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

• Published in: Neurochemical research Vol. 41; no. 9; pp. 2457 - 2469
• Main Authors: Qiu, Y., Chen, W. Y., Wang, Z. Y., Liu, F., Wei, M., Ma, C., Huang, Y. G.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-09-2016; Springer Nature B.V
• Subjects: Actin; Actin Cytoskeleton - metabolism; Activation; Amides - pharmacology; Animals; Attenuation; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cofilin; Cofilin 1 - metabolism; Cytoskeleton; Cytoskeleton - metabolism; Dorsal root ganglia; Enzyme inhibitors; Injury prevention; Kinases; LIM kinase; Lim Kinases - metabolism; Male; Nervous system; Neural plasticity; Neuralgia; Neuralgia - drug therapy; Neuralgia - metabolism; Neurochemistry; Neurology; Neurosciences; Original Paper; Pain; Pain perception; Phosphorylation - drug effects; Pyridines - pharmacology; Rats, Sprague-Dawley; Rho-associated kinase; rhoA GTP-Binding Protein - metabolism; RhoA protein; Scaffolds; Sciatic nerve; Signal Transduction - drug effects; Simvastatin; Simvastatin - pharmacology; Cofilin; CCI; RhoA; LIM kinase; Neuropathic pain
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-016-1958-1

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.