Donepezil prevents cognitive impairment and gut epithelial disruption in doxorubicin‐treated rats

AbstractBackgroundDonepezil (DPZ) is an acetylcholinesterase inhibitor used to improve cognitive function. We reported that it prevented doxorubicin (Dox)‐induced chemobrain. Gut epithelial disruption, gut dysbiosis and impaired essential microbial metabolites, such as short chain fatty acids (SCFAs), have found following Dox therapy. However, the impact of DPZ to prevent gut epithelial disruption and gut dysbiosis as well as disturbance of circulating SCFAs due to Dox‐induced chemobrain have been never investigated.MethodTwenty‐four rats were divided into sham rats, vehicle‐treated Dox rats, and DPZ‐treated Dox rats. Modified Novel Object Location and Recognition tests were used to evaluate cognitive function. At the end of the study, ileums were removed to investigate occludin protein expression, and PCR of ileal luminal contents were used to calculate Firmicutes to Bacteroidetes (F/B) ratio. Serum butyric acid, a representative of SCFAs, was assessed by Gas chromatography‐mass spectrometry.ResultDox‐rats developed cognitive impairment with gut epithelial disruption, gut dysbiosis and reduced essential microbial metabolites (serum butyric acid). DPZ significantly prevented cognitive decline in Dox‐rats (Fig 1A‐C). Furthermore, DPZ restored the expression of occludin in gut tissue, suggesting that DZP improved gut epithelial integrity in Dox‐rats (Fig 1D). DZP improved gut dysbiosis in Dox‐rats as indicated by attenuated F/B ratio (Fig 1E), but level of serum butyric acid between DZP‐treated Dox rats and vehicle‐treated Dox rats was not different (Fig 1F).ConclusionDPZ co‐treatment with Dox prevented Dox‐induced cognitive impairment. Although DZP protected gut epithelial disruption, and improved gut dysbiosis, however it could not help to increase circulating SCFAs. These findings suggest that DPZ, itself, cannot completely prevent the gut disturbance in rats with Dox‐induced chemobrain. Therefore, the probiotic supplement with DZP might be the other approach to prevent gut problem following chemotherapy.