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Stroke is the leading cause of death and disability worldwide, and ischemic stroke accounts for more than 85% of the stroke incidence. Tissue plasminogen activator (t-PA) is the only FDA-approved drug for ischemic stroke treatment with a narrow treatment time window of 4.5 h. Hemorrhagic transformation (HT) is a severe complication of delayed t-PA...
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... Our studies indicate that ONOO-can be a promising therapeutic target for reducing ischemic brain injury and hemorrhagic transformation [40,69,70]. ...
Oxidative/nitrosative stress and neuroinflammation are critical pathological processes in cerebral ischemia-reperfusion injury, and their intimate interactions mediate neuronal damage, blood-brain barrier (BBB) damage and hemorrhagic transformation (HT) during ischemic stroke. We review current progress towards understanding the interactions of oxidative/nitrosative stress and inflammatory responses in ischemic brain injury. The interactions between reactive oxygen species (ROS)/reactive nitrogen species (RNS) and innate immune receptors such as TLR2/4, NOD-like receptor, RAGE, and scavenger receptors are crucial pathological mechanisms that amplify brain damage during cerebral ischemic brain injury. Furthermore, we review the current progress of omics and systematic biology approaches for studying complex network regulations related to oxidative/nitrosative stress and inflammation in the pathology of ischemic stroke. Targeting oxidative/nitrosative stress and neuroinflammation could be a promising therapeutic strategy for ischemic stroke treatment.
We then review recent advances in discovering compounds from medicinal herbs with the bioactivities of simultaneously regulating oxidative/nitrosative stress and pro-inflammatory molecules for minimizing ischemic brain injury. These compounds include sesamin, baicalin, salvianolic acid A, 6-paradol, silymarin, apocynin, 3H-1,2-Dithiole-3-thione, (−)-epicatechin, rutin, Dl-3-N-butylphthalide, and naringin. We finally summarize recent developments of the omics and systematic biology approaches for exploring the molecular mechanisms and active compounds of Traditional Chinese Medicine (TCM) formulae with the properties of antioxidant and anti-inflammation for neuroprotection. The comprehensive omics and systematic biology approaches provide powerful tools for exploring therapeutic principles of TCM formulae and developing precision medicine for stroke treatment.
... The blood-brain barrier (BBB) disruption plays a critical role in the process of HT during thrombolytic treatment for ischemic stroke [7-9]. The BBB disruption and HT can be mediated by many pathological factors including free radicals, matrix metalloproteinases (MMPs), lowdensity lipoprotein receptor-related protein 1 (LRP-1), platelet-derived growth factor CC (PDGF-CC), high mobility group box 1 protein (HMGB1), and so forth [10][11][12]. Free radicals, especially reactive nitrogen species (RNS), play critical roles in MMP activation, BBB disruption, brain damages and HT in ischemic stroke in rodent ischemic stroke models and clinical studies [10,[12][13][14][15]. For examples, excessive nitric oxide (NO) production could downregulate caveolin-1, induce MMP activity, and trigger BBB dysfunction in cerebral ischemiareperfusion injury [16,17]. ...
... The BBB disruption and HT can be mediated by many pathological factors including free radicals, matrix metalloproteinases (MMPs), lowdensity lipoprotein receptor-related protein 1 (LRP-1), platelet-derived growth factor CC (PDGF-CC), high mobility group box 1 protein (HMGB1), and so forth [10][11][12]. Free radicals, especially reactive nitrogen species (RNS), play critical roles in MMP activation, BBB disruption, brain damages and HT in ischemic stroke in rodent ischemic stroke models and clinical studies [10,[12][13][14][15]. For examples, excessive nitric oxide (NO) production could downregulate caveolin-1, induce MMP activity, and trigger BBB dysfunction in cerebral ischemiareperfusion injury [16,17]. ...
Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0.5 h and followed by 19-h reperfusion. Baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24 h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation.
... RNS activate MMPs during ischemic brain injury [82] . Peroxynitrite was co-localized with MMP-9 in brain microvessels of the area showing Evans blue leakage, suggesting that ONOOmay induce MMP-9 activation and contribute to BBB disruption [32] . ...
... In addition, other compounds, such as resveratrol, curcumin, apocynin, caffeic acid, and tanshinone IIA, have been noted as good candidates for inhibiting RNS-mediated brain damage in cerebral ischemia-reperfusion injury or ischemic brain injury. We have reviewed their values as potential therapeutic agents in our previous articles [28,82,158] . The details have been discussed before and should not be repeated here. ...
Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO−), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.
... It is helpful to evaluate the efficacy of a drug with an objective recording instrument, such as an actigraph [11,12] , to establish quantitative parameters from body activity recordings for neurological deficits or use advanced testing technology to assess limb blood flow, etc. These methods refer to the combination of branches of medicine in the methodology, and this approach is also called GIM [13] . ...
Myeloperoxidase is an important inflammatory factor in the myeloid system, primarily expressed in neutrophils and microglia. Myeloperoxidase and its active products participate in the occurrence and development of hemorrhagic and ischemic stroke, including damage to the blood-brain barrier and brain. As a specific inflammatory marker, myeloperoxidase can be used in the evaluation of vascular disease occurrence and development in stroke, and a large amount of experimental and clinical data has indicated that the inhibition or lack of myeloperoxidase has positive impacts on stroke prognosis. Many studies have also shown that there is a correlation between the overexpression of myeloperoxidase and the risk of stroke. The occurrence of stroke not only refers to the first occurrence but also includes recurrence. Therefore, myeloperoxidase is significant for the clinical evaluation and prognosis of stroke. This paper reviews the potential role played by myeloperoxidase in the development of vascular injury and secondary brain injury after stroke and explores the effects of inhibiting myeloperoxidase on stroke prognosis. This paper also analyzes the significance of myeloperoxidase etiology in the occurrence and development of stroke and discusses whether myeloperoxidase can be used as a target for the treatment and prediction of stroke.
Hemorrhagic transformation (HT) is a common and serious complication following ischemic stroke, especially after tissue plasminogen activator (t-PA) thrombolysis, which is associated with increased mortality and disability. Due to the unknown mechanisms and targets of HT, there are no effective therapeutic drugs to decrease the incidence of HT. In recent years, many studies have found that neuroinflammation is closely related to the occurrence and development of HT after t-PA thrombolysis, including glial cell activation in the brain, peripheral inflammatory cell infiltration and the release of inflammatory factors, involving inflammation-related targets such as NF-κB, MAPK, HMGB1, TLR4 and NLRP3. Some drugs with anti-inflammatory activity have been shown to protect the BBB and reduce the risk of HT in preclinical experiments and clinical trials, including minocycline, fingolimod, tacrolimus, statins and some natural products. In addition, the changes in MMP-9, VAP-1, NLR, sICAM-1 and other inflammatory factors are closely related to the occurrence of HT, which may be potential biomarkers for the diagnosis and prognosis of HT. In this review, we summarize the potential inflammation-related mechanisms, targets, therapeutic drugs, and biomarkers associated with HT after t-PA thrombolysis and discuss the relationship between neuroinflammation and HT, which provides a reference for research on the mechanisms, prevention and treatment drugs, diagnosis and prognosis of HT.
Oxidative stress and inflammation are two critical pathological processes of cerebral ischemia-reperfusion injury. Myeloperoxidase (MPO) is a critical inflammatory enzyme and therapeutic target triggering both oxidative stress and neuroinflammation in the pathological process of cerebral ischemia-reperfusion injury. MPO is presented in infiltrated neutrophils, activated microglial cells, neurons, and astrocytes in the ischemic brain. Activation of MPO can catalyze the reaction of chloride and H2O2 to produce HOCl. MPO also mediates oxidative stress by promoting the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), modulating the polarization and inflammation-related signaling pathways in microglia and neutrophils. MPO can be a therapeutic target for attenuating oxidative damage and neuroinflammation in ischemic stroke. Targeting MPO with inhibitors or gene deficiency significantly reduced brain infarction and improved neurological outcomes. This article discusses the important roles of MPO in mediating oxidative stress and neuroinflammation during cerebral ischemia-reperfusion injury and reviews the current understanding of the underlying mechanisms. Furthermore, we summarize the active compounds from medicinal herbs with potential as MPO inhibitors for anti-oxidative stress and anti-inflammation to attenuate cerebral ischemia-reperfusion injury, and as adjunct therapeutic agents for extending the window of thrombolytic treatment. We highlight that targeting MPO could be a promising strategy for alleviating ischemic brain injury, which merits further translational study.
Tissue plasminogen activator (t-PA) remains to be the only FDA-approved drug for ischaemic stroke, but it has a restrictive therapeutic window with 4.5 hours. Beyond the golden time window, thrombolytic treatment carries the risk of haemorrhagic transformation (HT). The blood-brain barrier (BBB) disruption is a critical step in the t-PA-mediated HT. Although large efforts are made to explore the mechanisms of the BBB disruption and HT, the underlying mechanisms are largely unknown. Thrombolytic treatment for recanalization could produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) and mediate cerebral ischaemia-reperfusion injury. RNS, including nitric oxide (NO) and peroxynitrite (ONOO-), are important players in cerebral ischaemia-reperfusion injury. In particular, ONOO- and its derivatives could mediate neurovascular unit damages and induce the BBB disruption and HT possibly through interacting with different cellular signalling pathways including matrix metalloproteinase (MMPs), high mobility group Box 1 (HMGB1), toll-like receptor2/4, poly(ADP-ribose) polymerase, Src, ROCK, and GSK-3β. Herein, we review current progress about the roles of ONOO- in mediating those signalling pathways and their impacts on the t-PA-induced BBB disruption and HT. Subsequently, we discuss the values of natural compounds with the properties of scavenging ONOO- as adjunctive therapies to extend the therapeutic window of t-PA and attenuate haemorrhage transformation in ischaemic stroke.
