Effect of Tetrahydroaminoacridine, a Cholinesterase Inhibitor, on Cognitive Performance Following Experimental Brain Injury

Abstract

An emerging literature exists in support of deficits in cholinergic neurotransmission days to weeks following experimental traumatic brain injury (TBI). In addition, novel cholinomimetic therapeutics have been demonstrated to improve cognitive outcome following TBI in rats. We examined the effects of repeated postinjury administration of a cholinesterase inhibitor, tetrahydroaminoacridine (THA), on cognitive performance following experimental TBI. Rats were either injured at a moderate level of central fluid percussion TBI (2.1+/-0.1 atm) or were surgically prepared but not delivered a fluid pulse (sham injury). Beginning 24 h after TBI or sham injury, rats were injected (IP) daily for 15 days with an equal volume (1.0 ml/kg) of either 0.0, 1.0, 3.0, or 9.0 mg/kg THA (TBI: n = 8, 8, 10, and 7, respectively, and Sham: n = 5, 7, 8, 7, respectively). Cognitive performance was assessed on Days 11-15 after injury in a Morris water maze (MWM). Analysis of maze latencies over days indicated that chronic administration of THA produced a dose-related impairment in MWM performance in both the injured and sham groups, with the 9.0 mg/kg dose producing the largest deficit. The 1.0 and 3.0 mg/kg doses of THA impaired MWM performance without affecting swimming speeds. Thus, the results of this investigation do not support the use of THA as a cholinomimetic therapeutic for the treatment of cognitive deficits following TBI.

The cholinergic hypothesis of cognitive impairment caused by traumatic brain injury

“…Pike et al [37] reported that tetrahydroaminoacridine (tacrine) failed to improve cognitive performance in traumatically brain-injured rats, and actually worsened performance on the Morris water maze task. Although this finding may initially present a challenge to the cholinergic hypothesis and limit enthusiasm for the potential benefits of cholinesterase inhibition in this population, it is important to observe that tacrine also antagonizes Nmethyl-D-aspartate receptors [38].…”

A review of pharmacological treatments used in experimental models of traumatic brain injury

“…None of the doses were effective in attenuating cognitive decline after injury, and the highest dose appeared to worsen cognitive outcome. Pike and colleagues [22] offer several possible explanations for the negative behavioural effects reported in this study. Previous research has suggested that repeated cholinesterase inhibition may reduce ACh synthesis because extracellular ACh is forced to compete for choline uptake sites [80].…”

“…Although this score is an approximation, a basic comparison allows one to note the percentage of cognitive enhancement. THA [22] and haloperidol [50] were not included in the figure because each resulted in impaired cognitive performance. Olanzapine [50] and fluoxetine [23] were also not included because each resulted in a neutral effect on cognition.…”

“…Pike and coworkers [22] investigated the effects of chronic THA administration on MWM performance following TBI. Rats were subjected to central FP injury or sham procedure and then injected (ip) with saline, 1, 3, or 9 mg/kg THA beginning 24 hours after injury for 15 days.…”

“…It is inappropriate to assume that pharmacological agents will display the same effects in an injured brain as in a non-injured brain. Specifically, cognitive enhancing drugs in a non-injured brain may have no effect on or even impair cognition in an injured brain [22,23]. In addition, preclinical research typically uses cognitive and motor assessments to determine the efficacy of pharmacological treatments.…”