Bakuchiol ameliorates cerebral ischemia-reperfusion injury by modulating NLRP3 inflammasome and Nrf2 signaling
Graphical abstract
Introduction
Ischemic stroke is a common destructive cerebrovascular disease and the second leading cause of death in the world (Fisher and Saver, 2015). During the process, numerous harmful cascades can be set off, including ionic imbalance, excessive oxidative stress and inflammation, each of which may result in cell death (Juan et al., 2012). To date, the most efficient treatment for cerebral ischemia is to restore blood circulation and nutrient resupply in the brain, but it may cause more severe cerebral dysfunction in clinical practice, which is also known as cerebral ischemia and reperfusion (I/R) injury (Molina and Saver, 2005). Currently, researchers have identified multiple neuroprotective agents, but they have failed to benefit reperfusion damage (Chamorro et al., 2016). Thus, it is imperative to find more effective neuroprotective drugs to prevent brain I/R injury.
Neuroinflammation is one of the critical mechanisms in ischemic stroke, characterized by activation of microglia and subsequent pro-inflammatory cytokine release (Xin et al., 2019). The multi-protein complexes inflammasomes play a central role in inflammatory reactions after I/R injury. The nucleotide-binding domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) is a key inflammasome, which is mainly composed of the Nod-like receptor protein NLRP3, the adaptor protein apoptosis-associated speck-like protein (ASC), and caspase-1 (Zhou et al., 2010). Ischemic stroke can drive the activation of NLRP3 that regulates caspase-1 activation to form mature precursor cytokines, including pro-inflammatory interleukin-1β (IL-1β) and IL-18, eventually leading to the extravasation of cellular contents and cell death (Mohamed et al., 2015). In addition, the activation of nuclear factor erythroid 2 like 2 (Nrf2) pathway is tightly associated with inflammation after ischemic stroke, and it can inhibit activated inflammasomes to attenuate ischemic inflammatory damage (Hou et al., 2018; Xu et al., 2018). Therefore, alleviation of neuroinflammation may protect the brain from I/R injury.
Bakuchiol (BAK), [(1E,3S)-3-ethenyl-3,7-dimethyl-1,6-octadien-1-yl]phenol, is mainly extracted from the seeds of psoralea corylifolia, a famous traditional Chinese medicine of leguminosae plant family (Lim et al., 2011). Previous studies have shown that BAK possesses antibacterial, anti-inflammatory, anti-cancer, anti-oxidative activities, and exerts remarkable protective roles in liver fibrosis, diabetes and neurodegenerative diseases (Chen et al., 2010; Choi et al., 2010; Ohno et al., 2010). BAK has been proven to reduce I/R-induced myocardial damage via inhibiting oxidative stress and cell apoptosis (Feng et al., 2016). Besides, BAK is an effective immunosuppressant that inhibits lipopolysaccharide (LPS)-stimulated inflammatory response in BV-2 microglia and plays an anti-neuroinflammatory role in neurodegenerative diseases (Kim et al., 2016; Lim et al., 2019). BAK has also been reported to participate in the activation of the Nrf2 signaling pathway (Shoji et al., 2015). However, the effects of BAK on cerebral I/R injury and the possible mechanisms remain obscure.
In the present study, we aimed to determine whether BAK could ameliorate the inflammatory response after I/R injury in vivo and in vitro and its potential molecular mechanisms.
Section snippets
Experimental animals
Male C57BL/6 mice (10–12 weeks) were purchased from Liaoning Changsheng Biotechnology Co. Ltd (license no. SCXK [Liao] 2015-0001). Mice were fed for at least one week to acclimatize with free access to food and water under a suitable environment (temperature 22℃ ± 1℃, humidity 45 %–55 %, 12 h/12 h light/dark cycle). All experimental procedures were according to the Guidelines for the Care and Use of Laboratory Animals and approved by the Ethics Committee of Anhui University of Chinese Medicine.
Experimental groups and treatments
BAK improves MCAO/R-induced cerebral injury
As depicted in Fig. 1A, in our in vivo experiments, the mice were administrated with L-BAK or H-BAK, followed by subjection to 1 h of MCAO and 24 h of reperfusion. At the end of experiments, the neurological deficit was evaluated based on the scoring standards by Longa et al. (Longa et al., 1989). Here, the neurological score of mice in Sham group was expressed as zero. Compared with Sham group, the mice in MCAO group scored higher, while BAK administration significantly decreased the score
Discussion
The present study elucidated the regulatory effect of BAK on inflammatory response induced by cerebral I/R in vivo and in vitro. BAK treatment significantly reduced neurological deficit, infarct size and cerebral edema in MCAO/R-injured mice, indicating the protective function of BAK in I/R injury, which is consistent with the previous study (Liu et al., 2020). Additionally, BAK treatment blocked microglia activation and inhibited the activation of NLRP3 inflammasome, thereby mitigating
Funding
None.
Availability of data and materials
The data generated or analyzed of this study are included in this present article.
Declaration of Competing Interest
None.
References (43)
- et al.
Nrf2 signaling pathway: pivotal roles in inflammation
Biochimica et biophysica acta. Mol. Basis Dis.
(2017) - et al.
Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation
Lancet Neurol.
(2016) - et al.
Anti-tumor effects of bakuchiol, an analogue of resveratrol, on human lung adenocarcinoma A549 cell line
Eur. J. Pharmacol.
(2010) - et al.
Pathogenesis of acute stroke and the role of inflammasomes
Ageing Res. Rev.
(2013) - et al.
Future directions of acute ischaemic stroke therapy
Lancet Neurol.
(2015) - et al.
Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury
Behav. Brain Res.
(2018) - et al.
Applications of the Keap1-Nrf2 system for gene and cell therapy
Free Radic. Biol. Med.
(2015) - et al.
Estrogenic activities of Psoralea corylifolia L. Seed extracts and main constituents
Phytomedicine
(2011) - et al.
The biphasic function of microglia in ischemic stroke
Prog. Neurobiol.
(2017) Heme oxygenase-1/carbon monoxide as modulators of autophagy and inflammation
Arch. Biochem. Biophys.
(2019)
Bakuchiol is a phenolic isoprenoid with novel enantiomer-selective anti-influenza a virus activity involving Nrf2 activation
J. Biol. Chem.
Bakuchiol: a newly discovered warrior against organ damage
Pharmacol. Res.
Extracellular histones in tissue injury and inflammation
J. Mol. Med. (Berlin, Germany)
Rational modulation of the innate immune system for neuroprotection in ischemic stroke
Front. Neurosci.
Acacetin protects against cerebral ischemia-reperfusion injury via the NLRP3 signaling pathway
Neural Regen. Res.
Mouse model of middle cerebral artery occlusion
J. Vis. Exp.
Isolation and anti-inflammatory activity of Bakuchiol from Ulmus davidiana var. Japonica
J. Med. Food
AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3
Proc. Natl. Acad. Sci. U. S. A.
Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke
Cell Death Dis.
Bakuchiol attenuates myocardial ischemia reperfusion injury by maintaining mitochondrial function: the role of silent information regulator 1
Apoptosis
NLRP3 inflammasome: a promising target in ischemic stroke
Inflamm. Res.
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