title: HSP60 is involved in the neuroprotective effects of naloxone.
abstract: Heat shock protein (HSP)60 is primarily a mitochondrial protein. Previous experiments have found that changes in the location of intracellular HSP60 have been associated with apoptosis. Extracellular HSP60 mediates apoptosis via its ligand, Toll‑like receptor (TLR)-4. TLR-4 is an important factor expressed on microglia, with a central role in generating neuroimmune responses in the pathogenesis of neurodegenerative disorders. Naloxone is a highly effective nonselective opioid receptor antagonist, and has been reported to be pharmacologically beneficial for the treatment of brain diseases through inhibiting microglia activation. However, the mechanisms underlying these beneficial effects of naloxone remain poorly understood. The present study aimed to investigate the role of HSP60 in the neuroprotective effects of naloxone on the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated BV2 murine microglial cells and the possible signaling pathways involved. The results demonstrated that naloxone significantly inhibited the expression and release of HSP60 in BV2 cells. The expression levels of heat shock factor (HSF)-1 were upregulated in LPS‑activated BV2 cells, which indicated that the increased expression of HSP60 was driven by HSF-1 activation. However, increased HSF‑1 levels may be downregulated by naloxone. The levels of TLR‑4 were elevated in activated BV2 cells, and then inhibited by naloxone. Activation of TLR‑4 is characterized by activation of nuclear factor-κB (NF-κB) followed by the production of various proinflammatory and neurotoxic factors. Data from the present study demonstrated that naloxone reduced the expression levels of NF-κB and its upstream protein caspase‑3, and reduced the LPS-induced production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor α, interleukin-1β and interleukin-6 in BV2 microglia. In light of this data, it was concluded that naloxone may exert its neuroprotective and anti‑inflammatory effects by inhibiting microglia activation through a HSP60‑TLR‑4‑NF‑κB signaling pathway.
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Wenjing
authors: W
authors: Cheng
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Yunhong
authors: Y
authors: Li
authors: The General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China.
authors: Xiaolin
authors: X
authors: Hou
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Nan
authors: N
authors: Zhang
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Jiao
authors: J
authors: Ma
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Feijia
authors: F
authors: Ding
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Fan
authors: F
authors: Li
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Zhenhua
authors: Z
authors: Miao
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Yanli
authors: Y
authors: Zhang
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Qi
authors: Q
authors: Qi
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Guanghua
authors: G
authors: Li
authors: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China.
authors: Ying
authors: Y
authors: Shen
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Juan
authors: J
authors: Liu
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Weidong
authors: W
authors: Huang
authors: Basic Medical College of Ningxia Medical University, Ningxia Key Laboratory of Cerebrocranial Diseases, Yinchuan, Ningxia 750004, P.R. China.
authors: Yin
authors: Y
authors: Wang
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018834:Chaperonin 60 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D000076249:Heat Shock Transcription Factors; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D009270:Naloxone; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3