Valutazione delle vie di signalling indotte dal sistema del complemento nell’instaurarsi del dolore neuropatico: effetti di antagonisti dei recettori C5aR1 e C5aR2

Peripheral neuropathy and hypersensitivity reactions (HSRs), frequently associated with chemotherapy, represent common and debilitating adverse effects linked to the use of paclitaxel as an antineoplastic agent. Evidence indicates that paclitaxel binds to and activates complement component 5a receptors 1 and 2 (C5aR1, C5aR2), a mechanism identified as pivotal in the onset of paclitaxel-induced neuropathy and anaphylaxis. Prior research connecting interleukin-8 (IL-8) to paclitaxel-driven neurotoxicity prompted an investigation into the proteins responsible for IL-8 induction. Molecular docking simulations conducted via the Exscalate platform demonstrated a high binding affinity between paclitaxel and C5aR1 and 2. In vitro studies confirmed that the interaction between paclitaxel and C5aR1 is specific and competitive, leading, in particular for C5aR1, to the activation of intracellular NFκB/P38 signaling and c-Fos pathways. In neuronal F11 cells and rat dorsal root ganglia, C5aR1 blockade reduced neuropathological changes caused by paclitaxel. Similarly, in mice treated with paclitaxel, either genetic deletion of C5aR1 or its pharmacological inhibition significantly ameliorated symptoms of chemotherapy-induced peripheral neuropathy (CIPN), including cold and mechanical allodynia, and minimized chronic pathological alterations in the paw. Furthermore, inhibition of C5aR1 suppressed anaphylactic cytokine release triggered by paclitaxel in macrophages during in vitro experiments and reduced the incidence of HSRs in mouse models. These findings collectively identify C5aR1 as a key mediator in the pathogenesis of paclitaxel-induced CIPN and HSRs and highlight its potential as a therapeutic target for mitigating these severe adverse effects.