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Simvastatin Attenuates Neuropathic Pain by Inhibiting the RhoA/LIMK/Cofilin Pathway

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Abstract

Neuropathic pain occurs due to deleterious changes in the nervous system caused by a lesion or dysfunction. Currently, neuropathic pain management is unsatisfactory and remains a challenge in clinical practice. Studies have suggested that actin cytoskeleton remodeling may be associated with neural plasticity and may involve a nociceptive mechanism. Here, we found that the RhoA/LIM kinase (LIMK)/cofilin pathway, which regulates actin dynamics, was activated after chronic constriction injury (CCI) of the sciatic nerve. Treatments that reduced RhoA/LIMK/cofilin pathway activity, including simvastatin, the Rho kinase inhibitor Y-27632, and the synthetic peptide Tat-S3, attenuated actin filament disruption in the dorsal root ganglion and CCI-induced neuropathic pain. Over-activation of the cytoskeleton caused by RhoA/LIMK/cofilin pathway activation may produce a scaffold for the trafficking of nociceptive signaling factors, leading to chronic neuropathic pain. Here, we found that simvastatin significantly decreased the ratio of membrane/cytosolic RhoA, which was significantly increased after CCI, by inhibiting the RhoA/LIMK/cofilin pathway. This effect was highly dependent on the function of the cytoskeleton as a scaffold for signal trafficking. We conclude that simvastatin attenuated neuropathic pain in rats subjected to CCI by inhibiting actin-mediated intracellular trafficking to suppress RhoA/LIMK/cofilin pathway activity.

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Acknowledgments

This work was supported by the Grants of National Natural Science Foundation Committee of China (31070930 and 81200869). The authors are grateful to all study participants.

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Authors and Affiliations

  1. Department of Anesthesiology, Peking Union Medical College Hospital, CAMS & PUMC, Beijing, 100730, China

    Y. Qiu, W. Y. Chen, Z. Y. Wang, M. Wei & Y. G. Huang

  2. Department of Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China

    F. Liu & C. Ma

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  1. Y. Qiu
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  7. Y. G. Huang
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Correspondence to Y. G. Huang.

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Qiu, Y., Chen, W.Y., Wang, Z.Y. et al. Simvastatin Attenuates Neuropathic Pain by Inhibiting the RhoA/LIMK/Cofilin Pathway. Neurochem Res 41, 2457–2469 (2016). https://doi.org/10.1007/s11064-016-1958-1

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  • DOI: https://doi.org/10.1007/s11064-016-1958-1

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