Neuroprotective Effect of Kaempferol Glycosides against Brain Injury and Neuroinflammation by Inhibiting the Activation of NF-κB and STAT3 in Transient Focal Stroke

Abstract

BackgroundIschemic brain injury is associated with neuroinflammatory response, which essentially involves glial activation and neutrophil infiltration. Transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) contribute to ischemic neuroinflammatory processes and secondary brain injury by releasing proinflammatory mediators. Kaempferol-3-O-rutinoside (KRS) and kaempferol-3-O- glucoside (KGS) are primary flavonoids found in Carthamus tinctorius L. Recent studies demonstrated that KRS protected against ischemic brain injury. However, little is known about the underlying mechanisms. Flavonoids have been reported to have antiinflammatory properties. Herein, we explored the effects of KRS and KGS in a transient focal stroke model.Methodology/Principal FindingsRats were subjected to middle cerebral artery occlusion for 2 hours followed by 22 h reperfusion. An equimolar dose of KRS or KGS was administered i.v. at the beginning of reperfusion. The results showed that KRS or KGS significantly attenuated the neurological deficits, brain infarct volume, and neuron and axon injury, reflected by the upregulation of neuronal nuclear antigen-positive neurons and downregulation of amyloid precursor protein immunoreactivity in the ipsilateral ischemic hemisphere. Moreover, KRS and KGS inhibited the expression of OX-42, glial fibrillary acidic protein, phosphorylated STAT3 and NF-κB p65, and the nuclear content of NF-κB p65. Subsequently, these flavonoids inhibited the expression of tumor necrosis factor α, interleukin 1β, intercellular adhesion molecule 1, matrix metallopeptidase 9, inducible nitric oxide synthase, and myeloperoxidase.Conclusion/SignificanceOur findings suggest that postischemic treatment with KRS or KGS prevents ischemic brain injury and neuroinflammation by inhibition of STAT3 and NF-κB activation and has the therapeutic potential for the neuroinflammation-related diseases, such as ischemic stroke.

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

“…STATs are a family of transcription factors involved in many cellular activities [32]. It has been reported that STAT3 activation was found in numerous cell types in the brain including neurons, astrocytes, microglia, endothelial cells, monocytes and macrophages, involving in neuronal development, neuroprotection, and regeneration after ischemic injury [33,34,35]. Perez-Pinzon et al have demonstrated phosphorylation and nuclear translocation of STAT3 in response to preconditioning by OGD in mixed cortical-glial co-cultures [36].…”

Neuroinflammatory processes in cognitive disorders: Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

“…In experimental rat models, naringenin (50 mg/kg ip for 21 days) (Raza et al, 2013) or kaempferol glycosides from Carthamus tinctorius L. (7.5 or 10 mg/kg i.v. acute) showed a beneficial impact on neuroinflammation by inhibiting STAT3 and NF-κB after ischemic brain injury in rat (Yu et al, 2013).…”

“…In high fat fed C57Bl/6 mice supplemented with luteolin (10mg/kg) for 16 weeks, spatial memory was improved along with a decreased expression of inflammatory markers TNF-α, IL-1β, IL-6 and NF-kB, oxidative stress and neuronal insulin resistance, and an increased production of BDNF and synaptic proteins . Accordingly, kaempferol-3-O-rutinoside (10 mg/kg) and kaempferol-3-Oglucoside (7.5 mg/kg) significantly inhibited the level of IL-1β, iNOS, ICAM-1 and the metallopeptidase 9 (MMP-9) in ischemic brain-injured rats (Yu et al, 2013). Furthermore, oral administration of scuttelarin (5 or 20 mg/kg), a flavone extracted from Erigeron breviscapus, decreased the hypertension-induced expression of NF-κB, TNF-α, IL-1β and IL-18 in the cortex and the striatum of rat.…”

Polyphenols and brain health

“…For example, fisetin (0.05%, 6 months) reduced the protein expression of inflammatory markers in huAPPswe/PS1DE9 transgenic mice in an ERK-p25-mediated pathway without affecting the mRNA expression of NF-kB1 (Currais et al, 2014). Similarly, kaempferol-3-O-rutinoside (10 mg/kg) and kaempferol-3-O-glucoside (7.5 mg/kg) reduced the neuroinflammatory response by inhibiting signal transducer and activator of transcription 3 (STAT3) and NF-kB following an ischemic brain injury in rats (Yu et al, 2013). In addition, intervention trial with an anthocyanin extract from blueberries (300 mg/d for 3 weeks) significantly reduced the plasma concentration of NF-kB-related proinflammatory cytokines and chemokines (IL-4, IL-13, IL-8 and IFN-a) in a group of 120 men and women aged 40-74 years (Karlsen et al, 2007).…”