Methylmalonic acid induces inflammatory response and redox homeostasis disruption in C6 astroglial cells: potential glioprotective roles of melatonin and resveratrol.

Methylmalonic acidemia is a neurometabolic disorder biochemically characterized by the accumulation of methylmalonic acid (MMA) in different tissues, including the central nervous system (CNS). In this sense, it has been shown that high levels of this organic acid have a key role in the progressive neurological deterioration in patients. Astroglial cells actively participate in a wide range of CNS functions, such as antioxidant defenses and inflammatory response. Considering the role of these cells to maintain brain homeostasis, in the present study, we investigated the effects of MMA on glial parameters, focusing on redox homeostasis and inflammatory process, as well as putative mediators of these events in C6 astroglial cells. MMA decreased cell viability, glutathione levels, and antioxidant enzyme activities, increased inflammatory response, and changed the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NFκB), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and adenosine receptors, suggesting that these transcriptional factors and proteins may underlie the glial responses induced by MMA. Moreover, we also demonstrated the protective roles of melatonin and resveratrol against MMA-induced inflammation and decrease in glutathione levels. In summary, our findings support the hypothesis that astroglial changes are associated with pathogenesis of methylmalonic acidemia. In addition, we showed that these cells might be potential targets for preventive/therapeutic strategies by using molecules, such as melatonin and resveratrol, which mediated glioprotection in this inborn error of metabolism.

Glioprotective Effects of Resveratrol Against BMAA-Induced Astroglial Dysfunctions.

Astroglial cells play important roles in maintaining central nervous system (CNS) homeostasis. The neurotoxin ß-N-methylamino-L-alanine (BMAA) has usually been associated with neurodegeneration due to its toxic effects on neurons. However, little is known about the effects of BMAA on astroglial cells. Resveratrol, a natural polyphenol, represents a potential protective strategy against brain injuries. In the present study, we sought to investigate BMAA-induced astroglial dysfunctions and the glioprotective roles of resveratrol. BMAA did not impair astroglial cellular viability, but increased glutamate uptake, glutamate metabolism into glutamine, and reactive oxygen species production, while decreased glutathione (GSH) and superoxide dismutase (SOD)-based antioxidant defenses and triggers an inflammatory response. In contrast, resveratrol was able to prevent most of these BMAA-induced functional changes in astroglial cells. Moreover, both BMAA and resveratrol modulated the gene expression of molecular pathways associated with glutamate metabolism, redox homeostasis, and inflammatory response, which characterize their roles on astroglial functions. In this regard, BMAA downregulated adenosine receptors, peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), phosphoinositide-3-kinase (PI3K), and Akt, while resveratrol prevented these effects and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Our study, for the first time, demonstrates that BMAA directly impacts key astroglial functions, contributing to elucidating the cellular and molecular mechanisms of this toxin in the CNS. In addition, we reinforce the glioprotective effects of resveratrol against BMAA-induced astroglial dysfunctions.

Lipopolysaccharide Induces Gliotoxicity in Hippocampal Astrocytes from Aged Rats: Insights About the Glioprotective Roles of Resveratrol.

Astrocytes may undergo a functional remodeling with aging, acquiring a pro-inflammatory state. In line with this, resveratrol represents an interesting strategy for a healthier brain aging since it can improve glial functions. In the present study, we investigated the glioprotective role of resveratrol against lipopolysaccharide (LPS)-induced gliotoxicity in hippocampal aged astrocytes. Astrocyte cultures were obtained from aged rats (365 days old) and challenged in vitro with LPS in the presence of resveratrol. Cultured astrocytes from newborn rats were used as an age comparative for evaluating LPS gliotoxicity. In addition, aged rats were submitted to an acute systemic inflammation with LPS. Hippocampal astrocyte cultures were also obtained from these LPS-stimulated aged animals to further investigate the glioprotective effects of resveratrol in vitro. Overall, our results show that LPS induced a higher inflammatory response in aged astrocytes, compared to newborn astrocytes. Several inflammatory and gene expression alterations promoted by LPS in aged astrocyte cultures were similar in hippocampal tissue from aged animals submitted to in vivo LPS injection, corroborating our in vitro findings. Resveratrol, in turn, presented anti-inflammatory effects in aged astrocyte cultures, which were associated with downregulation of p21 and pro-inflammatory cytokines, Toll-like receptors (TLRs), and nuclear factor κB (NFκB). Resveratrol also improved astroglial functions. Upregulation of sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) represent potential molecular mechanisms associated with resveratrol-mediated glioprotection. In summary, our data show that resveratrol can prime aged astrocytes against gliotoxic stimuli, contributing to a healthier brain aging.

Gliotoxicity and Glioprotection: the Dual Role of Glial Cells.

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.