Donepezil’s Effects on Brain Regions

Donepezil is an acetylcholinesterase inhibitor¹. Acetylcholinesterase breaks down the neurotransmitter acetylcholine², thereby reducing acetylcholine signalling in the brain. Acetylcholine (ACh) enhances the encoding of new memories and therefore improves learning³. Donepezil improves cognitive performance in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), and is the most commonly prescribed acetylcholinesterase inhibitor (AChEI) for AD⁴. The effects of donepezil on the volumes of brain regions has been examined and may help explain its efficacy⁴.

In a recent study comparing healthy controls, untreated MCI patients and MCI patients treated with donepezil, volumes of brain regions and tests evaluating cognitive function were determined at baseline and 6 months post-initiation of treatment for the treated MCI group⁴. Donepezil improved scores on tests of cognitive function by minorly reducing ratings on geriatric depression and AD assessment scale-cognitive subscale, whilst significantly reducing clinical dementia rating by 14.1% and significantly increasing score on Korean version of the mini-mental state examination by 8% in 6 months⁴.

Grey matter (GM) volumes significantly increased post-treatment of donepezil in the putamen, globus pailldus, and inferior frontal gyrus regions of the brain but did not significantly differ from the untreated group when examining volume of the hippocampus⁴. However, longer duration of treatment with donepezil seems to reduce the rate of loss of hippocampal volume⁴.

These positive effects of donepezil on the brain may be explained through an increase in growth factors in the brain such as an increase in brain-derived neurotrophic factor (BDNF) seen in rats treated with donepezil⁴. BDNF increases neuronal survival, differentiation and synaptic plasticity, whilst promoting the breakdown of beta-amyloid plaque which is believed to contribute to AD⁴. The effects of BDNF provide a pro-cognitive, neuroprotective effect⁵. This increase in BDNF from donepezil is likely due to its pro-cholinergic signalling because cholinergic agonists increase BDNF expression as well as nerve growth factor (NGF) expression⁶, which shows the importance of cholinergic signalling for brain health.

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References:  

1. Kumar A, Sharma S. Donepezil. [Updated 2020 Aug 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513257/ 

2. Trang A, Khandhar PB. Physiology, Acetylcholinesterase. [Updated 2020 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539735/ 

3. Hasselmo M. E. (2006). The role of acetylcholine in learning and memory. Current opinion in neurobiology, 16(6), 710–715. https://doi.org/10.1016/j.conb.2006.09.002 

4. Kim, GW., Kim, BC., Park, K.S. et al. A pilot study of brain morphometry following donepezil treatment in mild cognitive impairment: volume changes of cortical/subcortical regions and hippocampal subfields. Sci Rep 10, 10912 (2020). https://doi.org/10.1038/s41598-020-67873-y 

5. Miranda, M., Morici, J. F., Zanoni, M. B., & Bekinschtein, P. (2019). Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Frontiers in cellular neuroscience, 13, 363. https://doi.org/10.3389/fncel.2019.00363 

6. da Penha Berzaghi M, Cooper J, Castrén E, Zafra F, Sofroniew M, Thoenen H, Lindholm D. Cholinergic regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) but not neurotrophin-3 (NT-3) mRNA levels in the developing rat hippocampus. J Neurosci. 1993 Sep;13(9):3818-26. doi: https://doi.org/10.1523/JNEUROSCI.13-09-03818.1993. PMID: 8366347; PMCID: PMC6576436. 

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