Inflammatory mechanisms in ischemic stroke: therapeutic approaches

Lakhan, Shaheen E; Kirchgessner, Annette L.; Hofer, Magdalena

doi:10.1186/1479-5876-7-97

Cited by 948 publications

(725 citation statements)

References 77 publications

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“…Microglial cells, which expresses LRP1, are resident macrophages within the CNS that become activated in pathological situations, including cerebral ischemia 58. Microglial activation results in oxidative stress and the release of inflammatory mediators, contributing to BBB breakdown, secondary neuronal injury, and development of cerebral edema 59. There is evidence that apoE‐mimetic peptides reduce these inflammatory responses in microglial cells, via LRP1, through the c‐Jun N‐terminal kinases (JNKs) pathway 60, 61.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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ObjectiveAt present, the absence of a pharmacological neuroprotectant represents an important unmet clinical need in the treatment of ischemic and traumatic brain injury. Recent evidence suggests that administration of apolipoprotein E mimetic therapies represent a viable therapeutic strategy in this setting. We investigate the neuroprotective and anti‐inflammatory properties of the apolipoprotein E mimetic pentapeptide, CN‐105, in a microglial cell line and murine model of ischemic stroke.MethodsTen to 13‐week‐old male C57/BL6 mice underwent transient middle cerebral artery occlusion and were randomly selected to receive CN‐105 (0.1 mg/kg) in 100 μL volume or vehicle via tail vein injection at various time points. Survival, motor‐sensory functional outcomes using rotarod test and 4‐limb wire hanging test, infarct volume assessment using 2,3,5‐Triphenyltetrazolium chloride staining method, and microglial activation in the contralateral hippocampus using F4/80 immunostaining were assessed at various time points. In vitro assessment of tumor necrosis factor‐alpha secretion in a microglial cell line was performed, and phosphoproteomic analysis conducted to explore early mechanistic pathways of CN‐105 in ischemic stroke.ResultsMice receiving CN‐105 demonstrated improved survival, improved functional outcomes, reduced infarct volume, and reduced microglial activation. CN‐105 also suppressed inflammatory cytokines secretion in microglial cells in vitro. Phosphoproteomic signals suggest that CN‐105 reduces proinflammatory pathways and lower oxidative stress.Interpretation CN‐105 improves functional and histological outcomes in a murine model of ischemic stroke via modulation of neuroinflammatory pathways. Recent clinical trial of this compound has demonstrated favorable pharmacokinetic and safety profile, suggesting that CN‐105 represents an attractive candidate for clinical translation.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Kolls

Soderblom

et al. 2017

Ann Clin Transl Neurol

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“…Nonsteroidal anti-inflammatory drugs effectively improved NDD outcome in preclinical and clinical trials [17,18] . Therefore, blockade of the microglial activationinduced inflammatory response may have important therapeutic potential for the treatment of NDD and stroke, which are associated with excessive microglial activation [19,20] .…”

Section: Discussionmentioning

confidence: 99%

Z-ligustilide attenuates lipopolysaccharide-induced proinflammatory response via inhibiting NF-κB pathway in primary rat microglia

Wang

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the anti-inflammatory effect of Z-ligustilide (LIG) on lipopolysaccharide (LPS)-activated primary rat microglia. Methods: Microglia were pretreated with LIG 1 h prior to stimulation with LPS (1 µg/mL). After 24 h, cell viability was tested with MTT, nitric oxide (NO) production was assayed with Griess reagent, and the content of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein (MCP-1) was measured with ELISA. Protein expression of the nuclear factor-κB (NF-κB) p65 subunit, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) was detected with immunocytochemistry 1 h or 24 h after LPS treatment. Results: LIG showed a concentration-dependent anti-inflammatory effect in LPS-activated microglia, without causing cytotoxicity. Pretreatment with LIG at 2.5, 5, 10, and 20 µmol/L decreased LPS-induced NO production to 75.9%, 54.4%, 43.1%, and 47.6% (P<0.05 or P<0.01), TNF-α content to 86.2%, 68.3%, 40.1%, and 39.9% (P<0.01, with the exception of 86.2% for 2.5 µmol/L LIG), IL-1β content to 31.5%, 27.7%, 0.6%, and 0% (P<0.01), and MCP-1 content to 84.4%, 50.3%, 45.1%, and 42.2% (P<0.05 or P<0.01), respectively, compared with LPS treatment alone. LIG (10 µmol/L) significantly inhibited LPS-stimulated immunoreactivity of activated NF-κB, COX-2, and iNOS (P<0.01 vs LPS group). Conclusion: LIG exerted a potent anti-inflammatory effect on microglia through inhibition of NF-κB pathway. The data provide direct evidence of the neuroprotective effects of LIG and the potential application of LIG for the treatment of the neuroinflammatory diseases characterized by excessive microglial activation.

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“…33,35 Thus, several inflammatory signaling cascades are a target of translational research for stroke. 54 Astrocytes participate in the immune response in various ways, including release of cytokines and chemokines. 55 In addition, signaling between astrocytes and microglia has important consequences for neuronal viability (see also the articles by Yenari, Kauppinen, and Swanson, by Loane and Byrnes, and by Lull and Block, in this issue).…”

Section: Astrocytes Edema and Volume Regulation In Strokementioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

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Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

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Inflammatory mechanisms in ischemic stroke: therapeutic approaches

Cited by 948 publications

References 77 publications

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

Z-ligustilide attenuates lipopolysaccharide-induced proinflammatory response via inhibiting NF-κB pathway in primary rat microglia

Targeting Astrocytes for Stroke Therapy

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