Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies.
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ABSTRACT:
SUBMITTER: Jurcau A
PROVIDER: S-EPMC8744548 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION: Restoration of blood flow following ischemic stroke can be achieved by means of thrombolysis or mechanical recanalization. However, for some patients, reperfusion may exacerbate the injury initially caused by ischemia, producing a so-called "cerebral reperfusion injury". Multiple pathological processes are involved in this injury, including leukocyte infiltration, platelet and complement activation, postischemic hyperperfusion, and breakdown of the blood-brain barrier. METHODS/RESULTS AND CONCLUSIONS: Magnetic resonance imaging (MRI) can provide extensive information on this process of injury, and may have a role in the future in stratifying patients' risk for reperfusion injury following recanalization. Moreover, different MRI modalities can be used to investigate the various mechanisms of reperfusion injury. Antileukocyte antibodies, brain cooling and conditioned blood reperfusion are potential therapeutic strategies for lessening or eliminating reperfusion injury, and interventionalists may play a role in the future in using some of these therapies in combination with thrombolysis or embolectomy. The present review summarizes the mechanisms of reperfusion injury and focuses on the way each of those mechanisms can be evaluated by different MRI modalities. The potential therapeutic strategies are also discussed.
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Project description:Neuroinflammation is one of the major causes of damage of the central nervous system (CNS) and plays a vital role in the pathogenesis of cerebral ischemia, which can result in long-term disability and neuronal death. Danhong injection (DHI), a traditional Chinese medicine injection, has been applied to the clinical treatment of cerebral stoke for many years. In this study, we investigated the protective effects of DHI on cerebral ischemia-reperfusion injury (CIRI) in rats and explored its potential anti-neuroinflammatory properties. CIRI in adult male SD rats was induced by middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. Results showed that DHI (0.5, 1, and 2 ml/kg) dose-dependently improved the neurological deficits and alleviated cerebral infarct volume and histopathological damage of the cerebral cortex caused by CIRI. Moreover, DHI (0.5, 1, and 2 ml/kg) inhibited the mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), intercellular cell adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in ischemic brains, downregulated TNF-α, IL-1β, and monocyte chemotactic protein-1 (MCP-1) levels in serum, and reduced the neutrophil infiltration (myeloperoxidase, MPO) in ischemic brains, in a dose-dependent manner. Immunohistochemical staining results also revealed that DHI dose-dependently diminished the protein expressions of ICAM-1 and COX-2, and suppressed the activation of microglia (ionized calcium-binding adapter molecule 1, Iba-1) and astrocyte (glial fibrillary acidic protein, GFAP) in the cerebral cortex. Western blot analysis showed that DHI significantly downregulated the phosphorylation levels of the proteins in nuclear factor κB (NF-κB) and mitogen-activated protein kinas (MAPK) signaling pathways in ischemic brains. These results indicate that DHI exerts anti-neuroinflammatory effects against CIRI, which contribute to the amelioration of CNS damage.
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Project description:Excessive and unresolved neuroinflammation is a key component of the pathological cascade in brain injuries such as ischemic stroke. Tripartite motif-containing 45 (TRIM45) is a ubiquitin E3 ligase involved in various critical biological processes. However, the role of TRIM45 in cerebral ischemia remains unknown. Here, we found that the TRIM45 protein was highly expressed in the peri-infarct areas of mice subjected to cerebral ischemia and reperfusion injury induced by middle cerebral artery occlusion. This study systemically evaluated the putative role of TRIM45 in the regulation of neuroinflammation during ischemic injury and the potential underlying mechanisms. We found that TRIM45 knockdown significantly decreased proinflammatory cytokine and chemokine production in primary cultured microglia challenged with oxygen-glucose deprivation and reoxygenation (OGD/R) treatment. Mechanistically, we demonstrated that TRIM45 constitutively interacted with TAB2 and consequently facilitated the Lys-63-linked polyubiquitination of TAB2, leading to the formation of the TAB1-TAK1-TAB2 complex and activation of TAK1, which was ultimately followed by activation of the nuclear factor-kappa B (NF-κB) signaling pathway. In an in vitro coculture Transwell system, downregulation of TRIM45 expression also inhibited the OGD/R-induced activation of microglia and alleviated neuronal apoptosis. More importantly, microglia-specific knockdown of TRIM45 in mice significantly reduced the infarct size, mitigated neurological deficit scores, and improved cognitive function after ischemic stroke. Taken together, our study reveals that the TRIM45-TAB2 axis is a crucial checkpoint that controls NF-κB signaling in microglia during cerebral ischemia and reperfusion injury. Therefore, targeting TRIM45 may be an attractive therapeutic strategy.
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Project description:Mitochondrial dynamics is a possible modulator of myocardial ischemia/reperfusion injuries (IRI). We previously reported that mice partially deficient in the fusion protein OPA1 exhibited higher IRI. Therefore, we investigated whether deficiency in the fission protein DRP1 encoded by Dnm1l gene would affect IRI in Dnm1l+/- mouse. After baseline characterization of the Dnm1l+/- mice heart, using echocardiography, electron microscopy, and oxygraphy, 3-month-old Dnm1l+/- and wild type (WT) mice were exposed to myocardial ischemia/reperfusion (I/R). The ischemic area-at-risk (AAR) and area of necrosis (AN) were delimited, and the infarct size was expressed by AN/AAR. Proteins involved in mitochondrial dynamics and autophagy were analyzed before and after I/R. Mitochondrial permeability transition pore (mPTP) opening sensitivity was assessed after I/R. Heart weight and left ventricular function were not significantly different in 3-, 6- and 12-month-old Dnm1l+/- mice than in WT. The cardiac DRP1 protein expression levels were 60% lower, whereas mitochondrial area and lipid degradation were significantly higher in Dnm1l+/- mice than in WT, though mitochondrial respiratory parameters and mPTP opening did not significantly differ. Following I/R, the infarct size was significantly smaller in Dnm1l+/- mice than in WT (34.6±3.1% vs. 44.5±3.3%, respectively; p<0.05) and the autophagic markers, LC3 II and P62 were significantly increased compared to baseline condition in Dnm1l+/- mice only. Altogether, data indicates that increasing fusion by means of Dnm1l deficiency was associated with protection against IRI, without alteration in cardiac or mitochondrial functions at basal conditions. This protection mechanism due to DRP1 haploinsufficiency increases the expression of autophagic markers.
| S-EPMC7993837 | biostudies-literature
Project description:Neuroinflammation mediated by activation of microglia and interruption of the blood-brain barrier (BBB) is an important factor that contributes to neuron death and infarct area diffusion in ischemia reperfusion injury. Finding novel molecules to regulate neuroinflammation is of significant clinical value. We have previously shown that adjudin, a small molecule compound known to possess antispermatogenic function, attenuates microglia activation by suppression of the NF-?B pathway. In this study we continued to explore whether adjudin could be neuroprotective by using the transient middle cerebral artery occlusion (tMCAO) model. Adjudin treatment after reperfusion significantly decreased the infarction volume and neuroscore compared to the vehicle group. Staining of CD11b showed that adjudin markedly inhibited microglial activation in both the cortex and the striatum, accompanied by a reduction in the expression and release of cytokines TNF-?, IL-1? and IL-6. Concomitantly, adjudin noticeably prevented BBB disruption after ischemia and reperfusion, as indicated by the reduction of IgG detection in the brain cortex and striatum versus the vehicle group. This finding was also corroborated by immunofluorescence staining and immunoblotting of tight junction-related proteins ZO-1, JAM-A and Occludin, where the reduction of these proteins could be attenuated by adjudin treatment. Moreover, adjudin obviously inhibited the elevated MMP-9 activity after stroke. Together these data demonstrate that adjudin protects against cerebral ischemia reperfusion injury, and we present an effective neuroinflammation modulator with clinical potential.
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Project description:Ischemic stroke accounts for nearly 80% of stroke cases. Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply, but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury, which are mediated by free radicals. As an important component of free radicals, reactive nitrogen species (RNS), including nitric oxide (NO) and peroxynitrite (ONOO(-)), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOO(-)) in ischemic brain, which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage. There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage. Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury. Herein, we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONOO(-) to treat ischemic stroke. We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemia-reperfusion injury.
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Project description:Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality amongst civilians and military personnel globally. Despite advances in our knowledge of the complex pathophysiology of TBI, the underlying mechanisms are yet to be fully elucidated. While initial brain insult involves acute and irreversible primary damage to the parenchyma, the ensuing secondary brain injuries often progress slowly over months to years, hence providing a window for therapeutic interventions. To date, hallmark events during delayed secondary CNS damage include Wallerian degeneration of axons, mitochondrial dysfunction, excitotoxicity, oxidative stress and apoptotic cell death of neurons and glia. Extensive research has been directed to the identification of druggable targets associated with these processes. Furthermore, tremendous effort has been put forth to improve the bioavailability of therapeutics to CNS by devising strategies for efficient, specific and controlled delivery of bioactive agents to cellular targets. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by an update on novel therapeutic targets and agents. Recent development of various approaches of drug delivery to the CNS is also discussed.
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Project description:Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular-pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.
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Project description:Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.
| S-EPMC8584561 | biostudies-literature
Project description:Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and a potent inflammatory stimulus for the innate immune response via toll-like receptor (TLR) 4 activation. Type 2 diabetes is associated with changes in gut microbiota and impaired intestinal barrier functions, leading to translocation of microbiota-derived LPS into the circulatory system, a condition referred to as metabolic endotoxemia. We investigated the effects of metabolic endotoxemia after experimental stroke with transient middle cerebral artery occlusion (MCAO) in a murine model of type 2 diabetes (db/db) and phenotypically normal littermates (db/+). Compared to db/+ mice, db/db mice exhibited an altered gut microbial composition, increased intestinal permeability, and higher plasma LPS levels. In addition, db/db mice presented increased infarct volumes and higher expression levels of LPS, TLR4, and inflammatory cytokines in the ischemic brain, as well as more severe neurological impairments and reduced survival rates after MCAO. Oral administration of a non-absorbable antibiotic modulated the gut microbiota and improved metabolic endotoxemia and stroke outcomes in db/db mice; these effects were associated with reduction of LPS levels and neuroinflammation in the ischemic brain. These data suggest that targeting metabolic endotoxemia may be a novel potential therapeutic strategy to improve stroke outcomes.
| S-EPMC7820690 | biostudies-literature