title: Trans-resveratrol attenuates high fatty acid-induced P2X7 receptor expression and IL-6 release in PC12 cells: possible role of P38 MAPK pathway.
abstract: Diabetic neuropathy (DNP) is the most common chronic complication of diabetes. Elevated free fatty acids (FFAs) have been recently recognized as major causes of inflammation and are relevant to the functional changes of nerve system in diabetes. Trans-resveratrol (RESV), a polyphenolic natural compound, has long been acknowledged to have anti-inflammation properties and may exert a neuroprotective effect on neuronal damage in diabetes, while the mechanisms underlying are largely unknown. Our previous study on differential PC12 cells cultured with high FFAs has shown chronic FFAs overload increased PC12 interleukin (IL)-6 release mediated by P2X7 receptor, a ligand-gated cation channel activated by extracellular adenosine triphosphate (ATP); a high FFA-induced activation of P38 mitogen-activated protein kinase (MAPK) pathway was pointed to be a potential underlying mechanism. Data from this study indicated that RESV, in a dose-dependent manner, reduced high FFA-induced IL-6 release by impeding the activation of P2X7 receptor, as shown by the results that both high FFA-elevated P2X7 receptor messenger RNA (mRNA) and protein expression as well as high FFA-evoked [Ca(2+)]i in response to 3'-O-(4-benzoyl) benzoyl-ATP (a selective P2X7 receptor agonist) were significantly attenuated. Meanwhile, high FFA-induced activation of P38 MAPK, an essential prerequisite for high FFA-activated P2X7 receptor and subsequent IL-6 release, was also dose-dependently abrogated by RESV. Furthermore, RESV may hamper the activation of P38a MAPK (one paramount P38 isoform) via forming hydrogen bonding with Thr175 residue, surrounding the two residues (Thy180 and Tyr182) essential for canonical activation of P38a MAPK. Taken together, RESV could inhibit high FFA-induced inflammatory IL-6 release mediated by P2X7 receptor through deactivation of P38 MAPK signaling pathway. All these results outline the potential mechanisms involved in the neuroprotective roles of RESV and highlight the clinical application of RESV in treatment of inflammation in relation to DNP.
authors.affiliation: Department of Physiology, JiangXi Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Chaopeng
authors.initials: C
authors.lastname: Xiong
authors.forename: Luling
authors.initials: L
authors.lastname: He
authors.forename: Bing
authors.initials: B
authors.lastname: Wu
authors.forename: Lulu
authors.initials: L
authors.lastname: Peng
authors.forename: Yajun
authors.initials: Y
authors.lastname: Cheng
authors.forename: Fuqing
authors.initials: F
authors.lastname: Jiang
authors.forename: Liping
authors.initials: L
authors.lastname: Tan
authors.forename: Lan
authors.initials: L
authors.lastname: Tang
authors.forename: Yunming
authors.initials: Y
authors.lastname: Tu
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yang
authors.forename: Changle
authors.initials: C
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.forename: Guilin
authors.initials: G
authors.lastname: Li
authors.forename: Chunping
authors.initials: C
authors.lastname: Zhang
authors.forename: Shuangmei
authors.initials: S
authors.lastname: Liu
authors.forename: Changshui
authors.initials: C
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.forename: Shangdong
authors.initials: S
authors.lastname: Liang
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000633:toxicity*; D015850:Interleukin-6 / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D058486:Receptors, Purinergic P2X7 / Q000096:biosynthesis*; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D005230:Fatty Acids, Nonesterified; D015850:Interleukin-6; D058486:Receptors, Purinergic P2X7; D013267:Stilbenes; D048051:p38 Mitogen-Activated Protein Kinases; D000077185:Resveratrol