State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Department of Adult Cardiac Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Eur J Cardiothorac Surg. 2018 Feb 1;53(2):400-408. doi: 10.1093/ejcts/ezx289.
Ischaemia/reperfusion injury may have deleterious consequences on heart transplantation. The underlying causes such as inflammation may also contribute to the pathogenesis of primary or chronic graft failure. We hypothesize that donepezil (DO), a reversible acetylcholinesterase inhibitor that increases cholinergic receptor activation, may protect the transplanted heart through increasing the level of acetylcholine, which in turn inhibits systemic inflammation in the recipients.
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).
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.
缺血/再灌注损伤可能对心脏移植产生有害影响。炎症等潜在原因也可能导致原发性或慢性移植物失功的发病机制。我们假设多奈哌齐（DO），一种可逆的乙酰胆碱酯酶抑制剂，可通过增加胆碱能受体激活来保护移植心脏，从而抑制受体的全身炎症反应。
首先，成功建立了 Lewis-Lewis 心脏移植模型，将 75 只大鼠随机分为 3 组：DO 组（单次灌胃 DO 治疗）、多奈哌齐+甲基烟碱组（α7 烟碱型乙酰胆碱受体抑制剂）和对照组。每组 10 只大鼠在给药后 24 h 处死，其余大鼠在手术后 1 个月观察。检查炎症状态、移植物存活和移植物功能。
与对照组相比，首次给药后 24 h DO 组血清肿瘤坏死因子 α 水平明显降低；这种趋势持续了 1 个月（P < 0.001）。此外，DO 抑制了受体大鼠 CD11b/18 阳性细胞浸润（P < 0.001）和心肌细胞凋亡（以末端脱氧核苷酸转移酶介导的 2'-脱氧尿苷 5'-三磷酸生物素 nick-end 标记阳性核的百分比表示，P = 0.039）。单独给予 DO 的大鼠心脏移植物存活 1 个月的百分比明显较高（DO 组为 80.0%，多奈哌齐+甲基烟碱组和对照组分别为 33.3%和 26.7%，P = 0.014）；DO 组的短轴缩短率明显高于其他 2 组（DO 组为 29.25 ± 1.84%，多奈哌齐+甲基烟碱组和对照组分别为 17.92 ± 3.69%和 17.07 ± 2.99%，P < 0.001）。DO 组的胶原容积分数低于其他 2 组（P < 0.001）。
我们的结果表明，通过抑制炎症信号通路，受体接受 DO 治疗可在移植后 1 个月内保护供体心脏。这些结果表明，DO 是一种保护移植心脏的新的、可行的长期策略。
