Background & Aims
Chemotherapy-induced neuropathic pain (CINP) remains a therapeutic conundrum, lacking US-FDA-approved drugs or effective treatments. Despite strides in understanding CINP’s pathophysiology, translating this knowledge into clinical outcomes remains elusive. Current pharmacotherapies, such as antidepressants and anticonvulsants, often result in undesirable side effects. The upregulation of Transient Receptor Protein Ankyrin 1 (TRPA1) during chemotherapy plays a pivotal role in CINP. Existing TRPA1 antagonists, though effective, pose inherent risks. In the present study explores a novel approach, employing small interfering RNA (siRNA) loaded into liposomes to selectively silence the TRPA1 gene, offering a more precise and safer intervention for CINP treatment.
Methods
Intrathecal administration of TRPA1-siRNA in rats was meticulously assessed for its efficacy in knocking down TRPA1 mRNA and protein expressions. To circumvent biodegradation challenges, TRPA1-siRNA was encapsulated in liposomes, with thorough characterization using advanced techniques. The formulated siRNA was administered via intrathecal and intravenous routes, and behavioral studies were conducted to comprehensively evaluate its effect on mechanical and cold hypersensitivity in chemotherapy-treated rats. The underlying mechanism of TRPA1 siRNA formulation was systematically explored.
Results
Protein and mRNA expression studies convincingly confirmed the successful validation of TRPA1 knockdown post-intrathecal administration. The developed TRPA1-siRNA-loaded liposomal formulation exhibited favorable characteristics through comprehensive characterization. Intrathecal and intravenous administration of the TRPA1 siRNA formulation significantly mitigated the attenuation of mechanical and cold hypersensitivity in neuropathic rats. Notably, sustained effects indicated controlled release, with plain siRNA showing no significant effects after day 3. Mechanistically, the silencing of the TRPA1 gene led to downregulated microglia activation and ICAM1, subsequently reducing the neuroinflammatory cascade in the spinal cord. Furthermore, the developed formulation significantly downregulated TRPA1 and IL6 mRNA expressions in the dorsal root ganglia (DRG) of intravenously administered neuropathic rats compared to intrathecally administered rats.
Conclusions
This study introduces a promising avenue for CINP treatment through the utilization of TRPA1-siRNA loaded liposomes, effectively addressing the limitations of traditional therapies. The approach demonstrates specific gene silencing without severe side effects, highlighting the potential of RNA interference (RNAi)-based gene therapy for personalized pain management. Additionally, this approach holds promise for future interventions in chronic pain scenarios.
References
1.Gomes-Da-Silva, L.C., Fonseca, N.A., Moura, V., Pedroso De Lima, M.C., Simões, S., Moreira, J.N., 2012. Lipid-based nanoparticles for siRNA delivery in cancer therapy: Paradigms and challenges. Acc. Chem. Res. 45, 1163–1171. https://doi.org/10.1021/ar300048p
2.Sadler, K.E., Stucky, C.L., 2019. Neuronal transient receptor potential (TRP) channels and noxious sensory detection in sickle cell disease. Neurosci. Lett. 694, 184–191. https://doi.org/10.1016/j.neulet.2018.11.056
3.Vandewauw, I., De Clercq, K., Mulier, M., Held, K., Pinto, S., Van Ranst, N., Segal, A., Voet, T., Vennekens, R., Zimmermann, K., Vriens, J., Voets, T., 2018. A TRP channel trio mediates acute noxious heat sensing. Nature 555, 662–666. https://doi.org/10.1038/nature26137
4.Weng, Y., Xiao, H., Zhang, J., Liang, X.J., Huang, Y., 2019. RNAi therapeutic and its innovative biotechnological evolution. Biotechnol. Adv. 37, 801–825. https://doi.org/10.1016/j.biotechadv.2019.04.012
Presenting Author
Akhilesh
Poster Authors
Akhilesh .
PhD
Indian Institute of Technology BHU, Varanasi India
Lead Author
Topics
- Mechanisms: Biological-Molecular and Cell Biology