Sodium butyrate protects against focal cerebral ischemic injury through the regulation of the nuclear receptor Nur77
Graphical abstract
The proposed mechanism of sodium butyrate-mediated protection against focal cerebral ischemic injury via the Nur77/NLRP3 pathway.
Introduction
Although focal cerebral ischemia is the leading cause of mortality and disability, effective treatments for this condition are yet to be developed [1]. Focal cerebral ischemia is a cerebrovascular disease caused by the sudden blockage of blood vessels and the loss of blood supply to specific brain regions. Due to the lack of blood supply, different degrees of ischemic injury occur around the infarcted tissue, leading to a high mortality rate and long-term neurological deficits [2]. The major contributors to the pathophysiology of cerebral ischemia are inflammatory responses to acute cerebral hypoxia–ischemia [3,4]. During the progression of cerebral ischemia, inflammatory cascades mediate the release of inflammatory factors and activate various inflammatory response pathways, which further induce neurological injuries [5]. Although cerebral ischemia can be effectively treated by thrombolytic therapy, this method is not ideal because the time window to administer thrombolytic therapy is narrow. Therefore, studies have focused on improving treatments for focal cerebral ischemia and reducing patient mortality [6].
The inhibition of neuronal pathways triggered by inflammatory responses has been proposed as a potential therapeutic option for patients with cerebral ischemia [7]. Pyrin domain-containing 3 (NLRP3) inflammasome, a NOD-like receptor family, is a tissue-damage sensor involved in the conversion of the pro-form of interleukin-1β (IL-1β) during neural inflammatory responses [8]. During the progression of cerebral ischemia, microglial NLRP3 inflammasomes are rapidly activated in an early stage; over time, they mainly accumulate in neurons [9]. Downstream products of NLRP3 originating from neurons, such as IL-1β and IL-18, can bind to their receptors on neurons, microglia, and endothelial cells; consequently, neuroinflammation and neuronal and glial cell death are exacerbated, thereby aggravating ischemic injury [10,11]. Thus, neuronal NLRP3 is a potential novel therapeutic target for ischemic injury.
Nuclear receptors negatively regulate neuronal NLRP3 inflammasomes under ischemic conditions. As such, nuclear receptors are promising targets for the treatment of cerebral ischemia [12,13]. Additionally, the nuclear receptor subfamily 4 group A1 (NR4A1 or Nur77) is a member of the orphan nuclear receptor family involved in neuronal apoptosis, differentiation, and inflammation [14,15]. Nur77 is protective against neuronal damage induced by oxygen and glucose deprivation (OGD) through the suppression of neuronal apoptosis [16]. The overexpression of Nur77 inhibits the production of pro-inflammatory mediators, such as IL-1β, inducible nitric oxide, and cyclooxygenase-2; it also protects against inflammation-mediated dopaminergic neuronal injury [17,18]. In cerebral ischemic rats, treatment with a Nur77 agonist ameliorates neuroinflammation and ischemic injury by regulating the Nur77/IL-10-related inflammation response signaling pathway [19]. Therefore, a potential regulatory link may exist between Nur77 and inflammasome pathways in cerebral ischemia-induced neuronal inflammation.
Sodium butyrate, a short-chain fatty acid produced by the gut microbiota, is an important neuromodulator in the central nervous system. Post-insult treatment with sodium butyrate significantly reduces infarct volume and improves neurological deficits in model rats with middle cerebral artery occlusion (MCAO) [20,21]. Sodium butyrate prevents cognitive dysfunction by modulating inflammatory responses and neurotrophic factor expression [22]. For instance, the administration of sodium butyrate in ischemic rats significantly suppresses the inflammatory cytokines, such as IL-1β and IL-18, in ischemic hemispheres [23]. Sodium butyrate can also facilitate apoptosis and inflammatory pathways mediated by G protein-coupled receptor 41 (GPR41) in OGD-induced neuronal injury [24]. Furthermore, the long-term administration of sodium butyrate modulates gut microbiota composition and lipopolysaccharide-related low-grade chronic inflammation [25]. Therefore, sodium butyrate plays a beneficial role in supporting bodily functions and promoting health. However, the protective effect and anti-neuroinflammatory mechanisms of sodium butyrate-mediated defense against cerebral ischemia have not been reported.
In this study, rats with MCAO were pretreated with sodium butyrate to explore its protective effect against cerebral ischemia. The effect of sodium butyrate on the neuronal NLRP3 signaling pathway mediated by Nur77 was investigated using an in vitro cell model of OGD-induced neuronal injury.
Section snippets
Rat middle cerebral artery occlusion model
Specific pathogen-free Wistar rats with a body weight of 250–280 g were purchased from Changchun Yisi Experimental Animal Technology Co., Ltd. They were housed in standard cages under controlled environmental conditions (25°C and a 12 h/12 h light/dark cycle) and given free access to standard pellet diet and water. The rats were randomly divided into three groups: the control (CON) group (n = 15), the MCAO group (n = 15), and the MCAO + 300 mg/kg NaBu group (n = 15). Sodium butyrate was
Protective effect of sodium butyrate on focal cerebral ischemia in rats
Sodium butyrate was administered to rats for seven consecutive days before MCAO to investigate its preventive effects on cerebral ischemia-related pathologies. The degree of MCAO-induced brain injury was analyzed by determining the cerebral infarction volume and neurological score. The infarct volume detected via TTC staining is shown in Fig. 1A and 1B. The infarct volume in the MCAO group (24.95% ± 3.999%) significantly increased compared with that in the CON group (p < 0.001). However, the
DISCUSSION
Focal cerebral ischemia is a cerebrovascular disease caused by the sudden blockage of blood vessels and the loss of blood supply to specific brain regions. The pathophysiology of cerebral ischemia possibly involves inflammation as a key step that has been identified as a potential therapeutic target [26,27]. An important neuromodulator, sodium butyrate, has shown neuroprotective effects on cerebral ischemia by improving mitochondrial respiration and acting as an antioxidant and
Author contributions
Lihui Men: Conceptualization, Data curation; Tongtong Song: Writing- Original draft preparation; Xi Wang: Methodology; Wenting Hui: Methodology; Wenjing Du and Yiwen Gu: Software; Siwei Zhang: Data curation; Xia Chen: Conceptualization, Supervision.
Funding
This study was supported by the Jilin Province Development and Reform Commission (Grant number 2016C023).
Declaration of Competing Interest
The authors declare no conflicts of interest.
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