Abbas Muzaffar, Alzarea Sami, Papke Roger L, Rahman Shafiqur
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University.
Department of Pharmacology and Therapeutics, University of Florida.
Drug Discov Ther. 2017;11(4):206-211. doi: 10.5582/ddt.2017.01038.
We have reported that 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) reduces lipopolysaccharide (LPS)-induced hyperalgesia and allodynia in mice. The objective of the present study was to determine the effects of TQS on LPS-induced activation of hippocampal inhibitor of κB (IκB) and cluster of differentiation 11b (CD11b) gene expression involving hyperalgesia and allodynia in mice. We also examined the effects of TQS on microglial phenotype following LPS administration. Pretreatment of TQS (4 mg/kg) reduced the expressions of IκB and CD11b mRNA. Pretreatment of methyllycaconitine (3 mg/kg), an α7 nAChR antagonist, reversed TQS-induced decrease in IκB and CD11b mRNA expressions in the hippocampus indicating the involvement of α7 nAChR. In addition, TQS (4 mg/kg) reversed the LPS-induced microglial morphological changes. These results suggest that TQS reduces LPS-induced IκB and CD11b gene expression and microglial activation associated with hyperalgesia and allodynia by targeting microglial α7 nAChR in the hippocampus.
我们曾报道，3a,4,5,9b-四氢-4-(1-萘基)-3H-环戊烷[c]喹啉-8-磺酰胺（TQS），一种α7烟碱型乙酰胆碱受体（nAChR）的正向变构调节剂（PAM），可减轻脂多糖（LPS）诱导的小鼠痛觉过敏和异常性疼痛。本研究的目的是确定TQS对LPS诱导的小鼠海马κB抑制蛋白（IκB）激活及与痛觉过敏和异常性疼痛相关的分化簇11b（CD11b）基因表达的影响。我们还研究了TQS对LPS给药后小胶质细胞表型的影响。TQS（4 mg/kg）预处理可降低IκB和CD11b mRNA的表达。α7 nAChR拮抗剂甲基lycaconitine（3 mg/kg）预处理可逆转TQS诱导的海马中IκB和CD11b mRNA表达的降低，表明α7 nAChR参与其中。此外，TQS（4 mg/kg）可逆转LPS诱导的小胶质细胞形态变化。这些结果表明，TQS通过靶向海马中的小胶质细胞α7 nAChR，减少LPS诱导的IκB和CD11b基因表达以及与痛觉过敏和异常性疼痛相关的小胶质细胞激活。
