RESUMEN
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of several antitumor agents resulting in progressive and often irreversible damage of peripheral nerves. In addition to their known anticancer effects, taxanes, including paclitaxel, can also induce peripheral neuropathy by activating microglia and astrocytes, which release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1ß), and chemokine (C-C motif) ligand 2 (CCL-2). All these events contribute to the maintenance of neuropathic or inflammatory response. Complement component 5a (C5a)/C5a receptor 1 (C5aR1) signaling was very recently shown to play a crucial role in paclitaxel-induced peripheral neuropathy. Our recent findings highlighted that taxanes have the previously unreported property of binding and activating C5aR1, and that C5aR1 inhibition by DF3966A is effective in preventing paclitaxel-induced peripheral neuropathy (PIPN) in animal models. Here, we investigated if C5aR1 inhibition maintains efficacy in reducing PIPN in a therapeutic setting. Furthermore, we characterized the role of C5aR1 activation by paclitaxel and the CIPN-associated activation of nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. Our results clearly show that administration of the C5aR1 inhibitor strongly reduced cold and mechanical allodynia in mice when given both during the onset of PIPN and when neuropathy is well established. C5aR1 activation by paclitaxel was found to be a key event in the induction of inflammatory factors in spinal cord, such as TNF-α, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP). In addition, C5aR1 inhibition significantly mitigated paclitaxel-induced inflammation and inflammasome activation by reducing IL-1ß and NLRP3 expression at both sciatic and dorsal root ganglia level, confirming the involvement of inflammasome in PIPN. Moreover, paclitaxel-induced upregulation of C5aR1 was significantly reduced by DF3966A treatment in central nervous system. Lastly, the antinociceptive effect of C5aR1 inhibition was confirmed in an in vitro model of sensory neurons in which we focused on receptor channels usually activated upon neuropathy. In conclusion, C5aR1 inhibition is proposed as a therapeutic option with the potential to exert long-term protective effect on PIPN-associated neuropathic pain and inflammation.
RESUMEN
Paclitaxel (PTX) is one of the most broadly used chemotherapeutic agents for the treatment of several tumor types including ovarian, breast, and non-small cell lung cancer. However, its use is limited by debilitating side effects, involving both gastrointestinal and behavioral dysfunctions. Due to growing evidence showing a link between impaired gut function and chemotherapy-associated behavioral changes, the aim of this study was to identify a novel therapeutic approach to manage PTX-induced gut and brain comorbidities. Mice were pre-treated with sodium butyrate (BuNa) for 30 days before receiving PTX. After 14 days, mice underwent to behavioral analysis and biochemical investigations of gut barrier integrity and microbiota composition. Paired evaluations of gut functions revealed that the treatment with BuNa restored PTX-induced altered gut barrier integrity, microbiota composition and food intake suggesting a gut-to-brain communication. The treatment with BuNa also ameliorated depressive- and anxiety-like behaviors induced by PTX in mice, and these effects were associated with neuroprotective and anti-inflammatory outcomes. These results propose that diet supplementation with this safe postbiotic might be considered when managing PTX-induced central side effects during cancer therapy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Microbioma Gastrointestinal , Enfermedades Intestinales , Neoplasias Pulmonares , Animales , Ácido Butírico/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Suplementos Dietéticos , Enfermedades Intestinales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Paclitaxel/efectos adversosRESUMEN
BACKGROUND/AIMS: We investigated (a) in vitro and in vivo the changes of biliary mass of the anionic peptide fraction, apolipoproteinA-I, immunoglobulin-A, albumin and cholesterol over time in the excluded gallbladder and (b) in vivo the localization in the gallbladder epithelium of the anionic peptide fraction and cholesterol absorbed from bile. METHODS: Native bile was substituted with pig bile containing radiolabeled cholesterol in the in vitro isolated intra-arterially perfused pig gallbladder (n=9) and in vivo in anestethized pigs with excluded gallbladders (n=6). The amount of cholesterol (scintillation counting) and proteins (enzyme-linked immunosorbent assay) in gallbladder bile were measured over time. The localization of the anionic peptide fraction and cholesterol absorbed from bile in the gallbladder epithelium was studied in vivo by immunohistochemistry and fluoro-phospho-imager analysis. RESULTS: The rate of biliary cholesterol disappeared from bile was a function of the initial concentration and of the biliary mass changes over time of the anionic peptide fraction, but not of that of the other biliary proteins. The anionic peptide fraction colocalized with biliary cholesterol absorbed by the gallbladder on the apical side of gallbladder epithelial cells. CONCLUSIONS: These data indirectly suggest that biliary anionic peptide fraction could favour biliary cholesterol absorption by the gallbladder epithelium.
Asunto(s)
Apoproteínas/análisis , Bilis/metabolismo , Proteínas de Unión al Calcio/análisis , Colesterol/análisis , Epitelio/metabolismo , Vesícula Biliar/metabolismo , Absorción , Albúminas/análisis , Animales , Apolipoproteína A-I/análisis , Bilis/química , Ensayo de Inmunoadsorción Enzimática , Epitelio/química , Vesícula Biliar/química , Inmunoglobulina A/análisis , Técnicas In Vitro , PorcinosRESUMEN
The abnormalities of gallbladder epithelial function involved in cholesterol gallstone pathogenesis are: 1) the impaired biliary lipid absorption and 2) an increased secretion of mucin gel. We developed a model of isolated in vitro intra-arterially perfused gallbladder and showed that the normal gallbladder epithelium absorbs high amounts of biliary cholesterol and phosphatidylcholine in a proportion determined by their molar ratio in the bile which enters the lumen. This physiological lipid absorption continuously reduces biliary cholesterol molar percentage in the gallbladder lumen and protects from gallstone formation by inhibiting cholesterol crystal precipitation. On the opposite, in the presence of cholesterol gallstone disease, even if the gallbladder epithelium is hyperplastic and hypertrophic, it absorbs cholesterol and phosphatidylcholine less efficiently and cholesterol crystal precipitation is favoured. Indirect evidence exists that the impaired gallbladder lipid absorption in cholesterol gallstone disease is not caused by inflammation and is not secondary to the presence of stones. The impaired mucosal function could be the consequence of excessive chronic enrichment of hepatic bile which enters the gallbladder. The mucin gel is the only biliary protein with an established pathogenetic role in cholesterol gallstone disease. The mucin gel is thought to favour gallstone formation by promoting cholesterol crystal precipitation and aggregation.