Abstract
AimGlycyrrhizin (GL) has been reported to protect against ischemia and reperfusion (I/R)-induced injury by inhibiting the cytokine activity of high mobility group box 1 (HMGB1). In the present study, the protective effects of GL against I/R injury, as well as the related molecular mechanisms, were investigated in rat brains.MethodsFocal cerebral I/R injury was induced by intraluminal filamentous occlusion of the middle cerebral artery (MCA) in Male Sprague-Dawley rats. GL alone or GL and rHMGB1 were administered intravenously at the time of reperfusion. Serum levels of HMGB1 and inflammatory mediators were quantified via enzyme-linked immunosorbent assay (ELISA). Histopathological examination, immunofluorescence, RT-PCR and western blotting analyses were performed to investigate the protective and anti-apoptotic effects and related molecular mechanisms of GL against I/R injury in rat brains.ResultsPre-treatment with GL significantly reduced infarct volume and improved the accompanying neurological deficits in locomotor function. The release of HMGB1 from the cerebral cortex into the serum was inhibited by GL administration. Moreover, pre-treatment with GL alleviated apoptotic injury resulting from cerebral I/R through the inhibition of cytochrome C release and caspase 3 activity. The expression levels of inflammation- and oxidative stress-related molecules including TNF-α, iNOS, IL-1β, and IL-6, which were over-expressed in I/R, were decreased by GL. P38 and P-JNK signalling were involved in this process. All of the protective effects of GL could be reversed by rHMGB1 administration.ConclusionsGL has a protective effect on ischemia-reperfusion injury in rat brains through the inhibition of inflammation, oxidative stress and apoptotic injury by antagonising the cytokine activity of HMGB1.
Highlights
Ischemic stroke remains one of the leading cause of death and disability worldwide
Recent insight into the basic mechanism involved in ischemic stroke indicates that endothelial dysfunctions along with oxidative stress and neuroinflammation represent key elements in the occurrence and development of ischemic brain damage that results in cell damage and death [1,2]
The aim of this study was to investigate the potential protective effect of GL, as well as the related mechanisms, against ischemia and reperfusion (I/R) injury in the rat brain, mainly in relation to the following aspects: (1) the neuroprotective effects of GL on focal cerebral ischemia; (2) the release of high mobility group box 1 (HMGB1) in rat serum and brain; (3) the effect of GL on the alleviation of apoptosis caused by I/R injury; (4) the expression of HMGB1-dependent inflammation- and oxidative stress-related molecules; (5) the involvement of certain Mitogen-activated protein kinases (MAPKs) pathways that are modulated by GL
Summary
Ischemic stroke remains one of the leading cause of death and disability worldwide. Within hours of the ischemic insult, infiltrating leukocytes, as well as resident brain cells including neurons and glia, may release pro-inflammatory mediators such as cytokines, chemokines, and oxygen/ nitrogen free radicals that contribute to the evolution of tissue damage [3]. The cerebral ischemia that occurs in brain cells affected by a stroke triggers a complex array of molecular and cellular alterations including the activation of signalling pathways that may either contribute to neuronal damage or protect neurons. Among the MAPK pathways known to be activated in neurons in response to ischemia are the JNK, ERK, and p38 MAPK pathways [4,5]
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