title: Novel epigallocatechin-3-gallate (EGCG) derivative as a new therapeutic strategy for reducing neuropathic pain after chronic constriction nerve injury in mice.
abstract: Neuropathic pain is common in peripheral nerve injury and often fails to respond to ordinary medication. Here, we investigated whether the two novel epigallocatechin-3-gallate (EGCG) polyphenolic derivatives, compound 23 and 30, reduce the neuropathic pain in mice chronic constriction nerve injury (CCI). First, we performed a dose-response study to evaluate nociceptive sensation after administration of EGCG and its derivatives 23 and 30, using the Hargreaves test at 7 and 21 days after injury (dpi). We daily administered EGCG, 23 and 30 (10 to 100 mg/Kg; i.p.) during the first week post-CCI. None of the doses of compound 23 caused significant pain diminution, whereas 50mg/kg was optimal for both EGCG and 30 to delay the latency of paw withdrawal. With 50 mg/Kg, we showed that EGCC prevented the thermal hyperalgesia from 7 to 21 dpi and compound 30 from 14 to 56 dpi. To evaluate the molecular mechanisms underpinning why EGCG and compound 30 differentially prevented the thermal hyperalgesia, we studied several biochemical parameters in the dorsal horn of the spinal cord at 14 and 56 dpi. We showed that the effect observed with EGCG and compound 30 was related to the inhibition of fatty acid synthase (FASN), a known target of these polyphenolic compounds. Additionally, we observed that EGCG and compound 30 reduced the expression of CCI-mediated inflammatory proteins and the nuclear localization of nuclear factor-kappa B at 14 dpi, but not at 56 dpi. We also strongly detected a decrease of synaptic plasma membrane levels of N-methyl-D-asparte receptor 2B in CCI-mice treated with compound 30 at 56 dpi. Altogether, compound 30 reduced the chronic thermal hyperalgesia induced by CCI better than the natural compound EGCG. Thus, our findings provide a rationale for the preclinical development of compound 30 as an agent to treat neuropathic pain.
authors: Grupo de Investigación de Anatomía Clínica, Embriología, Neurociencia y Oncología Molecular (NEOMA), Departamento de Ciencias Médicas, Facultad de Medicina, Universitat de Girona (UdG), Girona, Spain; Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Xavier
authors: X
authors: Xifró
authors: Grupo de Investigación de Anatomía Clínica, Embriología, Neurociencia y Oncología Molecular (NEOMA), Departamento de Ciencias Médicas, Facultad de Medicina, Universitat de Girona (UdG), Girona, Spain; Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Laura
authors: L
authors: Vidal-Sancho
authors: Grupo de Investigación de Anatomía Clínica, Embriología, Neurociencia y Oncología Molecular (NEOMA), Departamento de Ciencias Médicas, Facultad de Medicina, Universitat de Girona (UdG), Girona, Spain.
authors: Pere
authors: P
authors: Boadas-Vaello
authors: Laboratorio de Química Médica, Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid (UCM), Madrid, Spain.
authors: Carlos
authors: C
authors: Turrado
authors: Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors: Jordi
authors: J
authors: Alberch
authors: Grupo de Investigación de Anatomía Clínica, Embriología, Neurociencia y Oncología Molecular (NEOMA), Departamento de Ciencias Médicas, Facultad de Medicina, Universitat de Girona (UdG), Girona, Spain.
authors: Teresa
authors: T
authors: Puig
authors: Grupo de Investigación de Anatomía Clínica, Embriología, Neurociencia y Oncología Molecular (NEOMA), Departamento de Ciencias Médicas, Facultad de Medicina, Universitat de Girona (UdG), Girona, Spain.
authors: Enrique
authors: E
authors: Verdú
mesh_terms: D000818:Animals; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D054890:Fatty Acid Synthase, Type I / Q000096:biosynthesis / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017288:Pain Threshold; D059348:Peripheral Nerve Injuries; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D016207:Cytokines; D005227:Fatty Acids; D002392:Catechin; C045651:epigallocatechin gallate; D054890:Fatty Acid Synthase, Type I