Abstract
Hyperglycemia is associated with several complications in the brain, which are also characterized by inflammatory conditions. Astrocytes are responsible for glucose metabolism in the brain and are also important participants of inflammatory responses. Oxylipins are lipid mediators, derived from the metabolism of polyunsaturated fatty acids (PUFAs) and are generally considered to be a link between metabolic and inflammatory processes. High glucose exposure causes astrocyte dysregulation, but its effects on the metabolism of oxylipins are relatively unknown and therefore, constituted the focus of our work. We used normal glucose (NG, 5.5 mM) vs. high glucose (HG, 25 mM) feeding media in primary rat astrocytes-enriched cultures and measured the extracellular release of oxylipins (UPLC-MS/MS) in response to lipopolysaccharide (LPS). The sensitivity of HG and NG growing astrocytes in oxylipin synthesis for various serum concentrations was also tested. Our data reveal shifts towards pro-inflammatory states in HG non-stimulated cells: an increase in the amounts of free PUFAs, including arachidonic (AA), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, and cyclooxygenase (COX) mediated metabolites. Astrocytes cultivated in HG showed a tolerance to the LPS, and an imbalance between inflammatory cytokine (IL-6) and oxylipins release. These results suggest a regulation of COX-mediated oxylipin synthesis in astrocytes as a potential new target in treating brain impairment associated with hyperglycemia.
Highlights
Oxylipins represent a superfamily of bioactive lipid mediators, derived from the metabolism of polyunsaturated fatty acids (PUFAs), through a complex network of biochemical reactions [1,2,3]
The conversion of PUFAs into oxylipins occurs via four major pathways, involving cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 monooxygenases (CYP450), and non-enzymatically [1,4,5]
Primary rat astrocytes were cultured in medium with normal (5.5 mM) or high (25 mM) glucose concentrations
Summary
Oxylipins represent a superfamily of bioactive lipid mediators, derived from the metabolism of polyunsaturated fatty acids (PUFAs), through a complex network of biochemical reactions [1,2,3]. It became obvious that these processes change energy consumption and the relationships between different systems, primarily the metabolic and innate immune systems Besides their special roles in neuroinflammation [14,16], astrocytes are the primary contributors to glucose metabolism in the brain [29]. It was shown that a transcription factor, NFkB, and mitogen-activated protein kinase (MAPK) p38 and JNK, are involved in the glucose-induced glial toxicity [34,36] Both in vivo models of hyperglycemia and in vitro models of long-term cultivation of cells in a high glucose (HG) medium demonstrated an impairment of astrocyte functions, such as a decrement in gap junctional communication or oxidative stress induction [35,36,38]. Metabolites 2021, 11, 311 of HG on the oxylipin release in rat primary astrocytes and their ability to respond to a lipopolysaccharide (LPS) stimulation
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