Raloxifene attenuates oxidative stress and preserves mitochondrial function in astrocytic cells upon glucose deprivation

Abstract

Oxidative stress and mitochondrial dysfunction induced by metabolic insults are both hallmarks of various neurological disorders, whereby neuronal cells are severely affected by decreased glucose supply to the brain. Likely injured, astrocytes are important for neuronal homeostasis and therapeutic strategies should be directed towards improving astrocytic functions to improve brain's outcome. In the present study, we aimed to assess the actions of raloxifene, a selective estrogen receptor modulator in astrocytic cells under glucose deprivation. Our findings indicated that pretreatment with 1 µM raloxifene results in an increase in cell viability and attenuated nuclei fragmentation. Raloxifene's actions also rely on the reduction of oxidative stress and preservation of mitochondrial function in glucose‐deprived astrocytic cells, suggesting the possible direct effects of this compound on mitochondria. In conclusion, our results demonstrate that raloxifene's protective actions might be mediated in part by astrocytes in the setting of a metabolic insult.

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

“…As maintenance of neuronal homeostasis is an important function of astrocytes, to enhance astrocytic functions in this respect would present promising therapeutic strategies for improvement of brain function otherwise impaired by injury and disease. Encouragingly, it was found in cell culture that application of 1 µM raloxifene as a pretreatment to glucose-deprivation of astrocytic cells results in increases in cell viability and attenuation of nuclei fragmentation [ 57 ]. These favorable effects are associated with raloxifene reduction of oxidative stress and preservation of mitochondrial function [ 57 ].…”

“…Encouragingly, it was found in cell culture that application of 1 µM raloxifene as a pretreatment to glucose-deprivation of astrocytic cells results in increases in cell viability and attenuation of nuclei fragmentation [ 57 ]. These favorable effects are associated with raloxifene reduction of oxidative stress and preservation of mitochondrial function [ 57 ]. These results also suggested direct effects of raloxifene on mitochondria [ 57 ].…”

“…These favorable effects are associated with raloxifene reduction of oxidative stress and preservation of mitochondrial function [ 57 ]. These results also suggested direct effects of raloxifene on mitochondria [ 57 ]. In short, the data presented in Section 3.2 , Astrocytes, suggest that, apart from maintaining metabolic homeostasis, estrogenic targeting of the production and release of pro-inflammatory molecules by astrocytes is a promising venue to counteract brain inflammation associated with neurodegeneration that is part and parcel of brain injury and disease.…”

“…Moreover, in another study, it was observed that estradiol, raloxifene, and tamoxifen administrations were beneficial on mitochondrial oxidative stress, inflammation, and poly (ADP-ribose) polymerase (PARP) levels in the serum and brain of ovariectomized rats by modulating antioxidant systems, DNA damage, and cytokine production [ 77 ]. Oxidative stress and mitochondrial dysfunction are major participants in various neurological disorders, where neuronal cells are severely affected by a decreased glucose supply to the brain [ 57 ]. Moreover, in astrocytic cell culture, glucose-deprivation resulted in nuclei fragmentation.…”

Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds

“…In inflammatory in vitro and in vivo models, it has been shown that administration of oestradiol and selective ER modulators (SERMs) decreases the expression of the pro‐inflammatory cytokines IL‐1β, IL‐10 and TNFα . Raloxifene, another SERM, has also been shown to protect mitochondria in astrocytic cells exposed to glucose deprivation . By contrast, administration of oestradiol can modulate the mitogenic stimulation of B and T lymphocytes and, as a consequence, increase the production of immunoglobulins such as immunoglobulin M. Indeed, epidemiological studies have shown that women of any age experience lower rates of infection and mortality associated with inflammatory processes compared to men …”