ABSTRACT
Acrylamide is a well characterized neurotoxicant known to cause neuropathy and encephalopathy in humans and experimental animals. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in acrylamide-induced neuropathy, male C57Bl/6JJcl adult mice were exposed to acrylamide at 0, 200 or 300 ppm in drinking water and co-administered with subcutaneous injections of sulforaphane, a known activator of the Nrf2 signaling pathway at 0 or 25 mg/kg body weight daily for 4 weeks. Assessments for neurotoxicity, hepatotoxicity, oxidative stress as well as messenger RNA-expression analysis for Nrf2-antioxidant and pro-inflammatory cytokine genes were conducted. Relative to mice exposed only to acrylamide, co-administration of sulforaphane protected against acrylamide-induced neurotoxic effects such as increase in landing foot spread or decrease in density of noradrenergic axons as well as hepatic necrosis and hemorrhage. Moreover, co-administration of sulforaphane enhanced acrylamide-induced mRNA upregulation of Nrf2 and its downstream antioxidant proteins and suppressed acrylamide-induced mRNA upregulation of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) in the cerebral cortex. The results demonstrate that activation of the Nrf2 signaling pathway by co-treatment of sulforaphane provides protection against acrylamide-induced neurotoxicity through suppression of oxidative stress and inflammation. Nrf2 remains an important target for the strategic prevention of acrylamide-induced neurotoxicity.
Subject(s)
Inflammation/genetics , Isothiocyanates/pharmacology , NF-E2-Related Factor 2/genetics , Neurotoxicity Syndromes/genetics , Sulfoxides/pharmacology , Acrylamide/toxicity , Animals , Disease Models, Animal , Humans , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/pathology , Mice , Microglia/metabolism , Microglia/pathology , NF-kappa B/genetics , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/pathology , Nitric Oxide Synthase Type II/genetics , Oxidative Stress/genetics , Signal Transduction/drug effectsABSTRACT
BACKGROUND: RNA splicing, a fundamental step in gene expression, is aimed at intron removal and ordering of exons to form the protein's reading frame. OBJECTIVE: This review is focused on the role of RNA splicing in cancer biology; the splicing abnormalities that lead to tumor progression emerge as targets for therapeutic intervention. METHODS: We discuss the role of aberrant mRNA splicing in carcinogenesis and drug response. RESULTS AND CONCLUSION: Pharmacological modulation of RNA splicing sets the stage for treatment approaches in situations where mRNA splicing is a clinically meaningful mechanism of the disease.
