Tibolone regulates systemic metabolism and the expression of sex hormone receptors in the central nervous system of ovariectomised rats fed with high-fat and high-fructose diet

Coyoy-Salgado, Angélica; Segura-Uribe, Julia J.; Gallardo, Juan Manuel; Estrada-Cruz, Norma Angélica; Guerra‐Araiza, Christian

doi:10.1016/j.brainres.2020.147096

Cited by 8 publications

(4 citation statements)

References 76 publications

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“…However, it should be taken into account that there is little consensus in the literature regarding the effects of tibolone on the expression of ERα or ERβ. In a study by Coyoy‐Salgado et al, 57 tibolone showed no effect on ERα, although it reduced ERβ in the cortex and hypothalamus but not hippocampus of rats fed a high‐fat diet. In the breast, both receptor types are not modified by tibolone, 58 whereas this compound increases ERα in the uterus 59 .…”

Section: Discussionmentioning

confidence: 93%

Tibolone restrains neuroinflammation in mouse experimental autoimmune encephalomyelitis

Mancino

Lima

Roig

et al. 2021

J Neuroendocrinology

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Multiple sclerosis (MS) is an immune‐mediated and degenerating disease in which myelin sheaths are damaged as a result of chronic progressive inflammation of the central nervous system. Tibolone [(7α,17α)‐17‐hydroxy‐7‐methyl‐19‐norpregn‐5(10)‐en‐20‐in‐3‐one], a synthetic estrogenic compound with tissue‐specific actions and used for menopausal hormone therapy, shows neuroprotective and antioxidant properties both in vivo and in vitro. In the present study, we analyzed whether tibolone plays a therapeutic role in experimental autoimmune encephalomyelitis (EAE) mice, a commonly used model of MS. Female C57BL/6 mice were induced with the myelin oligodendrocyte glycoprotein MOG35–55 and received s.c. tibolone (0.08 mg kg–1) injection every other day from the day of induction until death on the acute phase of the disease. Reactive gliosis, Toll like receptor 4 (TLR4), high mobility group box protein 1 (HMGB1), inflammasome parameters, activated Akt levels and myelin were assessed by a real‐time polymerase chain reaction, immunohistochemistry, and western blot analysis. Our findings indicated that, in the EAE spinal cord, tibolone reversed the astrocytic and microglial reaction, and reduced the hyperexpression of TLR4 and HMGB1, as well as NLR family pyrin domain containing 3‐caspase 1‐interleukin‐1β inflammasome activation. At the same time, tibolone attenuated the Akt/nuclear factor kappa B pathway and limited the white matter demyelination area. Estrogen receptor expression was unaltered with tibolone treatment. Clinically, tibolone improved neurological symptoms without uterine compromise. Overall, our data suggest that tibolone may serve as a promising agent for the attenuation of MS‐related inflammation.

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Section: Discussionmentioning

confidence: 93%

Tibolone restrains neuroinflammation in mouse experimental autoimmune encephalomyelitis

Mancino

Lima

Roig

et al. 2021

J Neuroendocrinology

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“…Together, although research into the functionality of UQCR10 is still early we are seeing signals that it may be a significant contributor to regulating the functionality of the respirasome. Previous studies have shown that hormonal deprivation, such as in ovariectomy, can disrupt metabolic processes which can be ameliorated by Tibolone [ 39 ]. A fascinating metabolomic study by Chabrun et al showed the greater dysregulation of metabolites following gonadectomising in females than males, as well as the region-specific effects [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Respirasome Proteins Are Regulated by Sex-Hormone Interactions in the Brain

McGovern

Arévalo

Ciordia

et al. 2022

IJMS

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The existence of sex differences in disease incidence is attributed, in part, to sex differences in metabolism. Uncovering the precise mechanism driving these differences is an extraordinarily complex process influenced by genetics, endogenous hormones, sex-specific lifetime events, individual differences and external environmental/social factors. In fact, such differences may be subtle, but across a life span, increase susceptibility to a pathology. Whilst research persists in the hope of discovering an elegant biological mechanism to underpin sex differences in disease, here, we show, for the first time, that such a mechanism may be subtle in nature but influenced by multiple sex-specific factors. A proteomic dataset was generated from a gonadectomized mouse model treated with Tibolone, a menopausal hormone therapy. Following functional enrichment analysis, we identified that Alzheimer’s disease and the electron transport chain-associated pathways were regulated by sex-hormone interactions. Specifically, we identified that the expression of three respirasome proteins, NDUFA2, NDUFA7 and UQCR10, is significantly altered by compounding factors that contribute to sex differences. These proteins function in bioenergetics and produce reactive oxygen species, which are each dysregulated in many diseases with sex differences in incidence. We show sex-specific reprogrammed responses to Tibolone following gonadectomy, which primarily influence the expression of proteins contributing to metabolic pathways. This further infers that metabolic differences may underpin the observed sex differences in disease, but also that hormone therapy research now has potential in exploring sex-specific interventions to produce an effective method of prevention or treatment.

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“…35 Studies have shown that the regulation of estrogen and NF-κB p65/ IKKα signaling pathway may become an effective way to treat breast cancer. [36][37][38][39] Drugs that are effective in treating neuroinflammation may regulate the NF-κB p65/IKKα signaling pathway through androgen and estrogen receptors to inhibit neuroinflammation in hippocampus. [37][38][39] In future research, we will further study the effects of resatorvid on steroid receptors and related proteins to discover more effective therapeutic methods to treat BCCD.…”

Section: Discussionmentioning

confidence: 99%

<p>Resatorvid Relieves Breast Cancer Complicated with Depression by Inactivating Hippocampal Microglia Through TLR4/NF-κB/NLRP3 Signaling Pathway</p>

Luo¹,

Han²,

Pan³

et al. 2020

CMAR

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Background Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD). Methods The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo. Results The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood–brain barrier function. Conclusion In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.

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Tibolone regulates systemic metabolism and the expression of sex hormone receptors in the central nervous system of ovariectomised rats fed with high-fat and high-fructose diet

Cited by 8 publications

References 76 publications

Tibolone restrains neuroinflammation in mouse experimental autoimmune encephalomyelitis

Tibolone restrains neuroinflammation in mouse experimental autoimmune encephalomyelitis

Respirasome Proteins Are Regulated by Sex-Hormone Interactions in the Brain

<p>Resatorvid Relieves Breast Cancer Complicated with Depression by Inactivating Hippocampal Microglia Through TLR4/NF-κB/NLRP3 Signaling Pathway</p>

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