The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury

Crespo‐Castrillo, Andrea; Yanguas‐Casás, Natalia; Arévalo, María Ángeles; Azcoitia, Íñigo; Barreto, George E.; Garcia-Segura, Luis Miguel

doi:10.1007/s12035-018-1008-x

Cited by 31 publications

(24 citation statements)

References 99 publications

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“…In this regard, astrocytes are postulated as mediators of the action of tibolone in the CNS [118]. Indeed, a recent study has shown that tibolone reduces reactive astrogliosis in a model of TBI in ovariectomized female mice [169]. …”

Section: The Cns As a Target For Neuroprotective Estrogenic Compoundsmentioning

confidence: 99%

“…In vivo studies have shown that several estrogenic compounds, such as estradiol, phytoestrogens (genistein), some SERMs and tibolone, decrease reactive astrogliosis and glial scar formation after TBI [123, 169-171, 199-201]. After spinal cord injury, tamoxifen has been shown to first increase astrogliosis at day 2 after injury and then gradually decrease astrogliosis [202].…”

Section: Neuroprotective Actions Of Estrogenic Compounds After Tbimentioning

confidence: 99%

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Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

et al. 2018

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Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.

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Section: The Cns As a Target For Neuroprotective Estrogenic Compoundsmentioning

confidence: 99%

Section: Neuroprotective Actions Of Estrogenic Compounds After Tbimentioning

confidence: 99%

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

et al. 2018

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“…Previous studies have shown that tibolone 3-hydroxy metabolites activate ERs in human primary astrocytes [19] and that ERs, mainly ERβ, mediate different actions of tibolone on T98G astrocyte-like cells [14,15]. The direct actions of tibolone on astrocytes and astrocyte-like cells through ERs, together with the decreased neuronal loss in association with a reduction of reactive astrogliosis in the injured cortex of tibolone-treated mice [16], suggest that astrocytes may be involved in the neuroprotective actions of the steroid. Indeed, it is known that astrocytes mediate the neuroprotective actions of estradiol and other ER ligands in different CNS (central nervous system) pathologies [20,21].…”

Section: Introductionmentioning

confidence: 96%

“…Thus, the steroid reduces inflammation and prevents oxidative damage in BV-2 microglia exposed to palmitic acid [11] and protects T98G cells from glucose deprivation and palmitic acid toxicity [12][13][14], reducing oxidative stress and preserving mitochondrial membrane potential [14,15]. Furthermore, tibolone decreases in vivo the reactive response of microglia and astrocytes after a stab wound lesion of the cerebral cortex in ovariectomized female mice [16].…”

Section: Introductionmentioning

confidence: 97%

The synthetic steroid tibolone exerts sex-specific regulation of astrocyte phagocytosis under basal conditions and after an inflammatory challenge

Crespo‐Castrillo

Garcia-Segura

Arévalo

2020

J Neuroinflammation

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Background: Tibolone is a synthetic steroid used in clinical practice for the treatment of climacteric symptoms and osteoporosis. Active metabolites of tibolone, generated in target tissues, have an affinity for estrogen and androgen receptors. Astrocytes are direct targets for estrogenic compounds and previous studies have shown that tibolone protects brain cortical neurons in association with a reduction in reactive astrogliosis in a mouse model of traumatic brain injury. Since phagocytosis is a crucial component of the neuroprotective function exerted by astrocytes, in the present study, we have assessed whether tibolone regulates phagocytosis in primary astrocytes incubated with brain-derived cellular debris. Methods: Male and female astrocyte cell cultures were obtained from newborn (P0-P2) female and male Wistar rats. Astrocytic phagocytosis was first characterized using carboxylate beads, Escherichia coli particles, or brain-derived cellular debris. Then, the effect of tibolone on the phagocytosis of Cy3-conjugated cellular debris was quantified by measuring the intensity of Cy3 dye-emitted fluorescence in a given GFAP immunoreactive area. Before the phagocytosis assays, astrocytes were incubated with tibolone in the presence or absence of estrogen or androgen receptor antagonists or an inhibitor of the enzyme that synthesizes estradiol. The effect of tibolone on phagocytosis was analyzed under basal conditions and after inflammatory stimulation with lipopolysaccharide. Results: Tibolone stimulated phagocytosis of brain-derived cellular debris by male and female astrocytes, with the effect being more pronounced in females. The effect of tibolone in female astrocytes was blocked by a selective estrogen receptor β antagonist and by an androgen receptor antagonist. None of these antagonists affected tibolone-induced phagocytosis in male astrocytes. In addition, the inhibition of estradiol synthesis in the cultures enhanced the stimulatory effect of tibolone on phagocytosis in male astrocytes but blocked the effect of the steroid in female cells under basal conditions. However, after inflammatory stimulation, the inhibition of estradiol synthesis highly potentiated the stimulation of phagocytosis by tibolone, particularly in female astrocytes. Conclusions: Tibolone exerts sex-specific regulation of phagocytosis in astrocytes of both sexes, both under basal conditions and after inflammatory stimulation.

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“…Having in account the importance of astrocytes for brain inflammation, and the promising effects of tibolone for astrocytic and neuronal protection (Crespo-Castrillo et al, 2018), we developed a genomic-scale metabolic model of astrocytes, with the purpose of enlighten the metabolic pathways modulated by tibolone during an inflammatory response caused by the increased uptake of palmitate. We focused or attention, in the identification of metabolic changes related with the modulation of cytokines, the release of gliotransmitters and the neuroprotective effects mediated by tibolone in an inflammatory scenario (Wojtal et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach

et al. 2020

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Inflammation is a complex biological response to injuries, metabolic disorders or infections. In the brain, astrocytes play an important role in the inflammatory processes during neurodegenerative diseases. Recent studies have shown that the increase of free saturated fatty acids such as palmitic acid produces a metabolic inflammatory response in astrocytes generally associated with damaging mechanisms such as oxidative stress, endoplasmic reticulum stress, and autophagic defects. In this aspect, the synthetic neurosteroid tibolone has shown to exert protective functions against inflammation in neuronal experimental models without the tumorigenic effects exerted by sexual hormones such as estradiol and progesterone. However, there is little information regarding the specific mechanisms of tibolone in astrocytes during inflammatory insults. In the present study, we performed a genome-scale metabolic reconstruction of astrocytes that was used to study astrocytic response during an inflammatory insult by palmitate through Flux Balance Analysis methods and data mining. In this aspect, we assessed the metabolic fluxes of human astrocytes under three different scenarios: healthy (normal conditions), induced inflammation by palmitate, and tibolone treatment under palmitate inflammation. Our results suggest that tibolone reduces the L-glutamate-mediated neurotoxicity in astrocytes through the modulation of several metabolic pathways involved in glutamate uptake. We also identified a set of reactions associated with the protective effects of tibolone, including the upregulation of taurine metabolism, gluconeogenesis, cPPAR and the modulation of calcium signaling pathways. In conclusion, the different scenarios studied in our model allowed us to identify several metabolic fluxes perturbed under an inflammatory response and the protective mechanisms exerted by tibolone.

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The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury

Cited by 31 publications

References 99 publications

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury

The synthetic steroid tibolone exerts sex-specific regulation of astrocyte phagocytosis under basal conditions and after an inflammatory challenge

Multiple Pathways Involved in Palmitic Acid-Induced Toxicity: A System Biology Approach

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