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Establishing a Mouse Model of a Pure Small Fiber Neuropathy with the Ultrapotent Agonist of Transient Receptor Potential Vanilloid Type 1
Published on: February 13, 2018
Identifying potential inflammatory therapeutic targets and drug candidates in small fiber neuropathy: integrating
Guangyu Cai1,2,3, Jiawei Zheng4, Changmao Jiang1
1College of Anesthesia, Guizhou Medical University, Guiyang, Guizhou, China.
Objective:
This study aimed to investigate the causal associations between circulating inflammatory proteins and small fiber neuropathy (SFN) by integrating Mendelian randomization (MR) analysis with experimental validation in animal models, and to explore their potential as therapeutic targets.
Methods:
A two-sample bidirectional MR analysis was conducted to evaluate the genetic causal associations between 91 inflammatory proteins and SFN. A paclitaxel-induced SFN mouse model was developed to assess behavioral changes, intraepidermal nerve fiber density, and the expression levels of key inflammatory factors in serum, dorsal root ganglia, and spinal cord. Computational drug screening using deep learning (TransformerCPI 2.0) combined with molecular docking analysis screened small-molecule candidates with high predicted interaction likelihood to target proteins.
Results:
MR analysis nominated suggestive associations of C-C motif chemokine ligand 11 (CCL11, odds ratio (OR) = 1.460, 95% confidence interval (CI) = 1.059-2.012, p = 0.021) and interleukin 18 receptor 1 (IL18R1, OR = 1.186, 95% CI = 1.011-1.391, p = 0.036) with increased SFN risk, whereas monocyte chemotactic protein 2 (MCP2) showed a suggestive protective association (OR = 0.842, 95% CI = 0.731-0.970, p = 0.017). However, after Benjamini-Hochberg false discovery rate correction across 91 proteins, none of these associations remained significant. In a murine model, paclitaxel administration induced mechanical hypersensitivity and resulted in a reduction of intraepidermal nerve fiber density. Elevated expression levels of CCL11, MCP2, IL18R1 in affected tissues were observed. Utilizing deep learning and molecular docking techniques, several small-molecule compounds with high binding affinity to these inflammatory targets were screened, indicating their potential as candidate compounds for future therapeutic development.
Conclusion:
CCL11 and IL18R1 are suggested as potential inflammatory targets in SFN. MCP2 showed discordant genetic and experimental signals, which may reflect context-dependent regulation and differences between genetically predicted long-term effects and acute injury responses. This study applies an integrative framework that integrates genetic prediction, experimental validation, and drug discovery, providing novel insights into SFN pathogenesis and generates hypotheses for future intervention.
