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.

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.