title: Simvastatin Attenuates Neuropathic Pain by Inhibiting the RhoA/LIMK/Cofilin Pathway.
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.
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS & PUMC, Beijing, 100730, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS & PUMC, Beijing, 100730, China.
authors.forename: W Y
authors.initials: WY
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS & PUMC, Beijing, 100730, China.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS & PUMC, Beijing, 100730, China.
authors.forename: M
authors.initials: M
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Peking Union Medical College Hospital, CAMS & PUMC, Beijing, 100730, China. garybeijing@163.com.
authors.forename: Y G
authors.initials: YG
authors.lastname: Huang
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D051338:Cofilin 1 / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D054461:Lim Kinases / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000577:Amides; D051338:Cofilin 1; D011725:Pyridines; C108830:Y 27632; D019821:Simvastatin; D054461:Lim Kinases; D020742:rhoA GTP-Binding Protein
keywords: CCI; Cofilin; LIM kinase; Neuropathic pain; RhoA