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: 2.84).
05/2012; 1464:8-13. DOI: 10.1016/j.brainres.2012.04.054
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.
Available from: Shile Huang
- "Furthermore, ectopic expression of dn-c-Jun also strengthened celastrol inhibition of Cd-induced neuronal apoptosis. Our finding is in consistence with a recent report that celastrol has protective effect in rat cerebral ischemia model through down-regulation of phospho-JNK and phospho-c- Jun (Li et al. 2012). Therefore, our data support the notion that celastrol protects against Cd-induced neuronal apoptosis partially by blocking JNK pathway. "
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ABSTRACT: Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Celastrol, a plant-derived triterpene, has shown neuroprotective effects in various disease models. However, little is known regarding the effect of celastrol on Cd-induced neurotoxicity. Here we show that celastrol protected against Cd-induced apoptotic cell death in neuronal cells. This is supported by the findings that celastrol strikingly attenuated Cd-induced viability reduction, morphological change, nuclear fragmentation and condensation, as well as activation of caspase-3 in neuronal cells. Concurrently, celastrol remarkably blocked Cd-induced phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinases 1/2 (Erk1/2) and p38, in neuronal cells. Inhibition of JNK by SP600125 or overexpression of dominant negative c-Jun potentiated celastrol protection against Cd-induced cell death. Furthermore, pre-treatment with celastrol prevented Cd downregulation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and activation of Akt/mammalian target of rapamycin (mTOR) signaling in neuronal cells. Overexpression of wild-type PTEN enhanced celastrol inhibition of Cd-activated Akt/mTOR signaling and cell death in neuronal cells. The findings indicate that celastrol prevents Cd-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. Our results strongly suggest that celastrol may be exploited for the prevention of Cd-induced neurodegenerative disorders. This article is protected by copyright. All rights reserved.
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ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints leading to bone and cartilage damage. Untreated inflammatory arthritis can result in severe deformities and disability. The use of anti-inflammatory agents and biologics has been the mainstay of treatment of RA. However, the prolonged use of such agents may lead to severe adverse reactions. In addition, many of these drugs are quite expensive. These limitations have necessitated the search for newer therapeutic agents for RA. Natural plant products offer a promising resource for potential antiarthritic agents. We describe here the cellular and soluble mediators of inflammation-induced bone damage (osteoimmunology) in arthritis. We also elaborate upon various herbal products that possess antiarthritic activity, particularly mentioning the specific target molecules. As the use of natural product supplements by RA patients is increasing, this paper presents timely and useful information about the mechanism of action of promising herbal products that can inhibit the progression of inflammation and bone damage in the course of arthritis.
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ABSTRACT: Tetramethylpyrazine (TMP) has been used to treat ischemic stroke. However, scientific evidence related to its effectiveness or precise modes of neuroprotective action is largely unclear. This study provides evidence of an alternative target for TMP and sheds light on the mechanism of its physiological benefits. We report a global inhibitory effect of TMP on intracerebral cellular inflammatory response in a rat model of permanent cerebral ischemia. TMP exhibited a neuroprotective effect against ischemic deficits by reduction of behavioral disturbance, brain infarction, and edema. The results of immunohistochemistry, enzymatic assay, Western blot, real-time reverse transcriptase-polymerase chain reaction (RT-PCR), and flow cytometric analysis revealed that TMP reduced the percentages of activated macrophages/microglia and infiltrative lymphocytes, neutrophils, and macrophages and pro-inflammatory cytokine expression after cerebral ischemia. In parallel with these immunosuppressive phenomena, TMP also attenuated the activities of ischemia-induced inflammation-associated signaling molecules and transcription factors. Another finding in this study was that the anti-inflammatory and neuroprotective effects of TMP were accompanied by a further elevated expression of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in ipsilateral neurons and macrophages/microglia after cerebral ischemia. Taken together, our results suggest that both the promotion of endogenous defense capacity and the attenuation of the extent and composition percentage of the major cellular inflammatory responses via targeting of macrophages/microglia by elevating Nrf2/HO-1 expression might actively contribute to TMP-mediated neuroprotection against cerebral ischemia.
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