Impact of progestins on estrogen-induced neuroprotection: Synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate

被引:263
作者
Nilsen, J
Brinton, RD
机构
[1] Univ So Calif, Pharmaceut Sci Ctr, Dept Mol Pharmacol & Toxicol, Los Angeles, CA 90033 USA
[2] Univ So Calif, Pharmaceut Sci Ctr, Program Neurosci, Los Angeles, CA 90033 USA
关键词
D O I
10.1210/en.143.1.205
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Estrogen replacement therapy is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. To compare the impact of therapeutically relevant progestins on estrogen-induced neuroprotection, we treated primary hippocampal neuron cultures with 17beta-E2 and progestin, alone and in combination, 48 h before glutamate insult. Estrogen, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant but it attenuated the estrogen. induced neuroprotection when coadministered. We addressed the role of MAPK activation in neuroprotection by ovarian steroids. Estrogen and all three progestins tested, alone or in combination, activated MAPK, indicating another mechanism of protection. Bcl-2 expression has been shown to prevent cell death and is up-regulated by 17beta-E2. Progesterone and 19-norprogesterone, alone or in combination with estrogen, increased Bcl-2 expression. In contrast, MPA blocked estrogen-induced Bcl-2 expression when coadministered. These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease.
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页码:205 / 212
页数:8
相关论文
共 44 条
[31]   Increased risk of familial late-onset Alzheimer's disease in women [J].
Payami, H ;
Montee, K ;
Grimslid, H ;
Shattuc, S ;
Kaye, J .
NEUROLOGY, 1996, 46 (01) :126-129
[32]   Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women -: The Kame Project [J].
Rice, MM ;
Graves, AB ;
McCurry, SM ;
Gibbons, LE ;
Bowen, JD ;
McCormick, WC ;
Larson, EB .
ARCHIVES OF INTERNAL MEDICINE, 2000, 160 (11) :1641-1649
[33]   GENDER INFLUENCES OUTCOME OF BRAIN INJURY - PROGESTERONE PLAYS A PROTECTIVE ROLE [J].
ROOF, RL ;
DUVDEVANI, R ;
STEIN, DG .
BRAIN RESEARCH, 1993, 607 (1-2) :333-336
[34]   Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk [J].
Schairer, C ;
Lubin, J ;
Troisi, R ;
Sturgeon, S ;
Brinton, L ;
Hoover, R .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2000, 283 (04) :485-491
[35]  
Singer CA, 1999, J NEUROSCI, V19, P2455
[36]   Modulation of Bcl-2 expression: a potential component of estrogen protection in NT2 neurons [J].
Singer, CA ;
Rogers, KL ;
Dorsa, DM .
NEUROREPORT, 1998, 9 (11) :2565-2568
[37]   Estrogen protects primary cortical neurons from glutamate toxicity [J].
Singer, CA ;
Rogers, KL ;
Strickland, TM ;
Dorsa, DM .
NEUROSCIENCE LETTERS, 1996, 212 (01) :13-16
[38]  
Singh M, 1999, J NEUROSCI, V19, P1179
[39]   ESTROGEN ACTION IN THE REPRODUCTIVE-TRACT OF RHESUS-MONKEYS DURING ANTIPROGESTIN TREATMENT [J].
SLAYDEN, OD ;
HIRST, JJ ;
BRENNER, RM .
ENDOCRINOLOGY, 1993, 132 (04) :1845-1856
[40]   Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease [J].
Tang, MX ;
Jacobs, D ;
Stern, Y ;
Marder, K ;
Schofield, P ;
Gurland, B ;
Andrews, H ;
Mayeux, R .
LANCET, 1996, 348 (9025) :429-432