Celastrol Treatment Ameliorated Acute Ischemic Stroke‐Induced Brain Injury by Microglial Injury Inhibition and Nrf2/HO‐1 Pathway Activations

Abstract

Background. Stroke is the third main reason of mortality, which is the leading reason for adult disability in the globe. Poststroke inflammation is well known to cause acute ischemic stroke- (AIS-) induced brain injury (BI) exacerbation. Celastrol (CL) has exhibited anti-inflammatory activities in various inflammatory traits though underlying mechanisms remain unknown. So, the present investigation is aimed at studying CL protective mechanism against AIS-induced BI. Methods. A mouse model regarding middle cerebral artery occlusion and an oxygen-glucose deprivation (OGD) cell model with or not CL treatment were constructed to study CL protective effects. NF-E2-related factor 2 (Nrf2) was then silenced in BV2 microglia cells (BV2) to study Nrf2 role regarding CL-mediated neuroprotection. Results. The results showed that CL treatment suppressed AIS-induced BI by inhibiting NLRP3/caspase-1 pathway activations and induction of apoptosis and pyroptosis in vivo and in vitro. NLRP3/caspase-1 pathway blocking activation suppressed OGD-induced cell pyroptosis and apoptosis. Also, CL treatment reversed OGD-induced microglial injury by promoting Nrf2/heme oxygenase-1 (HO-1) pathway activations. Nrf2 downregulation reversed CL protective effects against OGD-induced microglial injury, pyroptosis, and apoptosis. Conclusion. The findings advise that CL treatment ameliorated AIS-induced BI by inhibiting microglial injury and activating the Nrf2/HO-1 pathway.

Die hard: necroptosis and its impact on age-dependent neuroinflammatory diseases

“…Celastrol, a root extract from the Chinese herb Tripterygium wilfordii, has been shown to mediate several inflammatory diseases such as rheumatoid arthritis, osteoarthritis (Gao et al, 2020;Jing et al, 2021), and autoimmune hepatitis (Shi et al, 2022). It has also been shown to be neuroprotective in Parkinson's disease (Zhang et al, 2021), acute ischemic stroke-induced brain injury (Cao et al, 2023), and spinal cord injury models (Dai et al, 2019). Celastrol may act through inhibition of the NF-κB signaling pathway by reducing NF-κB protein levels, as demonstrated in cells treated with high concentrations of the extract (Liang et al, 2023).…”