title: Tanshinone IIA reduces the risk of Alzheimer's disease by inhibiting iNOS, MMP‑2 and NF‑κBp65 transcription and translation in the temporal lobes of rat models of Alzheimer's disease.
abstract: Tanshinone IIA (Tan IIA), one of the major active constituents of the medicinal herb Salvia miltiorrhiza, has been reported to possess neuroprotective effects against the pathological features of Alzheimer's disease (AD), but the molecular mechanism underlying this effect remains unclear. To examine the effect of Tan IIA on AD, as well as the underlying molecular mechanisms, in vivo animal experiments and in vitro molecular biology investigations were employed in the present study. Firstly, a rat model of AD was successfully established by direct injection of the amyloid beta protein (Aβ) and then these rats were administered an interventional treatment of Tan IIA. The learning and memory ability of rats was evaluated in four groups (Control, Sham, AD and Tan IIA) utilizing a Morris water maze test. Quantitative (q)PCR was employed to detect the mRNA expression of inducible nitric oxide synthase (iNOS), matrix metalloproteinase‑2 (MMP‑2) and nuclear transcription factor kappa (NF‑κBp65) in temporal lobe tissues and protein expression was determined with western blot analysis. In addition, association analyses between iNOS, MMP‑2 and NF‑κBp65 at a transcriptional and translational level were performed utilizing Spearman's correlation analysis. In the present study, the results revealed that rats in the AD group demonstrated significant disruptions in learning and memory ability, and the symptoms were evidently reduced by Tan IIA. Furthermore, the upregulation of iNOS, MMP‑2 and NF‑κBp65 at a transcriptional and translational level in AD rats was distinctly inhibited by Tan IIA. Therefore, it was concluded that iNOS, MMP‑2 and NF‑κBp65 are involved in AD development, and Tan IIA may reduce AD risk by inhibiting transcription and translation of these genes. Furthermore, the positive correlation of iNOS and MMP‑2 with NF‑κBp65, respectively, provides evidence supporting the hypothesis that Tan IIA reduces AD risk by inhibiting iNOS and MMP‑2 at a transcriptional and translational level through the NF‑κB pathway. In summary, Tan IIA is an effective neuroprotective agent for AD therapy, and iNOS, MMP‑2 and NF‑κBp65 may be the potential molecular targets for manipulating this effect therapeutically.
authors.affiliation: Department of Biochemistry and Psychopharmacology, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Psychopharmacology, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China.
authors.forename: Chunbo
authors.initials: C
authors.lastname: Li
authors.affiliation: College of Basic Medical Sciences, The Second Military Medical University, Shanghai, P.R. China.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: College of Basic Medical Sciences, The Second Military Medical University, Shanghai, P.R. China.
authors.forename: Binghua
authors.initials: B
authors.lastname: Jiao
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010946:Plants, Medicinal / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013702:Temporal Lobe / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
chemical_list: D045784:Abietanes; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D051996:Transcription Factor RelA; C021751:tanshinone; D052247:Nitric Oxide Synthase Type II; D020778:Matrix Metalloproteinase 2