title: N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases.
abstract: The treatment of neuropathic pain remains a clinical challenge because of its unclear mechanisms and broad clinical morbidity. Matrix metalloproteinase (MMP)-9 and MMP-2 have previously been described as key components in neuropathic pain because of their facilitation of inflammatory cytokine maturation and induction of neural inflammation. Therefore, the inhibition of MMPs may represent a novel therapeutic approach to the treatment of neuropathic pain. In this study, we report that N-acetyl-cysteine (NAC), which is a broadly used respiratory drug, significantly attenuates neuropathic pain through a unique mechanism of MMP inhibition. Both the in vitro (0.1 mM) and in vivo application of NAC significantly suppressed the activity of MMP-9/2. Orally administered NAC (50, 100, and 200 mg/kg) not only postponed the occurrence but also inhibited the maintenance of chronic constrictive injury (CCI)-induced neuropathic pain in rats. The administration of NAC blocked the maturation of interleukin-1β, which is a critical substrate of MMPs, and markedly suppressed the neuronal activation induced by CCI, including inhibiting the phosphorylation of protein kinase Cγ, NMDAR1, and mitogen-activated protein kinases. Finally, NAC significantly inhibited CCI-induced microglia activation but elicited no notable effects on astrocytes. These results demonstrate an effective and safe approach that has been used clinically to alleviate neuropathic pain through the powerful inhibition of the activation of MMPs.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.|Research Division of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.|Research Division of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Lujie
authors.initials: L
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.|Research Division of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Xueting
authors.initials: X
authors.lastname: Deng
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.|Department of Pain Management, Cancer Biotherapy Center, The Second Affiliated Hospital of Nanjing Medical University, Jiangsu, China.
authors.forename: Chunyi
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.
authors.forename: Cailong
authors.initials: C
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.|Research Division of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.|Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.|Research Division of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Wenling
authors.initials: W
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.affiliation: Research Division of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Guangqin
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pain Management, Cancer Biotherapy Center, The Second Affiliated Hospital of Nanjing Medical University, Jiangsu, China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Liu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D000111:Acetylcysteine