Protective effect of celastrol in rat cerebral ischemia model: down-regulating p-JNK, p-c-Jun and NF-κB.

Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China.
Brain research (Impact Factor: 2.46). 05/2012; 1464:8-13. DOI: 10.1016/j.brainres.2012.04.054
Source: PubMed

ABSTRACT Oxidative stress and inflammatory damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Celastrol has been proved to elicit a vanity of biological effects through its anti-oxidant, anti-inflammatory properties in the treatment of Alzheimer's disease, systemic lupus erythematosus, and rheumatoid arthritis. However, little is known regarding the effect of celastrol in the acute phase of ischemic stroke. This study investigated the potential protective effects of celastrol and underlying mechanisms in cerebral ischemia. We used a permanent middle cerebral artery occlusion (pMCAO) model and administered celastrol intraperitoneally immediately after stroke. At 24h after stroke, we found that celastrol dramatically reduced neurological deficit, brain water content and infarct sizes, and downregulated the expression of p-JNK, p-c-Jun and NF-κB. The results indicated that celastrol may have the possibility of protective effect against ischemic injury, and this effect may be through downregulation of the expression of p-JNK, p-c-Jun and NF-κB.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Traumatic brain injury (TBI) induces severe harm and disability in many accident victims and combat-related activities. The heat shock proteins Hsp70/Hsp110 protect cells against death and ischemic damage. In this study, we used mice deficient in Hsp110 or Hsp70 to examine their potential requirement following TBI. Data indicate that loss of Hsp110 or Hsp70 increases brain injury and death of neurons. One of the mechanisms underlying the increased cell death observed in the absence of Hsp110 and Hsp70 following TBI is the increased expression of ROS-induced p53 target genes Pig1, Pig8 and Pig12. To examine whether drugs that increase the levels of Hsp70/Hsp110 can protect cells against TBI, we subjected mice to TBI and administered Celastrol or BGP-15. In contrast to Hsp110 or Hsp70i-deficient mice that were not protected following TBI and Celastrol treatment, there was a significant improvement of wild-type mice following administration of these drugs during the first week following TBI. In addition, assessment of neurological injury shows significant improvement of Contextual and Cued Fear Conditioning tests and beam balance in wild-type mice that were treated with Celastrol or BGP-15 following TBI compared to TBI-treated mice. These studies indicate a significant role of Hsp70/Hsp110 in neuronal survival following TBI and the beneficial effects of Hsp70/Hsp110 inducers toward reducing the pathological consequences of TBI. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 06/2014; · 3.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic kidney disease (CKD) is becoming a worldwide epidemic, driven largely by the dramatic rise in the prevalence of diabetes and obesity. Novel targets and treatments for CKD are, therefore, desperately needed-to both mitigate the burden of this disease in the general population and reduce the necessity for renal replacement therapy in individual patients. This Review highlights new insights into the mechanisms that contribute to CKD, and approaches that might facilitate the development of disease-arresting therapies for CKD. Particular focus is given to therapeutic approaches using antifibrotic agents that target the transforming growth factor β superfamily. In addition, we discuss new insights regarding the roles of vascular calcification, the NADPH oxidase family, and inflammation in the pathogenesis of CKD. We also highlight a new understanding regarding kidney energy sensing pathways (AMPK, sirtuins, and mTOR) in a variety of kidney diseases and how they are linked to inflammation and fibrosis. Finally, exciting new insights have been made into the role of mitochondrial function and mitochondrial biogenesis in relation to progressive kidney disease. Prospective therapeutics based on these findings will hopefully renew hope for clinicians and patients in the near future.
    Nature Reviews Nephrology 03/2014; · 7.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: All-trans retinoic acid (ATRA) is a revolutionary agent for acute promyelocytic leukemia (APL) treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1) expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS) which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1β secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.
    PLoS ONE 01/2014; 9(8):e105131. · 3.53 Impact Factor