Abstract
BackgroundPaclitaxel is a widely used and potent chemotherapeutic agent for the treatment of cancer. However, patients receiving paclitaxel often develop an acute pain syndrome for which there are few treatment options. Astrocytes play an important role in the pathogenesis of pain in multiple preclinical models, as well as in paclitaxel-treated rodents. However, it is still unclear what the exact contribution of astrocytes may be in paclitaxel-associated acute pain syndrome (P-APS).MethodsP-APS was modeled by a single systemic or intrathecal injection of paclitaxel and astrocyte contribution tested by immunohistochemical, pharmacological, and behavioral approaches. Cell cultures were also prepared to assess whether paclitaxel treatment directly activates astrocytes and whether intrathecal injection of paclitaxel-treated astrocytes produces pain that is reminiscent of P-APS.ResultsSystemic injection of paclitaxel resulted in increased expression of glial fibrillary acidic protein (a common marker of astrocytic activation), as well as both systemic or intrathecal injection of paclitaxel induced pain hypersensitivity indicated by the development of mechanical allodynia, which was significantly reversed by the astrocytic inhibitor L-α-AA. Cultured astrocytes were activated by paclitaxel with significant increases in protein levels for tumor necrosis factor-α (TNF-α) and stromal-derived cell factor 1 (SDF-1). Importantly, intrathecal injection of paclitaxel-activated astrocytes produced mechanical allodynia that was reversed by TNF-α and SDF-1 neutralizing antibodies.ConclusionOur results suggest for the first time that paclitaxel can directly activate astrocytes, which are sufficient to produce acute pain by releasing TNF-α and SDF-1. Targeting astrocytes and these cytokines may offer new treatments for P-APS.
Highlights
Paclitaxel is a widely used and potent chemotherapeutic agent for the treatment of cancer
Paclitaxel activates spinal astrocytes leading to mechanical allodynia To determine the activation of spinal astrocytes, we measured the protein levels of glial fibrillary acidic protein (GFAP) in spinal cord sections 6 h after systemic treatment of paclitaxel or vehicle solution (Fig. 1a)
Immunofluorescence showed that paclitaxel induced a significant increase of GFAP in the superficial laminae of dorsal horn of the mouse spinal cord, which is consistent with findings in rat spinal cord sections reported in a previous study [18]
Summary
Paclitaxel is a widely used and potent chemotherapeutic agent for the treatment of cancer. Astrocytes play an important role in the pathogenesis of pain in multiple preclinical models, as well as in paclitaxeltreated rodents It is still unclear what the exact contribution of astrocytes may be in paclitaxel-associated acute pain syndrome (P-APS). The paclitaxel-associated acute pain syndrome (P-APS) is distinguished by nature and temporal profile from paclitaxel-induced peripheral neuropathy [4], a potential relationship may exist between these two entities and drug doses [2, 4, 5]. Current therapeutic approaches for PAPS and peripheral neuropathy are limited, and often dose reduction or termination of the treatment are the only options, potentially affecting the optimal care of these patients [2, 6]. Identification of target-directed therapeutic approaches based on mechanistic insights is of paramount significance to improve the treatment of cancer patients [7, 8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
