[Exploring the intervention mechanism of modified Danggui buxue decoction on neuroinflammation in CIPN model mice...

Objective To investigate the intervention targets of modified Danggui buxue decoction on neuroinflammation in a chemotherapy-induced peripheral neuropathy(CIPN) model mice. Methods Sixty SPF-grade C57BL/6J mice were used. Except for the blank control group, the remaining 48 mice underwent ectopic transplantation of gastric cancer cells into the axilla and were randomly divided into four groups (n=12 per group): the gastric cancer group, the CIPN model group, the modified Danggui buxue decoction group, and Duloxetine group. Except for the gastric cancer group, mice in the other groups received intraperitoneal injections of oxaliplatin to establish a model of CIPN following platinum-based chemotherapy for gastric cancer. The drug intervention groups were administered their respective doses of medicinal solution by gavage, while the remaining groups received an equal volume of normal saline by gavage, once daily. After 28 days, performing behavioral experiments (mechanical pain threshold test and cold stimulation test), the dorsal root ganglia of the mice were collected for analysis of relevant indicators using transcriptomics, TEM, WB, and RT-PCR. Results Behavioral test results showed: After 28 days of administration, compared with the blank control group, the CIPN model group exhibited a downward trend in mechanical pain threshold and an upward trend in the frequency of paw withdrawal in response to cold stimulation. Compared with the CIPN model group, the gastric cancer group, modified Danggui buxue decoction group, and the Duloxetine group showed an upward trend in mechanical pain threshold and a downward trend in the frequency of paw withdrawal in response to cold stimulation. Transcriptomics results indicated that modified Danggui buxue decoctioned its effects by inhibiting NF-κB, ATM, and CCL21. Network pharmacology analysis suggested that modified Danggui buxue decoction might intervene in the occurrence of CIPN by suppressing IL-1β and IL-6 through TNF-α inhibition. TEM results revealed: Except for the blank control group, abnormal myelinated nerve fibers were observed in the dorsal root ganglia of the other four groups. Compared with the blank control group, the CIPN model group exhibited demyelination, dissolution of myelin sheaths, loosely arranged myelin lamellae, disrupted and dissolved mitochondrial cristae, and vacuolation. Compared with the CIPN model group, the modified Danggui buxue decoction group and the Duloxetine group showed alleviation of the aforementioned damage. WB and RT-PCR results showed: Compared with the blank control group, the protein and gene expression levels of ATM, NF-κB, CCL21, TNF-α, IL-1β, and IL-6 in the dorsal root ganglia of the CIPN model group were significantly increased. Compared with the CIPN model group, the protein and gene expression levels of ATM, NF-κB, CCL21, TNF-α, IL-1β, and IL-6 were significantly decreased in the gastric cancer group, modified Danggui buxue decoction group, and the Duloxetine group. Conclusion Modified Danggui buxue decoction may ameliorate pathological damage and pain symptoms in the dorsal root ganglia of a mouse model of oxaliplatin-induced peripheral neurotoxicity following gastric cancer chemotherapy. The mechanism is likely associated with the inhibition of the NF-κB signaling pathway in the dorsal root ganglia and the down regulation of ATM, NF-κB, CCL21, TNF-α, IL-1β, and IL-6 expression.