Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases.

Astrocytes play a pivotal role in maintaining brain homeostasis. Recent research has highlighted the significance of palmitic acid (PA) in triggering pro-inflammatory pathways contributing to neurotoxicity. Furthermore, Genomic-scale metabolic models and control theory have revealed that metabolic switches (MSs) are metabolic pathway regulators by potentially exacerbating neurotoxicity, thereby offering promising therapeutic targets. Herein, we characterized these enzymatic MSs in silico as potential therapeutic targets, employing protein-protein and drug-protein interaction networks alongside structural characterization techniques. Our findings indicate that five MSs (P00558, P04406, Q08426, P09110, and O76062) were functionally linked to nervous system drug targets and may be indirectly regulated by specific neurological drugs, some of which exhibit polypharmacological potential (e.g., Trifluperidol, Trifluoperazine, Disulfiram, and Haloperidol). Furthermore, four MSs (P00558, P04406, Q08426, and P09110) feature ligand-binding or allosteric cavities with druggable potential. Our results advocate for a focused exploration of P00558 (phosphoglycerate kinase 1), P04406 (glyceraldehyde-3-phosphate dehydrogenase), Q08426 (peroxisomal bifunctional enzyme, enoyl-CoA hydratase, and 3-hydroxyacyl CoA dehydrogenase), P09110 (peroxisomal 3-ketoacyl-CoA thiolase), and O76062 (Delta(14)-sterol reductase) as promising targets for the development or repurposing of pharmacological compounds, which could have the potential to modulate lipotoxic-altered metabolic pathways, offering new avenues for the treatment of related human diseases such as neurological diseases.

Network pharmacology and topological analysis on tibolone metabolites and their molecular mechanisms in traumatic brain injury.

Traumatic brain injury (TBI) is a pathology of great social impact, affecting millions of people worldwide. Despite the scientific advances to improve the management of TBI in recent years, we still do not have a specific treatment that controls the inflammatory process after mechanical trauma. The discovery and implementation of new treatments is a long and expensive process, making the repurpose of approved drugs for other pathologies a clinical interest. Tibolone is a drug in use for the treatment of symptoms associated with menopause and has been shown to have a broad spectrum of actions by regulating estrogen, androgen and progesterone receptors, whose activation exerts potent anti-inflammatory and antioxidant effects. In the present study, we aimed to investigate the therapeutic potential of the tibolone metabolites 3α-Hydroxytibolone, 3ß-Hydroxytibolone, and Δ4-Tibolone as a possible therapy in TBI using network pharmacology and network topology analysis. Our results demonstrate that the estrogenic component mediated by the α and ß metabolites can regulate synaptic transmission and cell metabolism, while the Δ metabolite may be involved in modulating the post-TBI inflammatory process. We identified several molecular targets, including KDR, ESR2, AR, NR3C1, PPARD, and PPARA, which are known to play critical roles in the pathogenesis of TBI. Tibolone metabolites were predicted to regulate the expression of key genes involved in oxidative stress, inflammation, and apoptosis. Overall, the repurposing of tibolone as a neuroprotective treatment for TBI holds promise for future clinical trials. However, further studies are needed to confirm its efficacy and safety in TBI patients.

Control Theory and Systems Biology: Potential Applications in Neurodegeneration and Search for Therapeutic Targets.

Control theory, a well-established discipline in engineering and mathematics, has found novel applications in systems biology. This interdisciplinary approach leverages the principles of feedback control and regulation to gain insights into the complex dynamics of cellular and molecular networks underlying chronic diseases, including neurodegeneration. By modeling and analyzing these intricate systems, control theory provides a framework to understand the pathophysiology and identify potential therapeutic targets. Therefore, this review examines the most widely used control methods in conjunction with genomic-scale metabolic models in the steady state of the multi-omics type. According to our research, this approach involves integrating experimental data, mathematical modeling, and computational analyses to simulate and control complex biological systems. In this review, we find that the most significant application of this methodology is associated with cancer, leaving a lack of knowledge in neurodegenerative models. However, this methodology, mainly associated with the Minimal Dominant Set (MDS), has provided a starting point for identifying therapeutic targets for drug development and personalized treatment strategies, paving the way for more effective therapies.

New Drug Design Avenues Targeting Alzheimer's Disease by Pharmacoinformatics-Aided Tools.

Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer's disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long time and excessive resources on complex experimental designs, making the drug design and development pipeline more efficient. In this review, we present from different perspectives how pharmacoinformatics tools can be useful when drug design programs are designed to tackle complex diseases such as AD, highlighting essential concepts, showing the relevance of artificial intelligence and new trends, as well as different databases and software with their main results, emphasizing the importance of coupling wet and dry approaches in drug design and development processes.

Network pharmacology reveals multitarget mechanism of action of drugs to be repurposed for COVID-19.

The coronavirus disease 2019 pandemic accelerated drug/vaccine development processes, integrating scientists all over the globe to create therapeutic alternatives against this virus. In this work, we have collected information regarding proteins from SARS-CoV-2 and humans and how these proteins interact. We have also collected information from public databases on protein-drug interactions. We represent this data as networks that allow us to gain insights into protein-protein interactions between both organisms. With the collected data, we have obtained statistical metrics of the networks. This data analysis has allowed us to find relevant information on which proteins and drugs are the most relevant from the network pharmacology perspective. This method not only allows us to focus on viral proteins as the main targets for COVID-19 but also reveals that some human proteins could be also important in drug repurposing campaigns. As a result of the analysis of the SARS-CoV-2-human interactome, we have identified some old drugs, such as disulfiram, auranofin, gefitinib, suloctidil, and bromhexine as potential therapies for the treatment of COVID-19 deciphering their potential complex mechanism of action.

A Bioinformatics Study of the Involved Mechanisms in Relapse and Drug Resistance of Tamoxifen-Treated Breast Cancer.

BACKGROUND: Breast cancer is currently among the most common causes of mortality in women. Estrogen and its subsequent signaling pathways play an important role in the occurrence of breast cancer relapse. Tamoxifen is the most common breast cancer treatment option in ER+ patients, which acts as an adjuvant endocrinotherapy with X-ray and surgery. This approach is recommended as the first-line treatment and has increased the survival rate of breast cancer patients and reduced the relapse cases. However, we can observe resistance to tamoxifen and relapse cases in one-third of patients treated with this drug, which has become a major concern. OBJECTIVE: The precise mechanisms of relapse and resistance to tamoxifen have not yet been identified and were explored in this study. METHODS: Microarray profiles of relapse and relapse-free patients were investigated to explain the processes leading to relapse and possibly to tamoxifen resistance. RESULTS: According to the preliminary analysis, 1460 genes showed increased expression while 1132 genes showed decreased expression. According to our default for inclusion (-2LogFC≥ + 2), 36 genes had increased expression (upregulated) while 33 genes had decreased expression (down-regulated). CONCLUSION: It seems that the mechanisms of resistance and relapse are multifactorial, and tumor cells induce relapse and resistance to tamoxifen through cell proliferation, survival, invasion, angiogenesis, extracellular matrix secretion, pump and membrane changes, and immune evasion.

Structural and functional computational analysis of nicotine analogs as potential neuroprotective compounds in Parkinson disease.

As the mechanism of interaction between nicotinic receptors with nicotine analogs is not yet fully understood, information at molecular level obtained from computational calculations is needed. In this sense, this work is a computational study of eight nicotine analogs, all with pyrrolidine ring modifications over a nicotine-based backbone optimized with B3LYP-D3/aug-cc-pVDZ. A molecular characterization was performed focusing on geometrical parameters such as pseudo-rotation angles, atomic charges, HOMO and LUMO orbitals, reactivity indexes and intermolecular interactions. Three analogs, A2 (3-(1,3-dimethyl-4,5-dihydro-1h-pirazole-5-yl) pyridine), A3 (3-(3-methyl-4,5-dihydro-1H-pyrazol-5-yl)-pyridine) and A8 (5-methyl-3-(pyridine-3-yl)-4,5-dihydroisoxazole), were filtered suggesting putative neuroprotective activity taking into account different reactivity values, such as their lowest hardness: 2.37 eV (A8), 2.43 eV (A2) and 2.56 eV (A3), compared to the highest hardness value found: 2.71 eV for A5 (3-((2S,4R)-4-(fluoromethyl)-1-methylpyrrolidine-2-il) pyridine), similar to the value of nicotine (2.70 eV). Additionally, molecular docking of all 8 nicotine analogs with the α 7 nicotinic acetylcholine receptor (α 7 nAChR) was performed. High values of interaction between the receptor and the three nicotine analogs were obtained: A3 (-7.1 kcal/mol), A2 (-6.9 kcal/mol) and A8 (-6.8 kcal/mol); whereas the affinity energy of nicotine was -6.4 kcal/mol. Leu116 and Trp145 are key residues in the binding site of α 7 nAChR interacting with nicotine analogs. Therefore, based upon these results, possible application of these nicotine analogs as neuroprotective compounds and potential implication at the design of novel Parkinson's treatments is evidenced.

(E)-Nicotinaldehyde O-Cinnamyloxime, a Nicotine Analog, Attenuates Neuronal Cells Death Against Rotenone-Induced Neurotoxicity.

Parkinson's disease (PD) is a neurodegenerative pathology characterized by resting tremor, rigidity, bradykinesia, and loss of dopamine-producing neurons in the pars compacta of the substantia nigra in the central nervous system (CNS) that result in dopamine depletion in the striatum. Oxidative stress has been documented as a key pathological mechanism for PD. Epidemiological studies have shown that smokers have a lower incidence of PD. In this aspect, different studies have shown that nicotine, a chemical compound found in cigarette, is capable of exerting beneficial effects in PD patients, but it can hardly be used as a therapeutic agent because of its inherent toxicity. Several studies have suggested that the use of nicotine analogs can have the same benefits as nicotine but lack its toxicity. In this study, we assessed the effects of two nicotine analogs, (E)-nicotinaldehyde O-cinnamyloxime and 3-(pyridin-3-yl)-3a,4,5,6,7,7a-hexahidrobenzo[d]isoxazole, in an in vitro model of PD. Initially, we performed a computational prediction of the molecular interactions between the nicotine analogs with the α7 nicotinic acetylcholine receptor (nAChR). Furthermore, we evaluated the effect of nicotine, nicotine analogs and rotenone on cell viability and reactive oxygen species (ROS) production in the SH-SY5Y neuronal cell line to validate possible protective effects. We observed that pre-treatment with nicotine or (E)-nicotinaldehyde O-cinnamyloxime (10 µM) improved cell viability and diminished ROS production in SH-SY5Y cells insulted with rotenone. These findings suggest that nicotine analogs have a potential protective effect against oxidative damage in brain pathologies.

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.

Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury.

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.

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

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.

In silico and in vitro analysis of boAP3d1 protein interaction with bovine leukaemia virus gp51.

The envelope glycoprotein 51 (gp51) is essential for bovine leukaemia virus (BLV) entry to bovine B-lymphocytes. Although the bovine adaptor protein 3 complex subunit delta-1 (boAP3D1) has been proposed as the potential receptor, the specific ligand-receptor interaction has not yet been completely defined and boAP3D1 receptor and gp51 3D structures have not been determined. This study was thus aimed at a functional annotation of boAP3D1 cellular adaptor protein and BLV gp51 and, proposing a reliable model for gp51-AP3D1 interaction using bioinformatics tools. The boAP3D1 receptor interaction patterns were calculated based on models of boAP3D1 receptor and gp51 complexes' 3D structures, which were constructed using homology techniques and data-driven docking strategy. The results showed that the participation of 6 key amino acids (aa) on gp51 (Asn170, Trp127, His115, Ala97, Ser98 and Glu128) and 4 aa on AP3D1 (Lys925, Asp807, Asp695 and Arg800) was highly probable in the interaction between gp51 and BLVR domains. Three gp51 recombinant peptides were expressed and purified to validate these results: the complete domain (rgp51), the N-terminal portion (rNgp51) and the C-terminal fragment (rCgp51); and binding assays to Madin-Darby bovine kidney (MDBK) cells were then carried out with each recombinant. It was found that rNgp51 preferentially bound to MDBK cells, suggesting this domain's functional role during invasion. The rNgp51-MDBK cell interaction was sensitive to trypsin (98% reduction) and chymotrypsin treatment (80% reduction). These results highlighted that the N-terminal portion of gp51 interacted in vitro with the AP3D1 receptor and provides a plausible in silico interaction model.

PDGF-BB Preserves Mitochondrial Morphology, Attenuates ROS Production, and Upregulates Neuroglobin in an Astrocytic Model Under Rotenone Insult.

Platelet-derived growth factor, subtype BB (PDGF-BB) is a mitogenic growth factor produced in different cell types such as platelets, fibroblasts, neurons, and astrocytes. Previous reports have shown that different PDGF isoforms exert a neuroprotective effect in neurons and astrocytes against multiple degenerative insults. Previously, we showed that pretreatment with PDGF-BB for 24 h increased cell viability, preserved nuclear morphology and mitochondrial membrane potential following stimulation with rotenone, and reduced free radical production nearly to control conditions. In the present study, we explored the potential mechanisms associated with PDGF-BB protection against oxidative damage. Our results showed that PDGF-BB protected astrocytic cells through multiple responses, including decrease in the expression of cytoskeleton proteins, attenuated free radicals (reactive oxygen species (ROS)) production, preservation of mitochondrial ultrastructure, and improved expression of neuroglobin (Ngb1). In summary, these findings point out that PDGF-BB protects astrocytic cells by a reduction in ROS production and activation of antioxidant mechanisms.

Gliomas: New Perspectives in Diagnosis, Treatment and Prognosis.

Gliomas are central nervous system tumors originated from glial cells, whose incidence and mortality is expected to rise in coming years, especially in developing countries. Diagnosis and classification of gliomas have largely relied on tumor histopathologic features that provide limited information regarding response to therapy or prognosis. Current treatment of gliomas is surgery combined with chemotherapy and/or radiotherapy. However, many tumors show a high resistance to these interventions, and recurrences are frequent since conventional therapies do not take into account the unique molecular features of different subtypes of glioma. Molecular genetics provide new insights in classifying gliomas and predicting response to therapy that can range from conventional treatments to new revolutionary therapeutic approaches. This article offers a review of the intracellular signaling pathways involved in carcinogenesis of gliomas, as well as a description of new tools for their diagnosis, prognosis, and treatment with a target-oriented approach.

L-Type Calcium Channels Modulation by Estradiol.

Voltage-gated calcium channels are key regulators of brain function, and their dysfunction has been associated with multiple conditions and neurodegenerative diseases because they couple membrane depolarization to the influx of calcium-and other processes such as gene expression-in excitable cells. L-type calcium channels, one of the three major classes and probably the best characterized of the voltage-gated calcium channels, act as an essential calcium binding proteins with a significant biological relevance. It is well known that estradiol can activate rapidly brain signaling pathways and modulatory/regulatory proteins through non-genomic (or non-transcriptional) mechanisms, which lead to an increase of intracellular calcium that activate multiple kinases and signaling cascades, in the same way as L-type calcium channels responses. In this context, estrogens-L-type calcium channels signaling raises intracellular calcium levels and activates the same signaling cascades in the brain probably through estrogen receptor-independent modulatory mechanisms. In this review, we discuss the available literature on this area, which seems to suggest that estradiol exerts dual effects/modulation on these channels in a concentration-dependent manner (as a potentiator of these channels in pM concentrations and as an inhibitor in nM concentrations). Indeed, estradiol may orchestrate multiple neurotrophic responses, which open a new avenue for the development of novel estrogen-based therapies to alleviate different neuropathologies. We also highlight that it is essential to determine through computational and/or experimental approaches the interaction between estradiol and L-type calcium channels to assist these developments, which is an interesting area of research that deserves a closer look in future biomedical research.

Tibolone protects astrocytic cells from glucose deprivation through a mechanism involving estrogen receptor beta and the upregulation of neuroglobin expression.

Tibolone, a synthetic steroid used for the prevention of osteoporosis and the treatment of climacteric symptoms in post-menopausal women, may exert tissue selective estrogenic actions acting on estrogen receptors (ERs). We previously showed that tibolone protects human T98G astroglial cells against glucose deprivation (GD). In this study we have explored whether the protective effect of tibolone on these cells is mediated by ERs. Experimental studies showed that both ERα and ERß were involved in the protection by tibolone on GD cells, being ERß preferentially involved on these actions over ERα. Tibolone increased viability of GD cells by a mechanism fully blocked by an ERß antagonist and partially blocked by an ERα antagonist. Furthermore, ERß inhibition prevented the effect of tibolone on nuclear fragmentation, ROS and mitochondrial membrane potential in GD cells. The protective effect of tibolone was mediated by neuroglobin. Tibolone upregulated neuroglobin in T98G cells and primary mouse astrocytes by a mechanism involving ERß and neuroglobin silencing prevented the protective action of tibolone on GD cells. In summary, tibolone protects T98G cells by a mechanism involving ERß and the upregulation of neuroglobin.

Implication of Green Tea as a Possible Therapeutic Approach for Parkinson Disease.

Green tea is a beverage consumed around the world that is believed to have substantial health benefits such as reducing the risk of cancer, cardiovascular diseases, diabetes and neurodegeneration. This beverage is prepared from the leaves (steamed and dried) of the Camellia sinesis plant and contains strong antioxidant and neuroprotective phenolic compounds from which the most important is (-)-Epigallocatechin-3-gallate. Parkinson's disease (PD) is the second more common neurodegenerative disorders, after Alzheimer's disease and is characterized by degeneration of dopaminergic neurons in the pars compact of the substantia nigra of the basal ganglia. It has been shown in pre-clinical and clinical studies that green tea may be able to prevent PD, but its optimal dose or a possible mechanism explaining its health benefit in PD has not been properly established. In this review, we discuss the potential role of green tea's phenolic compounds and their therapeutic effectin modulating key signaling pathways in the PD brain.

Mechanisms of PDGFRalpha promiscuity and PDGFRbeta specificity in association with PDGFB.

Platelet-derived growth factor receptor alpha (PDGFRalpha) interacts with PDGFs A, B, C and AB, while PDGFRbeta binds to PDGFs B and D, thus suggesting that PDGFRalpha is more promiscuous than PDGFRbeta. The structural analysis of PDGFRalpha-PDGFA and PDGFRalpha-PDGFB complexes and a molecular explanation for the promiscuity of PDGFRalpha and the specificity of PDGFRbeta remain unclear. In the present study, we modeled the three extracellular domains of PDGFRalpha using a previous crystallographic structure of PDGFRbeta as a template. Additionally, we analyzed the interacting residues of PDGFRalpha-PDGFA and PDGFRalpha-PDGFB complexes using docking simulations. The validation of the resulting complexes was evaluated by molecular dynamics simulations. Structural analysis revealed that changes of non-aromatic amino acids in PDGFRalpha to aromatic amino acids in PDGFRbeta (I139F, P267F and N204Y) may be involved in the promiscuity of PDGFRalpha. Indeed, substitution of amino acids with few probabilities of rotamer changes in PDGFRbeta (M133A, N163E and N179S) and energy stability due to the formation of hydrogen bond in PDGFRbeta could explain the specificity of PDGFRbeta. These results may be used as an input for a better and more specific drug and peptide design targeting diseases related with the malfunction of PDGFs and PDGFRalpha such as cancer and atherosclerosis.

PDGF-BB protects mitochondria from rotenone in T98G cells.

Rotenone is one of the most-studied neurotoxic substances as it induces oxidative stress processes both in cellular and animal models. Rotenone affects ATP generation, reactive oxygen species (ROS) production, and mitochondrial membrane potential in neurons and astrocyte-like cells. Previous epidemiologic studies have supported the role of neurotrophic factors such as BDNF and GDNF in neuroprotection mainly in neurons; however, only very few studies have focused on the importance of astrocytic protection in neurodegenerative models. In the present study, we assessed the neuroprotective effects of PDGF-BB against toxicity induced by rotenone in the astrocytic-like model of T98G human glioblastoma cell line. Our results demonstrated that pretreatment with PDGF-BB for 24 h increased cell viability, preserved nuclear morphology and mitochondrial membrane potential following stimulation with rotenone, and reduced ROS production nearly to control conditions. These observations were accompanied by important morphological changes induced by rotenone and that PDGF-BB was able to preserve cellular morphology under this toxic stimuli. These findings indicated that PDGF-BB protects mitochondrial functions, and may serve as a potential therapeutic strategy in rotenone-induced oxidative damage in astrocytes.

Tibolone protects T98G cells from glucose deprivation.

The steroidal drug Tibolone is used for the treatment of climacteric symptoms and osteoporosis in post-menopausal women. Although Tibolone has been shown to exert neuroprotective actions after middle cerebral artery occlusion, its specific actions on glial cells have received very little attention. In the present study we have assessed whether Tibolone exerts protective actions in a human astrocyte cell model, the T98G cells, subjected to glucose deprivation. Our findings indicate that Tibolone decreases the effects of glucose deprivation on cell death, nuclear fragmentation, superoxide ion production, mitochondrial membrane potential, cytoplasmic calcium concentration and morphological parameters. These findings suggest that glial cells may participate in the neuroprotective actions of Tibolone in the brain.