Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Jul;150(7):3162-8.
doi: 10.1210/en.2008-1247. Epub 2009 Mar 26.

The differences in neuroprotective efficacy of progesterone and medroxyprogesterone acetate correlate with their effects on brain-derived neurotrophic factor expression

Parmeet K Jodhka  1 , Paramjit Kaur, Wendy Underwood, John P Lydon, Meharvan Singh
Affiliations

The differences in neuroprotective efficacy of progesterone and medroxyprogesterone acetate correlate with their effects on brain-derived neurotrophic factor expression

Parmeet K Jodhka et al. Endocrinology. 2009 Jul.

Abstract

Whereas hormone therapy is used for the treatment of menopausal symptoms, its efficacy in helping reduce the risk of other diseases such as Alzheimer's disease has been questioned in view of the results of recent clinical trials that appeared inconsistent with numerous basic research studies that supported the beneficial effects of hormones. One possible explanation of this discrepancy may lie in the choice of hormone used. For example, we and others found that progesterone is neuroprotective whereas medroxyprogesterone acetate (MPA), the synthetic progestin used in hormone therapy, is not. Because our data suggest that progesterone-induced protection is associated with the induction of brain-derived neurotrophic factor (BDNF) levels and, importantly, can be blocked by inhibiting the neurotrophin signaling, we determined whether progesterone and medroxyprogesterone acetate differed in their ability to regulate BDNF levels in the explants of the cerebral cortex. We found that progesterone elicited an increase in both BDNF mRNA and protein levels, whereas medroxyprogesterone acetate did not. Furthermore, using both a pharmacological inhibitor of the progesterone receptor (PR) and PR knockout mice, we determined that the effects of progesterone were mediated by the classical PR. Our results underscore the fact that not all progestins have equivalent effects on the brain and suggest that the selection of the appropriate progestin may influence the success of hormone therapy formulations used in treating the menopause and/or reducing the risk for diseases associated with the postmenopausal period.

PubMed Disclaimer

Figures

Figure 1
Figure 1
P4 but not MPA protects against glutamate-induced cytotoxicity. Cerebral cortical explants were pretreated with P4 (100 nm) for 24 h before the administration of l-glutamate (Glut; 15 mm for 6 h). P4 prevented glutamate-induced LDH release, insofar as these values were not statistically different from vehicle-treated control. MPA, however, failed to prevent glutamate-induced LDH release. LDH release is expressed as a percentage of that seen in the vehicle-treated control (set at 100%), with the latter represented by the solid horizontal line. The graph shown represents data from three independent experiments. Data are presented as mean ± sem. *, P < 0.01 relative to vehicle-treated control; #, P < 0.05 vs. MPA + Glut group.
Figure 2
Figure 2
Differential regulation of BDNF mRNA by P4 and MPA. BDNF mRNA was assessed in cerebral cortical explants treated with P4 (100 nm) or MPA (100 nm) for 18 h. Using real-time RT-PCR, we found that P4 but not MPA elicited an increase in BDNF mRNA. Data are presented as mean ± sem of five independent experiments for P4 treatments and four independent experiments for MPA treatments. *, P ≤ 0.01 vs. control; #, P < 0.05 vs. control.
Figure 3
Figure 3
Differential regulation of total cellular BDNF content by MPA and P4. BDNF protein levels were assessed in cerebral cortical explants treated with P4 or MPA for 18 h using an ELISA. A, P4 induced an increase in BDNF expression at concentrations of 100 nm and 1 μm. B, MPA does not induce an increase in BDNF expression. There was a decrease in total cellular BDNF in cultures treated with 10 and 100 nm MPA. BDNF levels are presented as a percentage of the vehicle-treated control, represented by the solid horizontal line. Data are represented as mean ± sem. *, P < 0.01 relative to vehicle-treated control.
Figure 4
Figure 4
P4-induced BDNF expression is inhibited by RU486. Cerebral cortical explants were treated with P4 (100 nm) and the PR antagonist, RU486 (1 μm). BDNF mRNA was assessed in cerebral cortical explants after 18 h. A, Using real-time RT-PCR, we found that P4 induced an increase in BDNF mRNA, whereas RU486 inhibited the P4-induced response. The graph shown represents data from seven independent experiments for samples treated with P4 or P4 in presence of RU486 and five independent experiments for RU486 treatments. *, P < 0.0001 relative to vehicle-treated control; #, P < 0.0001 relative to P4-treated samples. B, BDNF protein levels were assessed in cerebral cortical explants using an ELISA. BDNF levels are presented as a percentage of the vehicle-treated control, represented by the solid horizontal line. The graph shown represents data from four independent experiments for samples treated with P4. There were five independent experiments for samples treated with P4 in presence of RU486 and four independent experiments for RU486 treatments. *, P < 0.05 relative to vehicle-treated control; #, P < 0.05 relative to P4-treated samples.
Figure 5
Figure 5
P4 fails to elicit an increase in BDNF expression in PRKO Mice. Cerebral cortical explants from P3 mice were treated for 18 h with P4. Using real-time RT-PCR, we found that P4 induced an increase in BDNF mRNA in cerebral cortical explants from wild-type but not PRKO mice. BDNF levels within the cultures derived from each genotype are presented as a percentage of their respective vehicle-treated controls (depicted by the solid horizontal line). Data are presented as mean ± sem from four independent experiments. *, P < 0.05; #, P < 0.01.
Figure 6
Figure 6
P4, but not its membrane impermeant form (P4-BSA), induces an increase in BDNF protein expression. A, BDNF mRNA was assessed in cerebral cortical explants treated with P4-BSA (100 nm) or an equimolar concentration of BSA alone (control) for 18 h. We found that P4-BSA did not induce statistically significant increase in BDNF cellular content. Data are presented as mean ± sem of three independent experiments. B, Western blot analysis revealed that P4-BSA elicited a time-dependent increase in ERK phosphorylation (P-ERK; upper panel), achieving maximal levels between 5 and 15 min and declining thereafter. P4 treatment (30 min) was used as the positive control and yielded ERK phosphorylation levels similar to that observed with P4-BSA at the same time point. In separate control experiments, we found that equimolar concentrations of BSA alone did not elicit ERK phosphorylation at similar time points (data not shown). The lower panel represents reprobing the phospho-blot for total ERK protein to ensure equal loading across lanes.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Simpkins JW, Singh M 2008 More than a decade of estrogen neuroprotection. Alzheimers Dement 4:S131–S136 - PubMed
    1. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones 3rd BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J 2003 Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2651–2662 - PubMed
    1. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH 2004 Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291:2947–2958 - PubMed
    1. Singh M, Sumien N, Kyser C, Simpkins JW 2008 Estrogens and progesterone as neuroprotectants: what animal models teach us. Front Biosci 13:1083–1089 - PMC - PubMed
    1. Simpkins JW, Singh M 2004 Consortium for the Assessment of Research on Progestins and Estrogens (CARPE), Fort Worth, Texas, August 1–3, 2003. J Womens Health (Larchmt) 13:1165–1168 - PubMed

Publication types

MeSH terms