ABSTRACT
Cancer is a common disease threatening human health, chemotherapy is widely used in clinical treatment of cancer, but chemotherapy-induced peripheral neuropathy (CIPN) has a relevant impact on life quality of cancer patients. Administration of gastrodin can relieve chronic pain to cancer patients with CIPN and attenuated the inflammatory response by reducing the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). However, its exact molecular mechanisms remain unclear. In this study, we established an animal model of CIPN using Walker-256 breast cancer cell and vincristine. We found that the mechanical and thermal pain threshold of rats was decreased with treatment of vincristine. Using gastrodin could restore the mechanical and thermal threshold without interfering anti-tumor effect of vincristine. Gastrodin relieved CIPN by inhibiting activation of spinal microglia through Fractalkine (CX3CL1) and its receptor CX3CR1, then inhibited P38/mitogen-activated protein kinase (MAPK) signaling pathway and reduced the expression of inflammatory factor TNF-α and interleukin-1ß (IL-1ß). Taking together, our study demonstrated that gastrodin is a potential drug for the treatment of CIPN and likely to improve cancer patient's life quality.
Subject(s)
Analgesics/pharmacology , Antineoplastic Agents, Phytogenic/toxicity , Benzyl Alcohols/pharmacology , Breast Neoplasms/drug therapy , Glucosides/pharmacology , Neuralgia/prevention & control , Peripheral Nervous System Diseases/prevention & control , Spine/drug effects , Vincristine/toxicity , Animals , CX3C Chemokine Receptor 1/metabolism , Chemokine CX3CL1/metabolism , Female , Interleukin-1beta , Microglia/drug effects , Microglia/metabolism , Neuralgia/chemically induced , Neuralgia/metabolism , Neuralgia/physiopathology , Pain Threshold/drug effects , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/physiopathology , Rats, Sprague-Dawley , Signal Transduction , Spine/metabolism , Spine/physiopathology , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Chemotherapy-induced peripheral neuropathy (CIPN) has a adverse impact to the living quality of cancer patients. This side effect of CIPN limit the dose of drug used in many chemotherapies, such as vincristine (VCR). The activation of microglia in the spinal dorsal horn is involved in the occurrence and development of neuropathic pain induced by VCR. Recent study has demonstrated that hypoxia induced microglia activation depends on Notch signaling, and it is involved in the release of many inflammatory related factors in microglia. In this work, we aimed to study that the role of Notch signaling pathway in microglia activation on a VCR-induced neuropathy rat model. Our results showed that the mechanical, thermal and cold pain threshold of rats was decreased by treatment of VCR, but N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor, relieved the hyperalgesia. Molecular analysis showed that activation of Notch signaling pathway increased after nerve injury and that DAPT could significantly inhibit the upregulation of Notch signaling pathway, the activation of microglia, and the release of pro-inï¬ammatory cytokines in the spinal. Taking together, Notch signaling pathway could be a potential therapeutic target to alleviate neuropathic pain.
