Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats

B. Blair Braden, Joshua S. Talboom, Ian D. Crain, Alain R. Simard, Ronald J. Lukas, Laszlo Prokai, Melissa R. Scheldrup, Bronson L. Bowman, Heather A. Bimonte-Nelson

Research output: Contribution to journalArticle

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Abstract

In women, medroxyprogesterone acetate (MPA) is the most commonly used progestin component of hormone therapy (HT). In vitro, MPA negatively impacts markers of neuronal health and exacerbates experimentally-induced neurotoxicity. There is in vitro evidence that these factors are driven by GABAergic and neurotrophic systems. Whether these effects translate to a negative impact on brain function has not been tested in vivo, clinically or preclinically. Here we evaluate the mnemonic and neurobiological effects of MPA in the surgically menopausal rat. Aged ovariectomized (OVX) rats were given subcutaneous vehicle, natural progesterone, low-dose MPA or high-dose MPA. Multiple cognitive domains were analyzed via the water radial-arm maze (WRAM) and Morris maze (MM). Cognitive brain regions were assayed for changes in the GABAergic system by evaluating GAD protein, the synthesizing enzyme for GABA, and neurotrophins. On the WRAM, both progestin types impaired learning. Further, high-dose MPA impaired delayed memory retention on the WRAM, and exacerbated overnight forgetting on the MM. While neurotrophins were not affected by progesterone or MPA treatment, both progestin types altered GAD levels. MPA significantly and progesterone marginally decreased GAD levels in the hippocampus, and both MPA and progesterone significantly increased GAD levels in the entorhinal cortex. These findings suggest that MPA, the most commonly used progestin in HT, is detrimental to learning and two types of memory, and modulates the GABAergic system in cognitive brain regions, in aged surgically menopausal rats. These findings, combined with in vitro evidence that MPA is detrimental to neuronal health, indicates that MPA has negative effects for brain health and function.

Original languageEnglish
Pages (from-to)444-453
Number of pages10
JournalNeurobiology of Learning and Memory
Volume93
Issue number3
DOIs
StatePublished - 1 Mar 2010

Fingerprint

Medroxyprogesterone Acetate
Progestins
Progesterone
Nerve Growth Factors
Brain
Water
Health
Learning
Repression (Psychology)
Hormones
Entorhinal Cortex
gamma-Aminobutyric Acid
Hippocampus
Therapeutics

Keywords

  • Aging
  • Cognition
  • Hormone therapy
  • Learning and memory
  • Menopause
  • Progestins

Cite this

Braden, B. Blair ; Talboom, Joshua S. ; Crain, Ian D. ; Simard, Alain R. ; Lukas, Ronald J. ; Prokai, Laszlo ; Scheldrup, Melissa R. ; Bowman, Bronson L. ; Bimonte-Nelson, Heather A. / Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats. In: Neurobiology of Learning and Memory. 2010 ; Vol. 93, No. 3. pp. 444-453.
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Braden, BB, Talboom, JS, Crain, ID, Simard, AR, Lukas, RJ, Prokai, L, Scheldrup, MR, Bowman, BL & Bimonte-Nelson, HA 2010, 'Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats', Neurobiology of Learning and Memory, vol. 93, no. 3, pp. 444-453. https://doi.org/10.1016/j.nlm.2010.01.002

Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats. / Braden, B. Blair; Talboom, Joshua S.; Crain, Ian D.; Simard, Alain R.; Lukas, Ronald J.; Prokai, Laszlo; Scheldrup, Melissa R.; Bowman, Bronson L.; Bimonte-Nelson, Heather A.

In: Neurobiology of Learning and Memory, Vol. 93, No. 3, 01.03.2010, p. 444-453.

Research output: Contribution to journalArticle

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T1 - Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats

AU - Braden, B. Blair

AU - Talboom, Joshua S.

AU - Crain, Ian D.

AU - Simard, Alain R.

AU - Lukas, Ronald J.

AU - Prokai, Laszlo

AU - Scheldrup, Melissa R.

AU - Bowman, Bronson L.

AU - Bimonte-Nelson, Heather A.

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N2 - In women, medroxyprogesterone acetate (MPA) is the most commonly used progestin component of hormone therapy (HT). In vitro, MPA negatively impacts markers of neuronal health and exacerbates experimentally-induced neurotoxicity. There is in vitro evidence that these factors are driven by GABAergic and neurotrophic systems. Whether these effects translate to a negative impact on brain function has not been tested in vivo, clinically or preclinically. Here we evaluate the mnemonic and neurobiological effects of MPA in the surgically menopausal rat. Aged ovariectomized (OVX) rats were given subcutaneous vehicle, natural progesterone, low-dose MPA or high-dose MPA. Multiple cognitive domains were analyzed via the water radial-arm maze (WRAM) and Morris maze (MM). Cognitive brain regions were assayed for changes in the GABAergic system by evaluating GAD protein, the synthesizing enzyme for GABA, and neurotrophins. On the WRAM, both progestin types impaired learning. Further, high-dose MPA impaired delayed memory retention on the WRAM, and exacerbated overnight forgetting on the MM. While neurotrophins were not affected by progesterone or MPA treatment, both progestin types altered GAD levels. MPA significantly and progesterone marginally decreased GAD levels in the hippocampus, and both MPA and progesterone significantly increased GAD levels in the entorhinal cortex. These findings suggest that MPA, the most commonly used progestin in HT, is detrimental to learning and two types of memory, and modulates the GABAergic system in cognitive brain regions, in aged surgically menopausal rats. These findings, combined with in vitro evidence that MPA is detrimental to neuronal health, indicates that MPA has negative effects for brain health and function.

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