Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARγ/Nrf2/NF-κB signaling pathway
Graphical abstract
Introduction
Ischemic stroke is one of the main causes of death and disability in developed countries [1]. Ischemic stroke occurs when blood supply to the brain becomes interrupted. Although cerebral ischemia causes high morbidity in the clinic, therapeutic options for acute ischemic stroke remain very limited, and few neuroprotective treatments have been successfully developed to prevent ischemic stroke.
Cerebral ischemia-reperfusion (I/R) injury after thrombolysis in stroke leads to the rapid death or apoptosis of neurons in ischemic penumbra. The process of neuronal injury after cerebral ischemia is very complicated, but an increasing number of studies has demonstrated that the inflammatory response plays an important role in the above process [2]. The increased production of inflammatory cytokines and proinflammatory mediators aggravates neurological injury and promotes apoptosis of neural cells following ischemia [3]. Therefore, preventing inflammation and apoptosis is a feasible strategy for ischemic stroke intervention.
Nuclear factor-kappa B (NF-κB) is a critical transcription factor that regulates inflammation and various autoimmune diseases [4]. Expression of a large number of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-lβ (IL-1β), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), can be regulated by the activation of NF-κB [5,6]. Studies suggest that NF-κB is activated in cerebral vascular endothelial cells, glial cells and neurons after cerebral ischemia, which triggers a dramatic increase in the expression of inflammatory cytokines, leading to an inflammatory cascade reaction and aggravating brain damage [7].
Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated nuclear transcription factor. PPARγ agonists have been reported to show anti-inflammatory and anti-oxidant effects in several models of central nervous system disorders, such as ischemic stroke, Alzheimer's disease and Parkinson's disease [8,9]. Several in vitro and in vivo studies demonstrate that PPARγ reduces proinflammatory cytokine release by inhibiting the nuclear transcription factor NF-κB [10,11].
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays an important role in the response to oxidative stress. In recent years, increasing evidence has shown that activation of the Nrf2 pathway significantly inhibits NF-κB and plays a protective role in the inflammatory response [12,13]. In brief, the interaction of Nrf2 and the NF-κB pathway plays an important role in the development of cerebral ischemia pathology and has become an important neuropathologic mechanism and therapeutic target.
Luteoloside (also called cynaroside or luteolin‑7‑O‑glucoside) is a flavonoid compound found in many plants and herbs. It has been reported that luteoloside has anti-oxidative, anti-inflammatory, antibacterial, antiviral, anticancer and other functions [[14], [15], [16], [17]]. For example, recent studies showed that luteoloside exerted cardioprotective effects in vitro [[18], [19], [20]]. However, there are few reports on the neuroprotective effects of luteoloside.
Therefore, this study was designed to evaluate the protective effects of luteoloside on cerebral I/R injury induced by middle cerebral artery embolism (MCAO) and to investigate whether the inflammatory response mediated by PPARγ/Nrf2/NF-kB signaling is implicated in this process.
Section snippets
Compounds and reagents
Luteoloside (purity > 98%) was obtained from Herbpurify Co., Ltd. (Chengdu, China). ToxinSensor™ Single Test Kit, GenScript Biotech Co., Ltd. (Nanjing, China). 2,3,5‑Triphenyltetrazolium chloride (TTC) was obtained from Solarbio Science & Technology Co., Ltd., (Beijing, China). TNF-α and IL-1β Enzyme-Linked Immunosorbent Assay (ELISA) kits were provided by Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Anti-IκBα, anti-p-IκBα, anti-p65, anti-p-p65, anti-PPARγ, anti-Nrf2 and lamin B
Luteoloside improved neural function and decreased damage and cerebral edema induced by MCAO in the rat brain
First, the effects of luteoloside on neural function in rats were evaluated by neurologic scores. There was no difference in the scores of the rats in the luteoloside group compared with those in the sham group (P > 0.05), and the scores of the MCAO rats were significantly increased (P ˂ 0.01). However, treatment with either luteoloside or nimodipine significantly decreased the scores compared with the MCAO-treatment group (Fig. 2A).
Next, the results showed that the administration of
Discussion
Cerebral ischemia remains the leading cause of morbidity and mortality worldwide, and no available drugs have been shown to be effective in clinical trials of ischemic stroke [1]. Therefore, the search for promising and safe neuroprotective agents is particularly urgent and important. Recently, many natural herbal extracts have attracted increasing attention because of their outstanding biological activities in many diseases. Luteoloside is a flavonoid compound that is widely found in plants
Acknowledgements
This research received specific grant from National Natural Science Foundation of China (31872311, 81273652, 81541072).
Conflict of interest
The authors declare that they have no competing interests.
References (41)
- et al.
Protective role of apigenin on rotenone induced rat model of Parkinson's disease: suppression of neuroinflammation and oxidative stress mediated apoptosis
Chem. Biol. Interact.
(2017) - et al.
Ampelopsin reduces endotoxic inflammation via repressing ROS-mediated activation of PI3K/Akt/NF-κB signaling pathways
Int. Immunopharmacol.
(2012) - et al.
Neuroinflammation and neuronal autophagic death were suppressed via rosiglitazone treatment: new evidence on neuroprotection in a rat model of global cerebral ischemia
J. Neurol. Sci.
(2015) - et al.
PPAR-α agonist fenofibrate protects against the damaging effects of MPTP in a rat model of Parkinson's disease
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2014) Ligands for the nuclear peroxisome proliferator-activated receptor gamma
Trends Pharmacol. Sci.
(2015)- et al.
PPARs and molecular mechanisms of transrepression
BBA-Mol. Cell Biol. L.
(2007) - et al.
Nrf2-keap1 system versus NF-κB: the good and the evil in chronic kidney disease?
Biochimie
(2012) - et al.
A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders
Mutat. Res. Fundam. Mol. Mech. Mutagen.
(2010) - et al.
Luteolin and luteolin‑7‑O‑glucoside strengthen antioxidative potential through the modulation of Nrf2/MAPK mediated HO-1 signaling cascade in RAW 264.7 cells
Food Chem. Toxicol.
(2014) - et al.
Luteoloside protects the uterus from Staphylococcus aureus - induced inflammation, apoptosis, and Injury
Inflammation
(2018)
Screening and identification of the antibacterial bioactive compounds from Lonicera japonica Thunb. leaves
Food Chem.
Probucol and atorvastatin in combination protect rat brains in MCAO model: upregulating peroxiredoxin2, Foxo3a and Nrf2 expression
Neurosci. Lett.
Bilobalide prevents ischemia-induced edema formation in vitro and in vivo
Neuroscience
Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage
Neurochem. Int.
Luteoloside protects the uterus from Staphylococcus aureus - induced inflammation, apoptosis, and injury
Inflammation
Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-κB signal transduction pathways in rats with ulcerative colitis
Int. Immunopharmacol.
Short communication: pheromonicin-SA affects mRNA expression of toll-like receptors, cytokines, and lactoferrin by Staphylococcus aureus-infected bovine mammary epithelial cells
J. Dairy Sci.
PPARgamma as a therapeutic target in central nervous system diseases
Neurochem. Int.
PPARγ ligands reduce inflammation and infarction size in transient focal ischemia
Neuroscience
Corrigendum to “Dieckol enhances the expression of antioxidant and detoxifying enzymes by the activation of Nrf2–MAPK signaling pathway in HepG2 cells”
Food Chem.
Cited by (90)
Cynaroside improved depressive-like behavior in CUMS mice by suppressing microglial inflammation and ferroptosis
2024, Biomedicine and PharmacotherapyPPAR agonists for the treatment of neuroinflammatory diseases
2024, Trends in Pharmacological SciencesA novel vanadium complex VO(p-dmada) inhibits neuroinflammation induced by lipopolysaccharide
2023, Chinese Chemical Letters
- 1
The first two authors equally contributed to this work.