Anti-Cholinesterase Inhibitors

Cerebrolysin and Cognitive Functioning

As explained by Alvarez et al. (2003), “Cerebrolysin (EBEWE Pharma, Unterach, Austria) is a peptide preparation obtained by standardized enzymatic breakdown of purified brain proteins, and comprises 25% low-molecular weight peptides and free amino acids (pg. 272).” Cerebrolysin has been demonstrated to have neuroprotective and neurotrophic effects, and has been linked to increased cognitive performance in an elderly population.

Table: Effect of Cerebrolysin on Cognitive Functioning


In an open-label trial of 20 patients with TBI Alvarez et al. (2003) found that cerebrolysin was associated with improved brain bioelectrical activity, as evidenced by a significant increase in fast beta frequencies. A brief neuropsychological battery (Syndrome Kurztest) consisting of nine subtests was administered to evaluate memory and attentional functions in patients undergoing treatment with cerebrolysin. There was an overall significant improvement in performance post treatment, suggesting patients experienced cognitive benefits from cerebrolysin treatment. Improvements were also seen in terms of recovery, as measured by the GOS (Alvarez et al. 2003). Together these findings suggest that cerebroylsin may represent an effective neuroprotective therapy with tangible cognitive benefits for individuals living with an ABI. Controlled trials are necessary to further explore the efficacy of this drug.


There is Level 4 evidence that cerebrolysin improves attention and memory function post ABI, as well as clinical outcome. 


Cerebrolysin may be beneficial for the improvement of clinical outcome and cognitive functioning following brain injury; however, controlled trials are needed to further evaluate its efficacy.


Donepezil and Cognitive Functioning

The effectiveness of donepezil, a cholinesterase inhibitor, in improving cognitive and memory functions following brain injury has been assessed. Cognitive impairments affect one’s ability to return to work or school, as well as their ability to live alone (Masanic et al. 2001). When tested with individuals diagnosed with Alzheimer’s disease, donepezil has been found to be useful in treating memory problems (Morey et al. 2003; Walker et al. 2004). Its impact on cognitive function and memory in a TBI population is explored in the table below. 

Table: Effects of Donepezil on Cognitive Functioning and Memory


In a RCT, Zhang et al. (2004) demonstrated that donepezil was associated with improvements in tasks of sustained attention and short-term memory, and that these improvements were sustained even after the washout period. Benefits associated with donepezil were also documented in an open-label study by Masanic et al. (2001) who found that the treatment tended to improve both short- and long-term memory of patients living with TBI. Improvements in memory were also reported by Morey et al. (2003) in their retrospective study who demonstrated that donepezil led to significant benefits in visual memory function. 

Khateb et al. (2005) found only modest improvement on the various neuropsychological tests used to measure executive function, attention and learning and memory. Of note results from the learning phase of Rey Auditory Verbal Memory Test (RAVMT) showed significant improvement (p<0.05). To assess improvement in executive function, results from the Stroop-colour naming test showed significant changes (p<0.03). On the test for Attentional Performance (TAP) a significant change was noted on the divided attention (errors) subsection of the test.


Based on a single RCT, there is Level 1b evidence that donepezil improves attention and short-term memory post ABI.

Based on two non-RCTs, there is Level 4 evidence that donepezil is effective in improving short-, long-term, and visual memory post ABI.


Donepezil helps to improve attention, short-term, long-term, and visual memory following brain injury.



Physostigmine is a cholinergic agonist that temporarily stops acetylcholinesterase which in turn slows the destruction of, and thereby increases the concentration of, acetylcholine at the synapse. Its use in Alzheimer’s disease has been examined at length. It has been proposed to improve memory in patients with head injury (McLean et al. 1987).

Table: Effects of Physostigmine on Memory


In a double-blind, placebo-controlled randomized trial, oral physostigmine was administered to males with TBI as an active treatment (Cardenas et al. 1994). The authors found that physostigmine led to significant improvements in long-term memory scores in 44% (n=16) of study participants. Those who responded favourably to the treatment, as indicated by their performance on the Selective Reminding Test (SRT), also demonstrated improved balance compared to non-responders (Cardenas et al. 1994).


Based on a single RCT, there is Level 1b evidence that oral physostigmine improves long-term memory in men with TBI. 


Physostigmine improves long-term memory in men with TBI.