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.
Highlights
Ischemic stroke can lead to extensive cerebral damage to gray matter and white matter and is a significant cause of morbidity and mortality in the world
At 22 h reperfusion after ischemia, the neurological score in the vehicletreated group increased to 3.2760.19, attributable to the brain injury induced by ischemia/reperfusion, whereas intravenous administration of an equimolar dose of KRS (10.0 mg/kg) or kaempferol-3-O- glucoside (KGS) (7.5 mg/kg) at the beginning of reperfusion significantly reduced the neurological scores to 1.8960.20 and 2.0060.14, respectively, compared with the vehicle-treated group (p,0.01)
We studied the effects of intravenous injection of KRS or KGS on neuroinflammation and brain injury in transient middle cerebral artery occlusion (tMCAO) rats
Summary
Ischemic stroke can lead to extensive cerebral damage to gray matter and white matter and is a significant cause of morbidity and mortality in the world. Aberrantly activated signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kB (NF-kB) can promote the transcription and expression of many genes that encode proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and inflammatory enzymes [5]. These proinflammatory mediators damage neurons and affect gliocytes, axons, and capillaries, thereby initiating secondary brain damage after ischemic stroke [6]. Transcription factors nuclear factor-kB (NF-kB) and signal transducer and activator of transcription 3 (STAT3) contribute to ischemic neuroinflammatory processes and secondary brain injury by releasing proinflammatory mediators. We explored the effects of KRS and KGS in a transient focal stroke model
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