Abstract：
Depression ranks as the fourth most prevalent global disease, with suicide incidents occurring at a younger age. Sulpiride (SUL), an atypical antidepressant drug acting as a dopamine D2 receptor antagonist and possessing anti-inflammatory properties, exhibits limited ability to penetrate the blood brain barrier (BBB). This weak penetration hampers its inhibitory effect on prolactin release in the pituitary gland, consequently leading to hyperprolactinemia. In order to enhance the central nervous system efficacy of sulpiride and reduce serum prolactin levels, we covalently linked sulpiride to VPALR derived from the nuclear DNA repair protein ku70. In vivo study on depressive mice using intraperitoneal injection of VPALR-SUL demonstrated a significant increase in struggle time and total distance compared to those treated with only sulpiride while also reducing serum prolactin concentration. The pharmacokinetic study results showed that VPALR-SUL prolonged half-life and increased bioavailability. In conclusion, VPALR-SUL exhibited potential for enhancing sulpiride transport across the BBB, augmenting its antidepressant effects, and reducing serum prolactin levels. This study laid a foundation for improving sulpiride delivery and developing novel antidepressants.
摘要：
抑郁症是全球第四大流行疾病，自杀事件发生在年轻的时候。舒必利(SUL),一种非典型的抗抑郁药物，作为多巴胺D2受体拮抗剂，具有抗炎特性，表现出穿透血脑屏障（BBB）的能力有限。这种微弱的渗透阻碍了其对垂体中催乳素释放的抑制作用，从而导致高催乳素血症。为了增强舒必利的中枢神经系统疗效，降低血清催乳素水平，我们将舒必利共价连接到源自核DNA修复蛋白ku70的VPALR。使用腹膜内注射VPALR-SUL对抑郁症小鼠的体内研究表明，与仅使用舒必利治疗的小鼠相比，挣扎时间和总距离显着增加，同时还降低了血清催乳素浓度。药代动力学研究结果表明，VPALR-SUL延长了半衰期，增加了生物利用度。总之,VPALR-SUL显示出增强舒必利跨BBB转运的潜力，增强其抗抑郁作用，降低血清催乳素水平.本研究为改善舒必利给药和开发新型抗抑郁药奠定了基础。
