Rosiglitazone up‐regulates glial fibrillary acidic protein via HB‐EGF secreted from astrocytes and neurons through PPARγ pathway and reduces apoptosis in high‐fat diet‐fed mice

Abstract

The anti-diabetic drug and peroxisome proliferator-activated receptor-gamma (PPARc) agonist, rosiglitazone, alters astrocyte activation; however, its mechanism remains less-known. We hypothesized participation of epidermal growth factor receptor (EGFR), known to control astrocyte reactivity. We first detected that rosiglitazone promoted glial fibrillary acidic protein (GFAP) expression in primary astrocytes as well as the mouse cerebral cortex, associated with increased EGFR activation. Screening for EGFR ligands revealed a rosiglitazone-mediated increase of heparin-binding epidermal growth factor (HB-EGF) in astrocytes, resulting in HB-EGF release into culture medium and mouse cerebrospinal fluid too. Treatment with HB-EGF-siRNA and EGFR inhibitors showed that the rosiglitazone-induced HB-EGF and p-EFGR were interdependent, which participated in GFAP increase. Interestingly, we observed that rosiglitazone could induce cellular and secreted-HB-EGF in neurons also, contributing toward the activated EGFR-induced GFAP in astrocytes. Probing whether these effects of rosiglitazone were PPARc-linked, revealed potential PPARc-responsive elements within HB-EGF gene. Moreover, gel-shift, site-directed mutagenesis, chromatinimmunoprecipitation and luciferase-reporter assays demonstrated a PPARc-dependent HB-EGF transactivation. Subsequently, we examined effects of rosiglitazone in a high-fat diet-fed diabetes mouse model, and supporting observations in the normal cortical cells, identified a rosiglitazone-induced GFAP, astrocyte and neuronal HB-EGF and secreted-HB-EGF in the cerebral cortex of diabetic mice. Moreover, assessing relevance of increased HB-EGF and GFAP revealed an anti-apoptotic role of rosiglitazone in the cerebral cortex, supported by a GFAP-siRNA as well as HB-EGF-siRNA-mediated increase in cleaved-caspase 3 and 9 levels in the rosiglitazone-treated astrocyte-neuron coculture. Overall, our study indicates that rosiglitazone may protect the brain, via a PPARc-dependent HB-EGF/EGFR signaling and increased GFAP.

The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness

“…In both brain regions, GWE led to robust upregulation of GFAP (Fig 5A-5C). Notably, administration of ROSI resulted in enhanced GFAP expression ( Fig 5A-5C), as previously reported [79].…”

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

“…PPARs, a group of ligand‐activated TFs, have dual effect on the expression of GFAP gene, that is, facilitatory and inhibitory. For instance, activation of PPARγ with rosiglitazone increases GFAP expression in primary astrocytes of mouse cerebral cortex through transactivation of epidermal growth factor receptor (Kushwaha et al, ). Similarly, docosahexaenoic acid (DHA)‐enriched fish oil‐caused GFAP augmentation in rats also depends on the activation of PPARγ by increasing fatty acid‐binding protein‐7 (FABP7) expression (Tripathi et al, ).…”

Antidiabetic treatment on memory and spatial learning: From the pancreas to the neuron

“…Kushwaha et al[ 27 ] have indicated the existence of a rosiglitazone-induced anti-apoptotic effect on cerebral cortical tissue of high-fat-diet diabetic mice, for which the underlying mechanisms have not been clearly established. PPAR-γ mediated epidermal growth factor signaling appears to be the most probable pathway by which both glial and neural cells are affected.…”