Protective actions of ovarian hormones in the serotonin system of macaques

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 kynurenin 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.

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

“…Our data were in agreement with previous reports in which melatonin was able to prevent the insult-related release of AIF from mitochondria (Liang et al 2012). Bethea et al (Bethea et al 2009) showed that AIF gene expression was significantly decreased by hormone therapy (E and E+P-treated animals) in laser-captured serotoninergic neurons.…”

Effect of a chronic treatment with an mGlu5 receptor antagonist on brain serotonin markers in parkinsonian monkeys

“…The hormonal status during the estrous cycle of female monkeys used by Huot et al (2012a) was not specified. Indeed, estradiol is known to modulate 5-HT 1A and 5-HT 2A receptor levels in non-human primates (Bethea et al, 2009;Sanchez et al, 2011).…”

Participation of the Monoaminergic System in the Antidepressant-Like Actions of Estrogens: A Review in Preclinical Studies

“…Together, these effects may contribute to increase the levels of monoamines in the synaptic clef and promote the activation of post-synaptic receptors such as 5-HT2A and -adrenergic receptors as well as the activation or deactivation of several signal transduction pathways such as cAMP-PKA and IP3-PKC, among others. These signal transduction pathways may contribute to the activation of transcription factors like CREB and promote neuroplastic remodeling and/or neuroprotection processes (Bethea et al, 2009) that could be effective in the development of strategies to cope with stress. Additionally, it has been reported that E2 administration decreases the activity of monoamine oxidase enzymes activity (type A and B) (involved in the degradation monoamines) in several areas of brain (Gundlah et al, 2002).…”