Oscoz-Susino Natalia, Luque Guillermina M, Minotti Florencia, Otero Patricia, Lavolpe Mariano, Ferrulli Mariana, Krapf Dario, Buffone Mariano G, Marín-Briggiler Clara I
Reproduction. 2025 Mar 3;169(4). doi: 10.1530/REP-24-0448. Print 2025 Apr 1.
The cyclic adenosine monophosphate (cAMP) pathway is essential for maintaining sperm physiology. This study examines a cAMP analog and a phosphodiesterase inhibitor that effectively enhance human sperm motility, thereby improving the efficiency of in vitro sperm selection.
cAMP plays a central role in sperm physiology. Various cAMP upregulators, both cAMP analogs and phosphodiesterase (PDE) inhibitors, have been used in handling human sperm in vitro, although conflicting results and variable responses among patients have been reported. This study aims to evaluate the ability of two compounds - Sp-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole 3'-5'-cyclic monophosphothioate (cBiMPs), a cAMP analog, and TAK-063, a specific PDE10A inhibitor - to enhance human sperm motility parameters and, consequently, improve sperm preparation procedures. Our results showed that both cBiMPs and TAK-063 significantly enhanced human sperm motility and hyperactivation compared to the control (dimethyl sulphoxide). They also increased protein phosphorylation levels without inducing premature acrosomal exocytosis or DNA fragmentation. The enhancement of sperm motility persisted for 4 h after their removal, surpassing the effects of known cAMP analogs (8-bromo-adenosine-3', 5'-cAMP (8-Br-cAMP) or dibutyryl cAMP (db-cAMP)) or PDE inhibitors (3-isobutyl-1-methylxanthine (IBMX) or pentoxifylline (PTX)). Furthermore, the presence of cBiMPs or TAK-063 during sperm selection resulted in higher recovery rates in comparison to the control, and these compounds effectively improved sperm motion in both fresh and cryopreserved samples with impaired motility. In conclusion, cBiMPs and TAK-063 exhibit potent and sustained effects on human sperm motility, enhancing the efficiency of sperm preparation techniques. The ability to improve sperm motility holds significant implications for male infertility treatment, facilitating the use of low complexity techniques such as intrauterine insemination or in vitro fertilization, and may also aid in selecting viable testicular sperm for intracytoplasmic sperm injection.
环磷酸腺苷（cAMP）途径对于维持精子生理功能至关重要。本研究考察了一种cAMP类似物和一种磷酸二酯酶抑制剂，它们能有效增强人类精子活力，从而提高体外精子筛选效率。
cAMP在精子生理功能中起核心作用。尽管有报道称结果相互矛盾且患者反应各异，但各种cAMP上调剂，即cAMP类似物和磷酸二酯酶（PDE）抑制剂，已被用于体外处理人类精子。本研究旨在评估两种化合物——cAMP类似物Sp-5,6-二氯-1-β-D-呋喃核糖基苯并咪唑3'-5'-环一磷酸硫酯（cBiMPs）和特异性PDE10A抑制剂TAK-063——增强人类精子活力参数的能力，进而改进精子制备程序。我们的结果表明，与对照组（二甲基亚砜）相比，cBiMPs和TAK-063均显著增强了人类精子活力和超活化能力。它们还提高了蛋白质磷酸化水平，且未诱导顶体过早胞吐或DNA片段化。去除cBiMPs和TAK-063后，精子活力增强持续了4小时，超过了已知cAMP类似物（8-溴腺苷-3',5'-环磷酸腺苷（8-Br-cAMP）或二丁酰环磷腺苷（db-cAMP））或PDE抑制剂（3-异丁基-1-甲基黄嘌呤（IBMX）或己酮可可碱（PTX））的效果。此外，在精子筛选过程中存在cBiMPs或TAK-063时，与对照组相比回收率更高，并且这些化合物有效改善了新鲜和冷冻保存且活力受损样本中的精子运动。总之，cBiMPs和TAK-063对人类精子活力表现出强大且持久的影响，提高了精子制备技术的效率。改善精子活力的能力对男性不育治疗具有重要意义，有助于使用如宫内人工授精或体外受精等低复杂性技术，也可能有助于为胞浆内单精子注射选择有活力的睾丸精子。
