Paradigm Shift to Neuroimmunomodulation for Translational Neuroprotection in Stroke

Amantea, Diana; Greco, Rosaria; Micieli, Giuseppe; Bagetta, Giacinto

doi:10.3389/fnins.2018.00241

Cited by 19 publications

(18 citation statements)

References 112 publications

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“…Morphological changes, occurring during the activation of microglia and astrocytes, or higher proliferation of NG2 glia, microglia and astrocytes are all hallmarks of ischemia (Davalos et al, 2005;Pforte et al, 2005;Burns et al, 2009;Anderova et al, 2011). Another set of pathogenic events, the aforementioned ischemic pathway (Figure 1), takes place in the nervous tissue affected by ischemia (Amantea et al, 2018). Such a series of biochemical processes is a typical consequence of cardiac arrest or stroke.…”

Section: Ischemic Pathwaymentioning

confidence: 99%

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Kirdajová

Kriška

Tureckova

et al. 2020

Front. Cell. Neurosci.

279

150

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A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is a prominent cause of death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose and oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion and ionic imbalance, followed by cell membrane depolarization, calcium (Ca 2+ ) overload, and extracellular accumulation of excitatory amino acid glutamate. If tight physiological regulation fails to clear the surplus of this neurotransmitter, subsequent prolonged activation of glutamate receptors forms a vicious circle between elevated concentrations of intracellular Ca 2+ ions and aberrant glutamate release, aggravating the effect of this ischemic pathway. The activation of downstream Ca 2+ -dependent enzymes has a catastrophic impact on nervous tissue leading to cell death, accompanied by the formation of free radicals, edema, and inflammation. After decades of "neuron-centric" approaches, recent research has also finally shed some light on the role of glial cells in neurological diseases. It is becoming more and more evident that neurons and glia depend on each other. Neuronal cells, astrocytes, microglia, NG2 glia, and oligodendrocytes all have their roles in what is known as glutamate excitotoxicity. However, who is the main contributor to the ischemic pathway, and who is the unsuspecting victim? In this review article, we summarize the so-far-revealed roles of cells in the central nervous system, with particular attention to glial cells in ischemiainduced glutamate excitotoxicity, its origins, and consequences.

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Section: Ischemic Pathwaymentioning

confidence: 99%

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Kirdajová

Kriška

Tureckova

et al. 2020

Front. Cell. Neurosci.

279

150

View full text Add to dashboard Cite

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“…Cerebral ischaemia ignites a complex, destructive cascade (Figure ) (Amantea, Greco, Micieli, & Bagetta, ; Davis & Pennypacker, ). Interruption of substrate and O 2 delivery stifles ATP production, causing Gibbs free energy of ATP hydrolysis (Δ G ATP ), the thermodynamic driving force for electrolyte transport and other critical cellular processes, to collapse.…”

Section: Adaptation To Intermittent Hypoxia: Robust Cerebroprotectionmentioning

confidence: 99%

“…In contrast, M2 microglia produce anti‐inflammatory cytokines, VEGF, BDNF, platelet‐derived growth factor and progranulin, which collectively suppress inflammation and promote axonal outgrowth, angiogenesis, oligodendrogenesis and remyelination (Hanisch & Kettenmann, ; Kanazawa et al., ; Lo, ). M2 microglia are the more numerous during the first 2 days after stroke; later, M1 microglia predominate (Amantea et al., ). Preventing this M2‐to‐M1 phenotypic shift may promote recovery from stroke (Wang et al., ).…”

Section: Adaptation To Intermittent Hypoxia: Robust Cerebroprotectionmentioning

confidence: 99%

“…Cerebral ischaemia ignites a complex, destructive cascade ( Figure 1) (Amantea, Greco, Micieli, & Bagetta, 2018;Davis & Pennypacker, 2017 Damaged neurons release purine nucleotides that provoke microglia to release inflammatory cytokines, drawing macrophages to the lesion (Iadecola & Anrather, 2011). These mechanisms culminate in death of brain parenchyma.…”

Section: Injury Mechanisms and Treatment Challenges Of Strokementioning

confidence: 99%

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Ischaemic and hypoxic conditioning: potential for protection of vital organs

Sprick

Mallet

Przyklenk

et al. 2019

Experimental Physiology

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New Findings What is the topic of this review?Remote ischaemic preconditioning (RIPC) and hypoxic preconditioning as novel therapeutic approaches for cardiac and neuroprotection. What advances does it highlight?There is improved understanding of mechanisms and signalling pathways associated with ischaemic and hypoxic preconditioning, and potential pitfalls with application of these therapies to clinical trials have been identified. Novel adaptations of preconditioning paradigms have also been developed, including intermittent hypoxia training, RIPC training and RIPC–exercise, extending their utility to chronic settings. Abstract Myocardial infarction and stroke remain leading causes of death worldwide, despite extensive resources directed towards developing effective treatments. In this Symposium Report we highlight the potential applications of intermittent ischaemic and hypoxic conditioning protocols to combat the deleterious consequences of heart and brain ischaemia. Insights into mechanisms underlying the protective effects of intermittent hypoxia training are discussed, including the activation of hypoxia‐inducible factor‐1 and Nrf2 transcription factors, synthesis of antioxidant and ATP‐generating enzymes, and a shift in microglia from pro‐ to anti‐inflammatory phenotypes. Although there is little argument regarding the efficacy of remote ischaemic preconditioning (RIPC) in pre‐clinical models, this strategy has not consistently translated into the clinical arena. This lack of translation may be related to the patient populations targeted thus far, and the anaesthetic regimen used in two of the major RIPC clinical trials. Additionally, we do not fully understand the mechanism through which RIPC protects the vital organs, and co‐morbidities (e.g. hypercholesterolemia, diabetes) may interfere with its efficacy. Finally, novel adaptations have been made to extend RIPC to more chronic settings. One adaptation is RIPC–exercise (RIPC‐X), an innovative paradigm that applies cyclical RIPC to blood flow restriction exercise (BFRE). Recent findings suggest that this novel exercise modality attenuates the exaggerated haemodynamic responses that may limit the use of conventional BFRE in some clinical settings. Collectively, intermittent ischaemic and hypoxic conditioning paradigms remain an exciting frontier for the protection against ischaemic injuries.

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“…Recent studies have suggested that Toll-like receptor (TLR)-mediated innate immune and inflammatory responses contribute to cerebral I/R injury [4,5]. TLR-mediated signaling pathways predominately activate NF-κB, which is a critical transcription factor that regulates the expression of genes involved in innate and inflammatory responses [6]. Consequently, TLRs may be important targets for the development of new treatment approaches for cerebral I/R injury [7].…”

Section: Introductionmentioning

confidence: 99%

Poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling

Wang

Zhong

et al. 2020

Preprint

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Objective: Toll-like receptor (TLR) activation plays an important role in cerebral ischemia-reperfusion injury. In addition, increasing evidence suggests that TLRs may affect cognitive behavior through TLR-mediated signaling. Here, we explored the protective effects of TLR3 on cognitive dysfunction after ischemia in the context of poly(I:C) preconditioning.Materials and Methods : Mice (n=84) were randomly divided into the sham group, AAV (vector) group, middle cerebral artery occlusion (MCAO) model group, poly(I:C) (pre) + MCAO model group, and AAV (TRAF6) + poly(I:C) (pre) + MCAO model group. The mice were injected i.p. with poly(I:C) (1.25 mg/g) 24 h prior to cerebral ischemia. Then, neurological scores were assessed, and the infarct volume was measured after cerebral ischemia-reperfusion. We evaluated the poly(I:C) preconditioning-induced attenuation of neuronal damage using Nissl and TUNEL staining. We assessed the poly(I:C) preconditioning-mediated inhibition of I/R-induced glial activation, inflammatory factor levels and TRAF6 expression. We also assessed whether TRAF6 affects poly(I:C) preconditioning to improve cognitive dysfunction and neuroprotection.Results: The results showed that compared with those of the sham group and AAV (vector) group, the functional neurological scores and focal infarct volume of the MCAO group and poly(I:C) preconditioning group were significantly increased. The results also showed that compared with those of the MCAO group, the functional neurological scores and focal infarct volume of the poly(I:C) preconditioning group were significantly reduced. Our results indicated that poly(I:C) preconditioning significantly attenuated neuronal apoptosis and cell loss. Poly(I:C) preconditioning also inhibited I/R-induced glial cell activation and reduced NF-κB, TNF-α and IL-β levels. Our findings showed that poly(I:C) preconditioning affected cognitive dysfunction following cerebral I/R. Here, we observed that poly(I:C) preconditioning affected the expression and distribution of TRAF6 following cerebral I/R. TRAF6 overexpression abolished poly(I:C)-induced neuroprotection and worsened cognitive dysfunction in cerebral I/R injury.Significance: Our findings suggested that poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling, which is a potential therapeutic target for the treatment of cognitive dysfunction after stroke.

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Paradigm Shift to Neuroimmunomodulation for Translational Neuroprotection in Stroke

Cited by 19 publications

References 112 publications

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Ischaemic and hypoxic conditioning: potential for protection of vital organs

Poly(I:C) preconditioning ameliorates cognitive dysfunction after cerebral I/R injury by inhibiting TRAF6 signaling

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