Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective
Reduced metabolites mediate neuroprotective effects of progesterone in the adult rat hippocampus. The synthetic progestin medroxyprogesterone acetate (Provera) is not neuroprotective
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DOI：
10.1002/neu.20293
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发表时间：
2006-08-01
期刊：
影响因子：
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通讯作者：
Garcia-Segura, Luis M.
中科院分区：
文献类型：
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作者：
Ciriza, Iratxe;Carrero, Paloma;Garcia-Segura, Luis M.
卵巢激素孕酮在不同的神经变性实验模型中具有神经保护作用。在神经系统中，孕酮通过酶5 α-还原酶代谢为5 α-二氢孕酮（DHP）。DHP随后通过由酶3 α-羟基类固醇脱氢酶催化的可逆反应还原为3 α，5 α-四氢孕酮（THP）。在这项研究中，我们分析了孕激素代谢是否参与神经保护作用的激素在门的卵巢切除大鼠海马注射红藻氨酸，兴奋性毒性细胞死亡的实验模型。Progesterone增加血浆和海马中DHP和THP的水平，并防止红藻氨酸诱导的神经元丢失。与孕酮相反，合成的孕酮醋酸甲羟孕酮（NIPA，Provera）不增加DHP和THP水平，并且不防止红藻氨酸诱导的神经元损失。给药5 m-还原酶抑制剂非那肽可防止孕酮给药导致血浆和海马中DHP和THP水平升高，并消除孕酮的神经保护作用。DHP和THP均对红藻氨酸具有神经保护作用。然而，吲哚美辛，3 α-羟基类固醇脱氢酶抑制剂的管理，阻断DHP和THP的神经保护作用，这表明这两种代谢产物是必要的孕酮的神经保护作用。总之，我们的研究结果表明，孕酮是神经保护红藻氨酸兴奋性毒性在体内，而合成的孕酮MPA不是，并建议孕酮代谢到其减少衍生物DHP和THP是必要的激素的神经保护作用。(c)2006 Wiley Periodicals，Inc.
The ovarian hormone progesterone is neuroprotective in different experimental models of neuro-degeneration. In the nervous system, progesterone is metabolized to 5 alpha-dihydroprogesterone (DHP) by the enzyme 5 alpha-reductase. DHP is subsequently reduced to 3 alpha,5 alpha-tetrahydroprogesterone (THP) by a reversible reaction catalyzed by the enzyme 3 alpha-hydroxysteroid dehydrogenase. In this study we have analyzed whether progesterone metabolism is involved in the neuroprotective effect of the hormone in the hilus of the hippocampus of ovariectomized rats injected with kainic acid, an experimental model of excitotoxic cell death. Progesterone increased the levels of DHP and THP in plasma and hippocampus and prevented kainic-acid-induced neuronal loss. In contrast to progesterone, the synthetic progestin medroxyprogesterone acetate (NIPA, Provera) did not increase DHP and THP levels and did not prevent kainic-acid-induced neuronal loss. The administration of the 5m-reductase inhibitor finasteride prevented the increase in the levels of DHP and THP in plasma and hippocampus as a result of progesterone administration and abolished the neuroprotective effect of progesterone. Both DHP and THP were neuroprotective against kainic acid. However, the administration of indomethacin, a 3 alpha-hydroxysteroid dehydrogenase inhibitor, blocked the neuroprotective effect of both DHP and THP, suggesting that both metabolites are necessary for the neuroprotective effect of progesterone. In conclusion, our findings indicate that progesterone is neuroprotective against kainic acid excitotoxicity in vivo while the synthetic progestin MPA is not and suggest that progesterone metabolism to its reduced derivatives DHP and THP is necessary for the neuroprotective effect of the hormone. (c) 2006 Wiley Periodicals, Inc.