Abstract
Early brain injury (EBI) is involved in the process of cerebral tissue damage caused by subarachnoid hemorrhage (SAH), and multiple mechanisms, such as apoptosis and inflammation, participate in its development. Mangiferin (MF), a natural C-glucoside xanthone, has been reported to exert beneficial effects against several types of organ injury by influencing various biological progresses. The current study aimed to investigate the potential of MF to protect against EBI following SAH via histological and biological assessments. A rat perforation model of SAH was established, and MF was subsequently administered via intraperitoneal injection at a low and a high dose. High-dose MF significantly lowered the mortality of SAH animals and ameliorated their neurological deficits and brain edema. MF also dose-relatedly attenuated SAH-induced oxidative stress and decreased cortical cell apoptosis by influencing mitochondria-apoptotic proteins. In addition, MF downregulated the activation of the NLRP3 inflammasome and NF-κB as well as the production of inflammatory cytokines, and the expression of Nrf2 and HO-1 was upregulated by MF. The abovementioned findings indicate that MF is neuroprotective against EBI after SAH and Nrf2/HO-1 cascade may play a key role in mediating its effect through regulation of the mitochondrial apoptosis pathway and activation of the NLRP3 inflammasome and NF-κB.
Highlights
Subarachnoid hemorrhage (SAH), a severe subtype of stroke, brings high morbidity and mortality to patients suffering from ruptured aneurysms and other cerebrovascular emergencies[1,2]
None of the rats in the Sham group died, and there was no significant difference between the subarachnoid hemorrhage (SAH) and Vehicle groups (Fig. 1B)
A series of pathophysiological changes occur during the period of Early brain injury (EBI), such as raised intracerebral pressure, reduced cerebral blood flow (CBF), blood-brain barrier (BBB) disruption, brain swelling/edema, acute vasospasm and dysfunction of autoregulation[3]
Summary
Subarachnoid hemorrhage (SAH), a severe subtype of stroke, brings high morbidity and mortality to patients suffering from ruptured aneurysms and other cerebrovascular emergencies[1,2]. Multiple pathophysiological mechanisms have been identified as being involved in the development of EBI secondary to SAH, including oxidative stress, neural cell apoptosis, and neuroinflammation[3,7]. It has been reported to influence the activation or expression of several signal cascades, such as NF-κB, Nrf2/HO-1, mitochondria-dependent pathways, and the NLRP3 inflammasome, and to target multiple cytokines and antioxidant enzymes, such as interleukin (IL)-6, tumor necrosis factor (TNF), superoxide dismutase (SOD), and catalase (CAT)[10,11,12,17,19,20,21]. In terms of the central nervous system, Yang et al demonstrated that MF effectively attenuated ischemic brain injury by regulating the release of inflammatory cytokines and upregulating the activity of endogenous antioxidant enzymes and the expression of the Nrf2/HO-1 signaling cascade[22]. Given the abovementioned pharmacological and biological properties, we hypothesized a possible benefit of MF against EBI after SAH, and we were the first to explore in detail the biological mechanisms of its effect via an experimental rat SAH model
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