Neuroprotective Effects of Celastrol on Transient Global Cerebral Ischemia Rats via Regulating HMGB1/NF-κB Signaling Pathway

Abstract

Cerebral ischemia is a major cause of brain dysfunction, neuroinflammation and oxidative stress have been implicated in the pathophysiological process of cerebral ischemia/reperfusion injury. Celastrol is a potent inhibitor of inflammation and oxidative stress that has little toxicity. The present study was designed to evaluate whether celastrol has neuroprotective effects through anti-inflammatory and antioxidant actions, and to elucidate the possible involved mechanisms in transient global cerebral ischemia reperfusion (tGCI/R) rats. Celastrol (1, 2, or 4 mg/kg) was administrated intraperitoneally immediately after reperfusion and the effect of celastrol on reverting spatial learning and memory impairment was determined by Morris water maze (MWM) task. Inflammatory response and oxidative stress, hippocampal neuronal damage and glial activation, and HMGB1/NF-κB signaling pathway proteins were also examined. Our results indicated that celastrol dose-dependently reduced hippocampal and serum concentration of proinflammatory markers (TNF-α, IL-1β, and IL-6) and oxidative stress marker (MDA), whereas the anti-inflammatory marker IL-10 and antioxidant markers (GSH, SOD, and CAT) were increased significantly in celastrol treated tGCI/R rats. Celastrol alleviated apoptotic neuronal death, inhibited reactive glial activation and proliferation and improved ischemia-induced neurological deficits. Simultaneously, we found that mechanisms responsible for the neuroprotective effect of celastrol could be attributed to its anti-inflammatory and antioxidant actions via inhibiting HMGB1/NF-κB signaling pathway. These findings provide a proof of concept for the further validation that celastrol may be a superior candidate for the treatment of severe cerebral ischemic patients in clinical practice in the future.

Naringin attenuates cerebral ischemia-reperfusion injury in rats by inhibiting endoplasmic reticulum stress

“…For example, suppression of ERS-mediated neuronal apoptosis by Iridoid glycosides from Radix Scrophulariae was proved, thus reducing local CI/R injury in rats [ 24 ]. And downregulation of NF-κB signaling pathway by celastrol was confirmed to cause neuroprotection in ischemic rats [ 25 ]. For further clarification of the relationship between the neuroprotection by Nar and ERS, measurement of ERS-related proteins GRP78, CHOP, caspase-12, and ATF6 by western blot was conducted.…”

Lipidomic Profiling of Ipsilateral Brain and Plasma after Celastrol Post-Treatment in Transient Middle Cerebral Artery Occlusion Mice Model

“…Sulfatide was reported to induce neuronal apoptosis and increase NF-κB, p-JNK, and p-c-Jun in brain [ 41 ]. Intriguingly, celastrol and sulfatide had the opposite effect on the same targets in brain, as celastrol was found to suppress the ischemic stroke-induced upregulation of NF-κB, p-JNK, and p-c-Jun [ 15 , 17 ]. Since NF-κB and JNK pathways act as a key role in regulating ischemia-induced apoptosis [ 42 , 43 ], the relationship between celastrol, sulfatide, and apoptosis attracted our attention.…”

“…Since NF-κB and JNK pathways act as a key role in regulating ischemia-induced apoptosis [ 42 , 43 ], the relationship between celastrol, sulfatide, and apoptosis attracted our attention. Previous studies have proved that the protective effect of celastrol on ischemic stroke is related to its regulation of apoptotic responses via inhibiting NF-κB [ 17 ]. In this study, our results confirmed that celastrol was able to prevent ischemia-induced neuronal apoptosis and regulate sulfatide metabolism.…”

“…More recently, celastrol has been reported to ameliorate ischemic stroke-induced brain injury by promoting IL-33/ST2-mediated M2 microglial polarization [ 16 ]. Another study also demonstrated that celastrol could attenuate neuroinflammation, decrease neuronal apoptosis and oxidative stress through inhibiting HMGB1/NF-κB signaling pathway, thereby alleviating cerebral I/R injury in rats [ 17 ]. These results indicated that celastrol may become a promising therapeutic drug for the treatment of ischemic stroke.…”

Cannabidiol confers neuroprotection in rats in a model of transient global cerebral ischemia: impact of hippocampal synaptic neuroplasticity

“…The effects of TGCI on spatial memory performance have been well documented [29][30][31][32]. Studies from our group showed deleterious effects of TGCI on retrograde memory in rats in the AvRM up to 39 days after the ischemic insult [33][34][35].…”