Salzano Giuseppina, Robert Vincent, Lomet Didier, Decourt Caroline, Hommet Elise, Derouin-Tochon Flavie, Hellier Vincent, Savina Farah, Vishwanatha Thimmalapura-Marulappa, Aucagne Vincent, Gref Ruxandra, Beltramo Massimiliano
Institut des Sciences Moléculaires d'Orsay (CNRS UMR 8214), Université Paris Saclay, Orsay, France.
Physiologie de la Reproduction et des Comportements (PRC) UMR7247 CNRS, IFCE, INRAE, Université de Tours, Nouzilly, France.
J Neuroendocrinol. 2022 Apr;34(4):e13121. doi: 10.1111/jne.13121. Epub 2022 Mar 31.
The modulation of the kisspeptin system holds promise as a treatment for human reproductive disorders and for managing livestock breeding. The design of analogs has overcome some unfavorable properties of the endogenous ligands. However, for applications requiring a prolongation of drug activity, such as ovulation induction in the ewe during the non-breeding season, additional improvement is required. To this aim, we designed and tested three formulations containing the kisspeptin analog C6. Two were based on polymeric nanoparticles (NP1 and NP2) and the third was based on hydrogels composed of a mixture of cyclodextrin polymers and dextran grafted with alkyl side chains (MD/pCD). Only the MD/pCD formulation prolonged C6 activity, as shown by monitoring luteinizing hormone (LH) plasma concentration (elevation duration 23.4 ± 6.1, 13.7 ± 4.7 and 12.0 ± 2.4 h for MD/pCD, NP1 and NP2, respectively). When compared with the free C6 (15 nmol/ewe), the formulated (MD/pCD) doses of 10, 15 and 30 nmol/ewe, but not the 90 nmol/ewe dose, provided a more gradual release of C6 as shown by an attenuated LH release during the first 6 h post-treatment. When tested during the non-breeding season without progestogen priming, only, the formulated 30 nmol/ewe dose triggered ovulation (50% of ewes). Hence, we showed that a formulation with an adapted action time would improve the efficacy of C6 with respect to inducing ovulation during the non-breeding season. This result suggests that formulations containing a kisspeptin analog might find applications in the management of livestock reproduction but also point to the possibility of their use for the treatment of some human reproductive pathologies.
亲吻素系统的调节有望成为治疗人类生殖障碍和管理家畜繁殖的方法。类似物的设计克服了内源性配体的一些不利特性。然而，对于需要延长药物活性的应用，如在非繁殖季节诱导母羊排卵，还需要进一步改进。为此，我们设计并测试了三种含有亲吻素类似物C6的制剂。两种基于聚合物纳米颗粒（NP1和NP2），第三种基于由环糊精聚合物和接枝烷基侧链的葡聚糖混合物组成的水凝胶（MD/pCD）。只有MD/pCD制剂延长了C6的活性，通过监测黄体生成素（LH）血浆浓度可以看出（MD/pCD、NP1和NP2的升高持续时间分别为23.4±6.1、13.7±4.7和12.0±2.4小时）。与游离C6（15 nmol/母羊）相比，制剂（MD/pCD）剂量为10、15和30 nmol/母羊，但90 nmol/母羊剂量除外，在治疗后前6小时LH释放减弱，显示出C6的释放更为缓慢。仅在非繁殖季节未经孕激素预处理测试时，制剂30 nmol/母羊剂量触发了排卵（50%的母羊）。因此，我们表明具有合适作用时间的制剂将提高C6在非繁殖季节诱导排卵方面的功效。这一结果表明，含有亲吻素类似物的制剂可能在管理家畜繁殖中找到应用，也指出了它们用于治疗某些人类生殖病理的可能性。
