Program in Neuroscience, University of Southern California, School of Pharmacy Pharmaceutical Sciences Center, Los Angeles, California 90033, USA.
Endocrinology. 2010 Dec;151(12):5782-94. doi: 10.1210/en.2010-0005. Epub 2010 Oct 13.
Previously, we demonstrated that progesterone (P(4)) promoted adult rat neural progenitor cell (rNPC) proliferation with concomitant regulation of cell-cycle gene expression via the P(4) receptor membrane component/ERK pathway. Here, we report the efficacy of seven clinically relevant progestins alone or in combination with 17β-estradiol (E(2)) on adult rNPC proliferation and hippocampal cell viability in vitro and in vivo. In vitro analyses indicated that P(4), norgestimate, Nestorone, norethynodrel, norethindrone, and levonorgestrel (LNG) significantly increased in rNPC proliferation, whereas norethindrone acetate was without effect, and medroxyprogesterone acetate (MPA) inhibited rNPC proliferation. Proliferative progestins in vitro were also neuroprotective. Acute in vivo exposure to P(4) and Nestorone significantly increased proliferating cell nuclear antigen and cell division cycle 2 expression and total number of hippocampal 5-bromo-2-deoxyuridine (BrdU)-positive cells, whereas LNG and MPA were without effect. Mechanistically, neurogenic progestins required activation of MAPK to promote proliferation. P(4), Nestorone, and LNG significantly increased ATP synthase subunit α (complex V, subunit α) expression, whereas MPA was without effect. In combination with E(2), P(4), Nestorone, LNG, and MPA significantly increased BrdU incorporation. However, BrdU incorporation induced by E(2) plus LNG or MPA was paralleled by a significant increase in apoptosis. A rise in Bax/Bcl-2 ratio paralleled apoptosis induced by LNG and MPA. With the exception of P(4), clinical progestins antagonized E(2)-induced rise in complex V, subunit α. These preclinical translational findings indicate that the neurogenic response to clinical progestins varies dramatically. Progestin impact on the regenerative capacity of the brain has clinical implications for contraceptive and hormone therapy formulations prescribed for pre- and postmenopausal women.
先前，我们证明孕激素（P(4)）通过 P(4)受体膜成分/ERK 途径促进成年大鼠神经祖细胞（rNPC）增殖，同时调节细胞周期基因表达。在此，我们报告了七种临床相关孕激素单独或与 17β-雌二醇（E(2)）联合使用对成年 rNPC 增殖以及体内外海马细胞活力的影响。体外分析表明，P(4)、诺孕酯、Nestorone、去氧孕烯、炔诺酮和左炔诺孕酮（LNG）显著增加 rNPC 增殖，而去氧孕烯醋酸酯则无影响，醋酸甲羟孕酮（MPA）抑制 rNPC 增殖。体外具有增殖作用的孕激素也具有神经保护作用。急性体内暴露于 P(4)和 Nestorone 显著增加增殖细胞核抗原和细胞分裂周期蛋白 2 的表达以及海马 5-溴-2-脱氧尿苷（BrdU）阳性细胞的总数，而 LNG 和 MPA 则无影响。从机制上讲，神经源性孕激素需要激活 MAPK 来促进增殖。P(4)、Nestorone 和 LNG 显著增加 ATP 合酶亚基α（复合物 V，亚基α）的表达，而 MPA 则无影响。与 E(2)联合使用时，P(4)、Nestorone、LNG 和 MPA 显著增加 BrdU 掺入。然而，E(2)加 LNG 或 MPA 诱导的 BrdU 掺入伴随着凋亡的显著增加。与 LNG 和 MPA 诱导的凋亡平行的是 Bax/Bcl-2 比值的升高。除 P(4)外，临床孕激素拮抗 E(2)诱导的复合物 V、亚基α的升高。这些临床前转化研究结果表明，临床孕激素对神经发生的反应差异很大。孕激素对大脑再生能力的影响对为绝经前和绝经后妇女开处方的避孕和激素治疗配方具有临床意义。
