PAC1 Receptor Mediates Electroacupuncture-Induced Neuro and Immune Protection During Cisplatin Chemotherapy.

Shanshan Li,Yinan Gong,Siru Qin,Yangyang Liu,Shenjun Wang,Yuxin Fang,Jiaqi Wang,Luis Ulloa,Suhong Zhao,Jin Huang,Yi Guo,Bin Wang,Zhifang Xu,Yongming Guo,Shanshan Lu

doi:10.3389/fimmu.2021.714244

Abstract

Platinum-based chemotherapy is an effective treatment used in multiple tumor treatments, but produces severe side effects including neurotoxicity, anemia, and immunosuppression, which limits its anti-tumor efficacy and increases the risk of infections. Electroacupuncture (EA) is often used to ameliorate these side effects, but its mechanism is unknown. Here, we report that EA on ST36 and SP6 prevents cisplatin-induced neurotoxicity and immunosuppression. EA induces neuroprotection, prevents pain-related neurotoxicity, preserves bone marrow (BM) hematopoiesis, and peripheral levels of leukocytes. EA activates sympathetic BM terminals to release pituitary adenylate cyclase activating polypeptide (PACAP). PACAP-receptor PAC1-antagonists abrogate the effects of EA, whereas PAC1-agonists mimic EA, prevent neurotoxicity, immunosuppression, and preserve BM hematopoiesis during cisplatin chemotherapy. Our results indicate that PAC1-agonists may provide therapeutic advantages during chemotherapy to treat patients with advanced neurotoxicity or neuropathies limiting EA efficacy.

Highlights

Platinum-based chemotherapy, such as cisplatin, carboplatin, and oxaliplatin are widely used in multiple tumors [1,2,3], but they produce severe side effects including neurotoxicity [4], anemia [5], immunosuppression [6], nephrotoxicity [7], and gastrointestinal toxicity [8]
These results show that cisplatin induces leukopenia affecting all leukocytes it was more detrimental to myeloid cells including neutrophils and monocytes, whereas EA preserved normal blood leukocyte counts
PAC1 inhibitor prevented the potential of EA to preserve hematopoietic cell proliferation (Figure 4G). These results show that inhibition of pituitary adenylate cyclase activating polypeptide (PACAP) receptor PAC1 prevents the protective effects of EA during cisplatin chemotherapy, suggesting that the protective effects of EA are mediated by PACAP production

Summary

Introduction

Platinum-based chemotherapy, such as cisplatin, carboplatin, and oxaliplatin are widely used in multiple tumors [1,2,3], but they produce severe side effects including neurotoxicity [4], anemia [5], immunosuppression [6], nephrotoxicity [7], and gastrointestinal toxicity [8]. Cisplatin-induced immunosuppression limits anti-tumor immune responses, treatment efficacy, and increases the risk of infections [9, 10]. Chemotherapy is often combined with complementary treatments to prevent immunosuppression, Neuroprotection During Chemotherapy such as EA or treatment with stimulating factors such as colony stimulating factor (CSF) to promote myeloid cell differentiation in the bone marrow (BM) [11]. CSF is not effective in restoring the proliferation of hematopoietic stem/progenitor cells (HSPCs), induces multiple complications such as bone pain [12], and increases the risk of tumor growth and metastasis by inducing myeloid-derived suppressor cells [13, 14]. There is an unmet clinical need to find safe and effective adjuvant treatments for chemotherapy-induced neurotoxicity and immunosuppression

Methods

Results

Conclusion