The potential of mitochondrial modulation by neuroglobin in treatment of neurological disorders.

Neuroglobin is the third member of the globin family to be identified in 2000 in neurons of both human and mouse nervous systems. Neuroglobin is an oxygen-binding globin found in neurons within the central nervous system as well as in peripheral neurons, that produces a protective effect against hypoxic/ischemic damage induced by promoting oxygen availability within the mitochondria. Numerous investigations have demonstrated that impaired neuroglobin functioning is implicated in the pathogenesis of multiple neurodegenerative disorders. Several in vitro and animal studies have reported the potential of neuroglobin upregulation in improving the neuroprotection through modulation of mitochondrial functions, such as ATP production, clearing reactive oxygen species (ROS), promoting the dynamics of mitochondria, and controlling apoptosis. Neuroglobin acts as a stress-inducible globin, which has been associated hypoxic/ischemic insults where it acts to protect the heart and brain, providing a wide range of applicability in the treatment of human disorders. This review article discusses normal physiological functions of neuroglobin in mitochondria-associated pathways, as well as outlining how dysregulation of neuroglobin is associated with the pathogenesis of neurodegenerative disorders.

Lipotoxicity, neuroinflammation, glial cells and oestrogenic compounds.

The high concentrations of free fatty acids as a consequence of obesity and being overweight have become risk factors for the development of different diseases, including neurodegenerative ailments. Free fatty acids are strongly related to inflammatory events, causing cellular and tissue alterations in the brain, including cell death, deficits in neurogenesis and gliogenesis, and cognitive decline. It has been reported that people with a high body mass index have a higher risk of suffering from Alzheimer's disease. Hormones such as oestradiol not only have beneficial effects on brain tissue, but also exert some adverse effects on peripheral tissues, including the ovary and breast. For this reason, some studies have evaluated the protective effect of oestrogen receptor (ER) agonists with more specific tissue activities, such as the neuroactive steroid tibolone. Activation of ERs positively affects the expression of pro-survival factors and cell signalling pathways, thus promoting cell survival. This review aims to discuss the relationship between lipotoxicity and the development of neurodegenerative diseases. We also elaborate on the cellular and molecular mechanisms involved in neuroprotection induced by oestrogens.

Secretome of Mesenchymal Stem Cells and Its Potential Protective Effects on Brain Pathologies.

Previous studies have indicated that mesenchymal stem cells (MSCs) have a fundamental role in the repair and regeneration of damaged tissues. There is strong evidence showing that much of the beneficial effects of these cells are due to the secretion of bioactive molecules-besides microRNAs, hormones, and neurotrophins-with anti-inflammatory, immunoregulatory, angiogenic, and trophic effects. These factors have been reported by many studies to possess protective effects on the nervous tissue. Although the beneficial effects of the secretory factors of MSCs have been suggested for various neurological diseases, their actions on astrocytic cells are not well understood. Hence, it is important to recognize the specific effects of MSCs derived from adipose tissue, in addition to the differences presented by the secretome, depending on the source and methods of analysis. In this paper, the different sources of MSCs and their main characteristics are described, as well as the most significant advances in regeneration and protection provided by the secretome of MSCs. Also, we discuss the possible neuroprotective mechanisms of action of the MSC-derived biomolecules, with special emphasis on the effect of MSCs derived from adipose tissue and their impact on glial cells and brain pathologies.

Growth Factors and Neuroglobin in Astrocyte Protection Against Neurodegeneration and Oxidative Stress.

Neurodegenerative diseases, such as Parkinson and Alzheimer, are among the main public health issues in the world due to their effects on life quality and high mortality rates. Although neuronal death is the main cause of disruption in the central nervous system (CNS) elicited by these pathologies, other cells such as astrocytes are also affected. There is no treatment for preventing the cellular death during neurodegenerative processes, and current drug therapy is focused on decreasing the associated motor symptoms. For these reasons, it has been necessary to seek new therapeutical procedures, including the use of growth factors to reduce α-synuclein toxicity and misfolding in order to recover neuronal cells and astrocytes. Additionally, it has been shown that some growth factors are able to reduce the overproduction of reactive oxygen species (ROS), which are associated with neuronal death through activation of antioxidative enzymes such as catalase, superoxide dismutase, glutathione peroxidase, and neuroglobin. In the present review, we discuss the use of growth factors such as PDGF-BB, VEGF, BDNF, and the antioxidative enzyme neuroglobin in the protection of astrocytes and neurons during the development of neurodegenerative diseases.

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

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.

Correction to: Growth Factors and Neuroglobin in Astrocyte Protection Against Neurodegeneration and Oxidative Stress.

The original version of this article unfortunately contained a typo error. The name of author "Ghulam Md Ashrad" should be written as "Ghulam Md Ashraf".

Mitochondrial Neuroglobin Is Necessary for Protection Induced by Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cells in Astrocytic Cells Subjected to Scratch and Metabolic Injury.

Astrocytes are specialized cells capable of regulating inflammatory responses in neurodegenerative diseases or traumatic brain injury. In addition to playing an important role in neuroinflammation, these cells regulate essential functions for the preservation of brain tissue. Therefore, the search for therapeutic alternatives to preserve these cells and maintain their functions contributes in some way to counteract the progress of the injury and maintain neuronal survival in various brain pathologies. Among these strategies, the conditioned medium from human adipose-derived mesenchymal stem cells (CM-hMSCA) has been reported with a potential beneficial effect against several neuropathologies. In this study, we evaluated the potential effect of CM-hMSCA in a model of human astrocytes (T98G cells) subjected to scratch injury. Our findings demonstrated that CM-hMSCA regulates the cytokines IL-2, IL-6, IL-8, IL-10, GM-CSF, and TNF-α, downregulates calcium at the cytoplasmic level, and regulates mitochondrial dynamics and the respiratory chain. These actions are accompanied by modulation of the expression of different proteins involved in signaling pathways such as AKT/pAKT and ERK1/2/pERK, and may mediate the localization of neuroglobin (Ngb) at the cellular level. We also confirmed that Ngb mediated the protective effects of CM-hMSCA through regulation of proteins involved in survival pathways and oxidative stress. In conclusion, regulation of brain inflammation combined with the recovery of fundamental cellular aspects in the face of injury makes CM-hMSCA a promising candidate for the protection of astrocytes in brain pathologies.

Blockade of Neuroglobin Reduces Protection of Conditioned Medium from Human Mesenchymal Stem Cells in Human Astrocyte Model (T98G) Under a Scratch Assay.

Previous studies have indicated that paracrine factors (conditioned medium) increase wound closure and reduce reactive oxygen species in a traumatic brain injury in vitro model. Although the beneficial effects of conditioned medium from human adipose tissue-derived mesenchymal stem cells (hMSCA-CM) have been previously suggested for various neurological diseases, their actions on astrocytic cells are not well understood. In this study, we have explored the effect of hMSCA-CM on human astrocyte model (T98G cells) subjected to scratch assay. Our results indicated that hMSCA-CM improved cell viability, reduced nuclear fragmentation, attenuated the production of reactive oxygen species, and preserved mitochondrial membrane potential and ultrastructural parameters. In addition, hMSCA-CM upregulated neuroglobin in T98G cells and the genetic silencing of this protein prevented the protective action of hMSCA-CM on damaged cells, suggesting that neuroglobin is mediating, at least in part, the protective effect of hMSCA-CM. Overall, this evidence suggests that the use of hMSCA-CM is a promising therapeutic strategy for the protection of astrocytic cells in central nervous system (CNS) pathologies.

Conditioned Medium of Human Adipose Mesenchymal Stem Cells Increases Wound Closure and Protects Human Astrocytes Following Scratch Assay In Vitro.

Astrocytes perform essential functions in the preservation of neural tissue. For this reason, these cells can respond with changes in gene expression, hypertrophy, and proliferation upon a traumatic brain injury event (TBI). Different therapeutic strategies may be focused on preserving astrocyte functions and favor a non-generalized and non-sustained protective response over time post-injury. A recent strategy has been the use of the conditioned medium of human adipose mesenchymal stem cells (CM-hMSCA) as a therapeutic strategy for the treatment of various neuropathologies. However, although there is a lot of information about its effect on neuronal protection, studies on astrocytes are scarce and its specific action in glial cells is not well explored. In the present study, the effects of CM-hMSCA on human astrocytes subjected to scratch assay were assessed. Our findings indicated that CM-hMSCA improved cell viability, reduced nuclear fragmentation, and preserved mitochondrial membrane potential. These effects were accompanied by morphological changes and an increased polarity index thus reflecting the ability of astrocytes to migrate to the wound stimulated by CM-hMSCA. In conclusion, CM-hMSCA may be considered as a promising therapeutic strategy for the protection of astrocyte function in brain pathologies.

Tibolone Reduces Oxidative Damage and Inflammation in Microglia Stimulated with Palmitic Acid through Mechanisms Involving Estrogen Receptor Beta.

High concentrations of palmitic acid in plasma increase both the inflammation associated with obesity and the susceptibility to develop a neurodegenerative event. In the brain, the inflammatory response is mediated by activated microglial cells, which undergo morphological and biochemical changes and can directly affect cell viability. Recent evidence shows that the use of estrogenic compounds can control microglia-induced inflammation with promising results. In this study, we explored the actions of the synthetic steroid tibolone on BV-2 microglia cells stimulated with palmitic acid. Our results demonstrated that tibolone increased cell viability and reduced nuclear fragmentation and the production of reactive oxygen species, as well as preserved mitochondrial membrane potential. These effects were accompanied by reduced nuclear translocation of NF-κB p65, upregulation of neuroglobin, and improved antioxidant defense. Furthermore, estrogen receptor beta (ERß) inhibition partially dampened tibolone's protective actions in BV-2 cells stimulated with palmitic acid. In conclusion, tibolone protects BV-2 cells by a mechanism involving ERß and upregulation of neuroglobin.