBI+donepezil: 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg).

FIG. 2.

Mean (±SEM) walking ability as measured by time (sec) to traverse an elevated wooden beam prior to, and after, traumatic brain injury (TBI) or sham injury. All TBI+donepezil groups were significantly impaired relatively to the SHAM group (**p<0.0001). At the two highest doses of chronic donepezil (TBI+donepezil: 2.0 and 3.0 mg/kg), rats displayed significantly slower recovery in beam walk ability during the 5 testing days compared with TBI+vehicle, TBI+donepezil (0.5 m/kg), and TBI+donepezil (1.0 mg/kg) (*p<0.0005, Bonferroni post-hoc tests).

FIG. 3.

Mean (±SEM) time (sec) to locate a hidden (submerged) platform in the Morris water maze test. There were substantial traumatic brain injury (TBI)-induced water maze performance deficits in all TBI groups compared with SHAM controls (**p<0.0001). At the highest donepezil dose (3.0 mg/kg), TBI rats displayed significantly slower recovery rates of spatial learning abilities compared with the TBI+vehicle group (*p<0.0001) and the TBI+donepezil (0.5 mg/kg) group (p<0.0021).