Celastrol protects against early brain injury after subarachnoid hemorrhage in rats through alleviating blood-brain barrier disruption and blocking necroptosis

Abstract

Background: Subarachnoid hemorrhage (SAH) is a life-threatening disease worldwide, and effective pharmaceutical treatment is still lacking. Celastrol is a plant-derived triterpene which showed neuroprotective potential in several types of brain insults. This study aimed to investigate the effects of celastrol on early brain injury (EBI) after SAH. Methods: A total of sixty-one male Sprague-Dawley rats were used in this study. Rat SAH endovascular perforation model was established to mimic the pathological changes of EBI after SAH. Multiple methods such as 3.0T MRI scanning, immunohistochemistry, western blotting and propidium iodide (PI) labeling were used to explore the therapeutic effects of celastrol on SAH. Results: Celastrol treatment attenuated SAH-caused brain swelling, reduced T2 lesion volume and ventricular volume in MRI scanning, and improved overall neurological score. Albumin leakage and the degradation of tight junction proteins were also ameliorated after celastrol administration. Celastrol protected blood-brain bairrer integrity through inhibiting MMP-9 expression and anti-neuroinflammatory effects. Additionally, necroptosisrelated proteins RIP3 and MLKL were down-regulated and PI-positive cells in the basal cortex were less in the celastrol-treated SAH group than that in untreated SAH group. Conclusions: Celastrol exhibits neuroprotective effects on EBI after SAH and deserves to be further investigated as an add-on pharmaceutical therapy.

Neuroprotective Effects of Celastrol in Neurodegenerative Diseases-Unscramble Its Major Mechanisms of Action and Targets

“…These effects were related to celastrol induced activation of MAPKs and PI3K/Akt/mTOR pathways [ 30 ]. Celastrol ameliorated tight junction protein disruption after rat subarachnoid hemorrhage (SAH) to protect BBB integrity by decreasing MMP-9 expression and attenuating pro-inflammatory cytokines expression [ 31 ]. Celastrol is a BBB-penetrable compound, which may lay a foundation for maintaining the integrity of BBB and treating CNS disorders [ 32 ].…”

“…Celastrol significant attenuated I/R-induced hippocampal injury by inhibiting the AK005401/MAP3K12 signaling and activating the PI3K/Akt pathway [ 71 ]. In addition, celastrol attenuated brain swelling and protected the barrier function of BBB in the SAH rats [ 31 ]. Overall, celastrol shows obvious neuroprotective roles in a variety of stroke models, and how to promote its clinical transformation is the focus of next research.…”

Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage

“… Chen et al (2019a) reported that anti-TNF-α treatment can significantly improve endothelial cell necroptosis and blood-brain barrier damage and further improve nerve function after stroke. In a SAH experimental study, celastrol administration decreased the expression levels of necroptosis-related proteins RIPK3 and MLKL, which exhibited neuroprotective effects on EBI ( Xu et al, 2021 ). Similarly, necrostatin-1, a small-molecule inhibitor of necroptosis, can potentially prevent SAH-induced necroptosis by suppressing the activity of the RIPK3/MLKL signaling pathway ( Chen et al, 2019b ).…”

Celastrol: A Promising Agent Fighting against Cardiovascular Diseases

“…Additionally, celastrol was shown to protect against early brain injury (EBI) after subarachnoid haemorrhage (SAH) [ 92 ]. In the rat SAH endovascular perforation model, celastrol improves neurological function, reduces brain swelling caused by SAH, and T2 lesion volume and ventricular volume.…”