Author:
Hu Yingying,Nan Yan,Lin Hongzhou,Zhao Qianlei,Chen Tingting,Tao Xiaoyue,Ding Bingqing,Lu Liying,Chen Shangqin,Zhu Jianghu,Guo Xiaoling,Lin Zhenlang
Abstract
Abstract
Background
Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear.
Methods
Here, we established both in vitro and in vivo models of HI brain damage using CoCl2-treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models.
Results
Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA.
Conclusions
We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE.
Impact
We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries.
Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.
Publisher
Springer Science and Business Media LLC
Reference58 articles.
1. Kurinczuk, J. J., White-Koning, M. & Badawi, N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum. Dev. 86, 329–338 (2010).
2. Lawn, J., Shibuya, K. & Stein, C. No cry at birth: global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths. Bull. World Health Organ 83, 409–417 (2005).
3. Montaldo, P., Pauliah, S. S., Lally, P. J., Olson, L. & Thayyil, S. Cooling in a low-resource environment: lost in translation. Semin. Fetal Neonatal Med. 20, 72–79 (2015).
4. Adstamongkonkul, D. & Hess, D. C. Ischemic conditioning and neonatal hypoxic ischemic encephalopathy: a literature review. Cond. Med. 1, 9–16 (2017).
5. Greco, P. et al. Pathophysiology of hypoxic-ischemic encephalopathy: a review of the past and a view on the future. Acta Neurol. Belg. 120, 277–288 (2020).