Protective actions of ovarian hormones in the serotonin system of macaques.

Full Abstract

The serotonin neurons of the dorsal and medial raphe nuclei project to all areas of the forebrain and play a key role in mood disorders. Hence, any loss or degeneration of serotonin neurons could have profound ramifications. In a monkey model of surgical menopause with hormone replacement and no neural injury, E and P decreased gene expression in the dorsal raphe nucleus of c-jun n-terminal kinase (JNK1) and kynurenine mono-oxygenase (KMO) that promote cell death. In concert, E and P increased gene expression of superoxide dismutase (SOD1), VEGF, and caspase inhibitory proteins that promote cellular resilience in the dorsal raphe nucleus. Subsequently, we showed that ovarian steroids inhibit pivotal genes in the caspase-dependent and caspase-independent pathways in laser-captured serotonin neurons including apoptosis activating factor (Apaf1), apoptosis-inducing factor (AIF) and second mitochondria-derived activator of caspases (Smac/Diablo). SOD1 was also increased specifically in laser-captured serotonin neurons. Examination of protein expression in the dorsal raphe block revealed that JNK1, phosphoJNK1, AIF and the translocation of AIF from the mitochondria to the nucleus decreased with hormone therapy, whereas pivotal execution proteins in the caspase pathway were unchanged. In addition, cyclins A, B, D1 and E were inhibited, which would prevent re-entry into the cell cycle and catastrophic death. These data indicated that in the absence of gross injury to the midbrain, ovarian steroids inhibit the caspase-independent pathway and cell cycle initiation in serotonin neurons. To determine if these molecular actions prevented cellular vulnerability or death, we examined DNA fragmentation in the dorsal raphe nucleus with the TUNEL assay (terminal deoxynucleotidyl transferase nick end labeling). Ovarian steroids significantly decreased the number of TUNEL-positive cells in the dorsal raphe. Moreover, TUNEL staining prominently colocalized with TPH immunostaining, a marker for serotonin neurons. In summary, ovarian steroids increase the cellular resilience of serotonin neurons and may prevent serotonin neuron death in women facing decades of life after menopause. The survival of serotonin neurons would support cognition and mental health.

Author information

Author/s: Bethea, Cynthia L (CL); Reddy, Arubala P (AP); Tokuyama, Yukari (Y); Henderson, Jessica A (JA); Lima, Fernanda B (FB);

Affiliation: Divisions of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR 97006, United States. betheac(-atsign-)ohsu.edu

Grants: HD 18185 (Agency:NICHD NIH HHS) ; MH62677 (Agency:NIMH NIH HHS) ; RR00163 (Agency:NCRR NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Review

Journal: Frontiers in neuroendocrinology (Front Neuroendocrinol), published in United States. (Language: eng)

Reference: 2009-Jul; vol 30 (issue 2) : pp 212-38

Dates: Created 2009/06/23; Completed 2009/08/17;

PMID: 19394356, status: MEDLINE (last retrieved date: 8/21/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals
Cell Death - physiology
Cell Survival - drug effects
DNA Fragmentation - drug effects
Estrogens - pharmacology; therapeutic use
Female
Gene Expression Profiling
Gene Expression Regulation - drug effects
Hormone Replacement Therapy
Humans
Lasers

Lasers
Macaca
Menopause - drug effects
Neurons - cytology; drug effects; physiology
Neuroprotective Agents - metabolism; pharmacology; therapeutic use
Oligonucleotide Array Sequence Analysis
Ovariectomy
Progesterone - pharmacology; therapeutic use
Proto-Oncogene Proteins c-bcl-2 - metabolism
Raphe Nuclei - cytology; physiology
Serotonin - metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Estrogens (0) ; Neuroprotective Agents (0) ; Proto-Oncogene Proteins c-bcl-2 (0) ; Serotonin (50-67-9) ; Progesterone (57-83-0)

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