Glial cells (astrocytes, oligodendrocytes and microglia) are critical for the central nervous system (CNS) in both physiological and pathological conditions. With this in mind, several studies have indicated that glial cells play key roles in the development and progression of CNS diseases. In this sense, gliotoxicity can be referred as the cellular, molecular, and neurochemical changes that can mediate toxic effects or ultimately lead to impairment of the ability of glial cells to protect neurons and/or other glial cells. On the other hand, glioprotection is associated with specific responses of glial cells, by which they can protect themselves as well as neurons, resulting in an overall improvement of the CNS functioning. In addition, gliotoxic events, including metabolic stresses, inflammation, excitotoxicity, and oxidative stress, as well as their related mechanisms, are strongly associated with the pathogenesis of neurological, psychiatric and infectious diseases. However, glioprotective molecules can prevent or improve these glial dysfunctions, representing glial cells-targeting therapies. Therefore, this review will provide a brief summary of types and functions of glial cells and point out cellular and molecular mechanisms associated with gliotoxicity and glioprotection, potential glioprotective molecules and their mechanisms, as well as gliotherapy. In summary, we expect to address the relevance of gliotoxicity and glioprotection in the CNS homeostasis and diseases.

The hypothalamus is a crucial integrative center in the central nervous system, responsible for the regulation of homeostatic activities, including systemic energy balance. Increasing evidence has highlighted a critical role of astrocytes in orchestrating hypothalamic functions; they participate in the modulation of synaptic transmission, metabolic and trophic support to neurons, immune defense, and nutrient sensing. In this context, disturbance of systemic energy homeostasis, which is a common feature of obesity and the aging process, involves inflammatory responses. This may be related to dysfunction of hypothalamic astrocytes. In this regard, the aim of this study was to evaluate the neurochemical properties of hypothalamic astrocyte cultures from newborn, adult, and aged Wistar rats. Age-dependent changes in the regulation of glutamatergic homeostasis, glutathione biosynthesis, amino acid profile, glucose metabolism, trophic support, and inflammatory response were observed. Additionally, signaling pathways including nuclear factor erythroid-derived 2-like 2/heme oxygenase-1 p38 mitogen-activated protein kinase, nuclear factor kappa B, phosphatidylinositide 3-kinase/Akt, and leptin receptor expression may represent putative mechanisms associated with the cellular alterations. In summary, our findings indicate that as age increases, hypothalamic astrocytes remodel and exhibit changes in their neurochemical properties. This process may play a role in the onset and/or progression of metabolic disorders.

Zika virus (ZIKV) infection during pregnancy was associated with microcephaly in neonates, but clinical and experimental evidence indicate that ZIKV also causes neurological complications in adults. However, the changes in neuron-glial communication, which is essential for brain homeostasis, are still unknown. Here, we report that hippocampal slices from adult rats exposed acutely to ZIKV showed significant cellular alterations regarding to redox homeostasis, inflammatory process, neurotrophic functions and molecular signalling pathways associated with neurons and glial cells. Our findings support the hypothesis that ZIKV is highly neurotropic and its infection readily induces an inflammatory response, characterized by an increased expression and/or release of pro-inflammatory cytokines. We also observed changes in neural parameters, such as adenosine receptor A2a expression, as well as in the release of brain-derived neurotrophic factor and neuron-specific enolase, indicating plasticity synaptic impairment/neuronal damage. In addition, ZIKV induced a glial commitment, with alterations in specific and functional parameters such as aquaporin 4 expression, S100B secretion and glutathione synthesis. ZIKV also induced p21 senescence-associated gene expression, indicating that ZIKV may induce early senescence. Taken together, our results indicate that ZIKV-induced neuroinflammation, involving nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NFκB) pathways, affects important aspects of neuron-glia communication. Therefore, although ZIKV infection is transient, long-term consequences might be associated with neurological and/or neurodegenerative diseases.

Leptin is an adipose tissue-derived hormone that acts on the hypothalamus in order to maintain energy homeostasis. However, leptin can also induce an inflammatory response. Increasing evidence has highlighted a critical role of astrocytes in the effects of leptin on the hypothalamus. In addition, astrocytes participate in neuroinflammation by producing and releasing a wide range of inflammatory mediators. In this study, we aimed to investigate the age-dependent effect of leptin on pro- and anti-inflammatory cytokines released by the hypothalamic astrocyte cultures obtained from newborn, adult, and aged Wistar rats. In hypothalamic astrocytes from newborn rats, leptin did not change the release of pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). On the other contrary, leptin increased the release of both TNF-α and IL-1β in astrocyte cultures from adult and aged animals. Regarding the anti-inflammatory cytokine interleukin 10 (IL-10), we did not observe any change in response to leptin. In conclusion, our data suggests a pro-inflammatory action of leptin on the hypothalamus during aging. This in turn may be related to the triggering of metabolic disorders, as both of these conditions are associated with neuroinflammation.