High Glucose Shifts the Oxylipin Profiles in the Astrocytes towards Pro-Inflammatory States

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.

Long-Term Exposure of Cultured Astrocytes to High Glucose Impact on Their LPS-Induced Activation

“…The most interesting data are those about how glucose affects the activation of astrocytes, which is seen during brain damage and is thought to be part of the inflammatory response. A number of previous studies have reported the influence of high glucose on glial morphology and reactivity, both in vitro and in vivo [11,14,31,38]. In experiments in vivo, streptozotocin-induced diabetes in mice led to significantly increased activation of microglia and astroglia, the loss of neurons, and cognitive dysfunctions [38].…”

“…In vitro, high glucose levels (30 mM/L) resulted in changes in the expression of cytoskeleton proteins such as GFAP and vimentin [12]. Additionally, in astrocytes, high glucose levels can also induce the expression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1) and interleukin-4 (IL-4) [13,14]. These cytokines are signaling molecules that can promote inflammation and contribute to the progression of diabetic cerebral neuropathy.…”

The gut microbiota‐astrocyte axis: Implications for type 2 diabetic cognitive dysfunction

“…The metabesity factor HMG20A is increased under mild inflammation induced by obesity and IR, inducing reactive astrocyte hyperplasia, protecting neurons from metabolic stress, and re‐establishing glucose homeostasis 107 . Regulating COX‐mediated oxylipin synthesis in astrocytes as a novel potential target in the treatment of hyperglycemia‐associated brain injury 108 …”

“…107 Regulating COX-mediated oxylipin synthesis in astrocytes as a novel potential target in the treatment of hyperglycemia-associated brain injury. 108 The Proinflammatory cytokine produced by dysbacteriosis is an important immune signal that directly activates astrocytes. The db/db mice have significantly increased escape latency at 6, 18, and 26 weeks of age, and their senescence-associated cognitive decline is associated with the gut microbiome.…”

“… 107 Regulating COX‐mediated oxylipin synthesis in astrocytes as a novel potential target in the treatment of hyperglycemia‐associated brain injury. 108 …”