Donepezil protects glycerol-induced acute renal failure through the cholinergic anti-inflammatory and nitric oxide pathway in rats
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
Authors: Sun, Guodong; Wang, Jialei; Wang, Pan; Ren, Huimin; Yue, Yuedong; Song, Zhengmin; Fu, Xiaobin
Abstract
Objectives Inflammation as well as oxygen metabolite play important roles in renal injury during pathogenesis of rhabdomyolysis induced myoglobinuric acute renal failure (ARF). The aim of this study was to investigate the protective effects of donepezil on immune responses in rats with glycerol-induced ARF. Methods Sixty male rats were randomly divided into six groups, the rats were given normal saline (10 ml/kg, i.m.), glycerol (50%, 10 ml/kg, i.m.), glycerol plus dexamethasone (0.1 mg/kg, i.g.), and glycerol plus donepezil (1, 5 and 10 mg/kg, i.g.) respectively. After two weeks of glycerol injections, the kidney tissues and blood samples were harvested for future biochemical and pathology analysis. The levels of creatinine (Cr) and urea nitrogen (BUN) in plasma, the content of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activity, total nitric oxide synthase (TNOS), inducible nitric oxide synthase (iNOS), endothelial NO synthase (eNOS) were evaluated in renal tissues. In addition, interleukin-6 (IL-6), tumor necrosis factors-alpha (TNF-alpha) in renal tissues were also determined. Results Donepezil treatment protected rats from renal dysfunction in a dose-dependent manner and through the cholinergic anti-inflammatory pathway. Additionally, donepezil significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the IL-6, TNF-alpha, nitric oxide content and oxidative damage. Conclusions These data indicate that donepezil exerts a protective anti-inflammatory effect during ARF through the cholinergic pathway and Nitric oxide pathway. In addition, this study could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation and other injury.
Cytokine dysregulation in children with cerebral palsy
DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY
Authors: Zareen, Zunera; Strickland, Tammy; Fallah, Lida; McEneaney, Victoria; Kelly, Lynne; McDonald, Denise; Molloy, Eleanor J.
Abstract
Aim To examine pro- and anti-inflammatory cytokines in children with cerebral palsy (CP) at baseline and in response to endotoxin (lipopolysaccharide), and correlate outcomes compared with age-matched comparisons, to evaluate their ability to mount an immune response. Method Serum cytokines were assessed in 12 children (eight males, four females; mean age 10y 1mo [SD 1y 8mo], 6-16y) with CP against 12 age-matched comparisons (eight males, four females; mean age 9y 1mo [SD 1y 1mo]). Pro- and anti-inflammatory cytokines (interleukin-1 beta, interleukin-2, interleukin-6, interleukin-8, interleukin-10, interleukin-18, tumour necrosis factor [TNF]-alpha, TNF-beta, interferon-gamma, granulocyte-macrophage colony-stimulating factor [GM-CSF], vascular endothelial growth factor [VEGF], erythropoietin, and interleukin-1 receptor antagonist) were measured at baseline and in response to in vitro simulation with lipopolysaccharide by multiplex enzyme-linked immunosorbent assay. Results Significantly higher erythropoietin was found at baseline in children with CP compared with the comparison group. There was a strong response to lipopolysaccharide for interleukin-8, VEGF, TNF-alpha, and GM-CSF in both children with CP and the comparison group; however, there was significant lipopolysaccharide hyporesponsiveness in children with CP compared with the comparison group for interleukin-1 alpha, interleukin-1 beta, interleukin-2, and interleukin-6. Interpretation Altered cytokine responses in children with CP compared with the comparison group demonstrate an altered inflammatory state that may contribute to ongoing sequelae and could be a target for therapy.