Recipient treatment with acetylcholinesterase inhibitor donepezil attenuates primary graft failure in rats through inhibiting post-transplantational donor heart ischaemia/reperfusion injury

Our results reveal that treatment of the recipient with DO protects the donor hearts for 1 month after transplantation through suppressing the signalling pathway of inflammation. These results suggest that DO is a novel and clinically feasible strategy to protect the donor heart in transplantation in the long term.

First, Lewis-Lewis heart transplantation model was successfully established, and 75 rats were randomly assigned into 3 groups: the DO group (received single dose of intragastric DO treatment), the donepezil + methyllycaconitine group (α7 nicotinic acetylcholine receptor inhibitor) and the control group. Ten rats per group were sacrificed at 24 h after drug administration, whereas the rest of the groups were observed 1 month after surgery. The status of inflammation, survival of the graft and function of the graft were examined.

Serum tumour necrosis factor α level was significantly lower in the donepezil group when compared with the control group 24 h after first drug administration; this trend was maintained for 1 month (P < 0.001). Furthermore, DO inhibited CD11b/18-positive cell infiltration (P < 0.001) and myocardiocyte apoptosis (as shown by the percentage of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick-end labelling-positive nuclei, P = 0.039) in the recipient rats at 24 h after the first drug administration. The percentage of cardiac grafts that survived for 1 month in rats given DO alone was significantly higher (80.0%, 33.3% and 26.7% in the DO, donepezil + methyllycaconitine and control groups, respectively, P = 0.014); the fractional shortening value of the DO group was significantly higher than that in the other 2 groups (29.25 ± 1.84%, 17.92 ± 3.69% and 17.07 ± 2.99% in the DO, donepezil + methyllycaconitine and control group, respectively, P < 0.001). The collagen volume fraction was lower in the DO group than in the other 2 groups (P < 0.001). Conclusions: Our results reveal that treatment of the recipient with DO protects the donor hearts for 1 month after transplantation through suppressing the signalling pathway of inflammation. These results suggest that DO is a novel and clinically feasible strategy to protect the donor heart in transplantation in the long term.