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

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.

Clinical Efficacy and Potential Mechanisms of Acupoint Stimulation Combined With Chemotherapy in Combating Cancer: A Review and Prospects

“…In addition, the maintenance of inflammatory signaling homeostasis plays a complex role in hematopoietic stem cell maintenance ( 96 ), activation, proliferation, and differentiation, while exposure to acute or chronic inflammation can have deleterious effects on hematopoietic stem cell hematopoiesis and self-renewal. Although chemotherapeutic agents can directly inhibit BM hematopoietic stem cell function, sympathetic neurotoxic injury via the BM also contributes to BM suppression and leukopenia ( 57 ). Thus, chemotherapy-induced cognitive impairment, neuropathic pain, adverse GI, and BM suppression may share a common pathological mechanism, specifically, neuroinflammation.…”

“…Our recent study has shown that EA on ST36 and SP6 prevents neurotoxicity, preserves BM hematopoiesis, and myeloid ontogenesis during cisplatin chemotherapy. EA induced both neuro and immune protection by inducing the neurogenic production of PACAP, which preserves BM hematopoiesis via the PAC1 receptor ( 57 ).…”

Mechanism of traditional Chinese medicine in treating overactive bladder

“…Xian-jia-tang, a Traditional Chinese medicine decoction, could significantly inhibit the expression of K v2.1 and K v1.5 in detrusor muscle, but increased the expression of BK, SK 2/3 and K ATP , suggesting that the effect of Xian-jia-tang on BOO rats was related to the K + channel in detrusor muscle [ 70 ]. In addition, acupuncture could be upregulated, pituitary adenylate cyclase-activating polypeptide [ 71 ], and then cAMP-activated PKA, promoting phosphorylation of K + channel and hyperpolarization of the cell membrane. This indirectly inhibits the activity of L-type voltage-dependent calcium channels on the cell membrane, prevents extracellular Ca 2+ from entering muscle cells, reduces intracellular Ca 2+ concentration and promotes the relaxation of smooth muscle cells [ 72 ].…”

Research Progress on Improving the Efficiency of CDT by Exacerbating Tumor Acidification

“… 9 Chemotherapy and radiotherapy, as treatments for cancer, have serious side effects, including toxicity and immunosuppression, which limit their anti-tumor efficacy and increase the risk of infection. 10 , 11 Compared to them, CDT agents are less prone to serious side effects and drug resistance. Simultaneously, there is no need to be limited by oxygen and near-infrared light (NIR) as that of photothermal therapy (PTT) or photodynamic therapy (PDT).…”