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      Protective Effects of Chlorogenic Acid on Cerebral Ischemia/Reperfusion Injury Rats by Regulating Oxidative Stress-Related Nrf2 Pathway

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          Cerebral ischemia-reperfusion (CI/R) injury is caused by blood flow recovery after ischemic stroke. Chlorogenic acid (CGA, 5-O-caffeoylquinic acid) is a major polyphenol component of Coffea canephora, Coffea arabica L. and Mate ( Ilex paraguariensis A. StHil.). Previous studies have shown that CGA has a significant neuroprotective effect and can improve global CI/R injury. However, the underlying molecular mechanism of CGA in CI/R injury has not been fully revealed.


          In this study, CI/R rat model was constructed. The rats were randomly divided into nine groups with ten in each group: Control, CGA (500 mg·kg-1), CI/R, CI/R + CGA (20 mg·kg-1), CI/R + CGA (100 mg·kg-1), CI/R + CGA (500 mg·kg-1), ML385 (30 mg·kg-1), CI/R + ML385 (30 mg·kg-1), CI/R + CGA + ML385. Cerebral infarction volume was detected by TTC staining. Brain pathological damage was detected by H&E staining. Apoptosis of cortical cells was detected by TUNEL staining. The expression of related proteins was detected by RT-qPCR and Western blotting.


          Step-down test and Y maze test showed that CGA dose-dependently mitigated CI/R-induced brain damage and enhanced learning and spatial memory. Besides, CGA promoted the expression of BDNF and NGF in a dose-dependent manner and alleviated CI/R-induced nerve injury. Moreover, CGA increased the activity of SOD and the level of GSH, as well as decreased production of ROS and LDH and the accumulation of MDA. Notably, CGA attenuated oxidative stress-induced brain injury and apoptosis and inhibited the expression of apoptosis-related proteins (cleaved caspase 3 and caspase 9). Additionally, CGA reversed CI/R induced inactivation of Nrf2 pathway and promoted Nrf2, NQO-1 and HO-1 expression. Nrf2 pathway inhibitor ML385 destroyed this promotion.


          All the data indicated that CGA had a neuroprotective effect on the CI/R rats by regulating oxidative stress-related Nrf2 pathway.

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          Most cited references 31

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          Current Mechanistic Concepts in Ischemia and Reperfusion Injury.

          Ischemia-reperfusion injury is associated with serious clinical manifestations, including myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. Ischemia-reperfusion injury is a critical medical condition that poses an important therapeutic challenge for physicians. In this review article, we present recent advances focusing on the basic pathophysiology of ischemia-reperfusion injury, especially the involvement of reactive oxygen species and cell death pathways. The involvement of the NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system are also described. When the blood supply is re-established after prolonged ischemia, local inflammation and ROS production increase, leading to secondary injury. Cell damage induced by prolonged ischemia-reperfusion injury may lead to apoptosis, autophagy, necrosis, and necroptosis. We highlight the latest mechanistic insights into reperfusion-injury-induced cell death via these different processes. The interlinked signaling pathways of cell death could offer new targets for therapeutic approaches. Treatment approaches for ischemia-reperfusion injury are also reviewed. We believe that understanding the pathophysiology ischemia-reperfusion injury will enable the development of novel treatment interventions.
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            Stroke injury, cognitive impairment and vascular dementia☆

            The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25–30% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood–brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
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              Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice.

              Recent studies have shown that Toll-like receptors (TLRs) are involved in cerebral ischemia/reperfusion (I/R) injury. This study was to investigate the role of TLR2 and TLR4 in acute focal cerebral I/R injury. Cerebral infarct size, neurological function and mortality were evaluated. NFsmall ka, CyrillicB binding activity, phosphorylation of Ismall ka, CyrillicBalpha, Akt and ERK1/2 were examined in ischemic cerebral tissue by EMSA and Western blots. Compared to wild type (WT) mice, in TLR4 knockout (TLR4KO) mice, brain infarct size was decreased (2.6+/-1.18% vs 11.6+/-1.97% of whole cerebral volume, p<0.05) and neurological function was maintained (7.3+/-0.79 vs 4.7+/-0.68, p<0.05). However, compared to TLR4KO mice, TLR2 knockout (TLR2KO) mice showed higher mortality (38.2% vs 13.0%, p<0.05), decreased neurological function (2.9+/-0.53 vs 7.3+/-0.79, p<0.05) and increased brain infarct size (19.1+/-1.33% vs 2.6+/-1.18%, p<0.05). NFsmall ka, CyrillicB activation and Ismall ka, CyrillicBalpha phosphorylation were attenuated in TLR4KO mice (1.09+/-0.02 and 1.2+/-0.04) compared to TLR2KO mice (1.31+/-0.02 and 2.2+/-0.32) after cerebral ischemia. Compared to TLR4KO mice, in TLR2KO mice, the phosphorylation of Akt (0.2+/-0.03 vs 0.9+/-0.16, p<0.05) and ERK1/2 (0.8+/-0.06 vs 1.3+/-0.17) evoked by cerebral I/R was attenuated. The present study demonstrates that TLR2 and TLR4 play differential roles in acute cerebral I/R injury. Specifically, TLR4 contributes to cerebral I/R injury, while TLR2 appears to be neuroprotective by enhancing the activation of protective signaling in response to cerebral I/R.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                07 January 2020
                : 14
                : 51-60
                [1 ]Department of Neurology, Luoyang Central Hospital Affiliated to Zhengzhou University , Luoyang, Henan 471000, People’s Republic of China
                [2 ]Department of Ultrasound, The Affiliated Children's Hospital of Xi’an Jiaotong University , Xi’an, Shaanxi, 710003, People’s Republic of China
                Author notes
                Correspondence: Zhan Zhang The Affiliated Children's Hospital of Xi’an Jiaotong University , No. 69, Xijuyuan Lane, Lianhu District, Xi’an City, Shaanxi Province710003, People’s Republic of ChinaTel +86-29-13991941239 Email o9al8i37sz3r@sina.com
                © 2020 Liu et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, References: 42, Pages: 10
                This study is supported by the Project of Luoyang Science and Technology Bureau (1603002A-9).
                Original Research


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