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 pro-inflammatory 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.
Highlights
Stroke, known as cerebrovascular accident is a major health problem worldwide (Villa et al, 2018), it is usually classified as ischemic, due to lack of blood flow, or hemorrhagic, due to bleeding (Koh and Park, 2017)
Neurological score was improved in celastrol treated transient global cerebral ischemia reperfusion (tGCI/R) rats with the most obvious improvement effect in 4 mg/kg group, the neurological scores were fairly stable in all groups during the 7-days after 4-VO
We demonstrated that plant-derived celastrol treatment after tGCI/R could partially inhibit glial activation and proliferation, attenuate neuroinflammation, mitigate oxidative stress, rescue hippocampal apoptotic neuronal death and improve neurological outcome and survivals
Summary
Known as cerebrovascular accident is a major health problem worldwide (Villa et al, 2018), it is usually classified as ischemic, due to lack of blood flow, or hemorrhagic, due to bleeding (Koh and Park, 2017). Transient global cerebral ischemia (GCI) may occur in a multitude of clinical settings including cardiac arrest (Frisch et al, 2017), severe hypotension and shock (Block, 1999; Wen et al, 2018), craniocerebral trauma (Veenith et al, 2016) and serious cerebrovascular accident (Johnston et al, 2019). Thrombolytic therapy can reduce the neurological deficits caused by ischemic stroke, but there is a risk of bleeding after thrombolytic recanalization and further aggravating brain damage (Koh and Park, 2017). Neuroinflammation and oxidative stress play important roles in the pathogenesis of cerebral ischemia, numerous studies suggested that anti-inflammatory and/or anti-oxidant agents could alleviate brain damage and improve neurological outcome in stroke models (Peng et al, 2015; Chen T. et al, 2017). Neuroinflammation inhibition and free radical ablation for prevention of post-ischemic brain injury is proposed to be useful in clinical settings
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