title: Chotosan improves Aβ1-42-induced cognitive impairment and neuroinflammatory and apoptotic responses through the inhibition of TLR-4/NF-κB signaling in mice.
abstract: BACKGROUND
  Recently, the focus on neuroinflammation is intensified as its complex pathophysiological role has emerged in multiple central nervous system(CNS) disorders. Chotosan (CTS), known as a traditional herbal formula, is often utilized to treat relevant nervous system diseases in China. It was demonstrated effectively to alleviate cognitive deficit associated with aging, diabetes, hypoperfusion and cerebral ischemia. However, the effects of CTS on Aβ1-42-induced cognitive dysfunction remain unclear. Here, we further investigated the effects of chotosan on memory performance, neuroinflammation and apoptotic responses.
  
  
  METHODS
  The learning and memory ability is evaluated by Morris water maze (MWM) task and Y-maze test following intrahippocampal infusion of aggregated Aβ1-42. The expression level of toll-like receptor 4 (TLR-4), NF-κB p65, Bcl-2 and Bax was examined by Western blot. TLR-4 level is also assessed by immunohistochemistry (IHC). Enzyme-linked immunosorbent assay (ELISA) was conducted to determine the generation of inflammatory mediators. The caspase-3 activity is analyzed by commercial kits.
  
  
  RESULTS
  The repeated treatment with CTS (750mg/kg or 375mg/kg per day) for 3 weeks significantly restored Aβ1-42-induced memory impairment in mice. Meanwhile, this treatment also remarkably reduced TLR-4 and NF-κB p65 expression accompanying with the diminished release of proinflammatory cytokines including TNF-α and IL-1β in hippocampus. The neuronal apoptosis is also inhibited as evidenced by increase in Bcl-2/Bax ratio and decrease in pro-apoptotic protein caspase-3 activity compared to that of the model mice.
  
  
  CONCLUSIONS
  Our results show for the first time that chotosan can ameliorate Aβ1-2-induced memory dysfunction via inhibiting neuroinflammation and apoptosis at least partially mediated by TLR-4/NF-κB signaling pathway.
authors.affiliation: Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Lejian
authors.initials: L
authors.lastname: Hu
authors.affiliation: Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: fengfeng@cpu.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Feng
authors.affiliation: Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qu
authors.affiliation: Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: liuwenyuan8506@163.com.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D016229:Amyloid beta-Peptides; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D010446:Peptide Fragments; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D004365:Drugs, Chinese Herbal; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010446:Peptide Fragments; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C120250:choto-san
keywords: Alzheimer's disease; Apoptosis; Chotosan; Neuroinflammation; Toll-like receptor 4