Inhibition of astrocytic activity alleviates sequela in acute stages of intracerebral hemorrhage

Chiu, Cheng-Di; Yao, Nai-Wei; Guo, Jeng-Hung; Shen, Chiung‐Chyi; Lee, Hsu‐Tung; Chiu, You-Pen; Ji, Hui-Ru; Chen, Xian Xiu; Chen, Chun-Chung; Chang, Chen

doi:10.18632/oncotarget.22022

Cited by 24 publications

(19 citation statements)

References 54 publications

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“…Blood-brain barrier disruption was most severe at 6 hours after collagenase injection, the earliest time point tested. This result is consistent with prior observations by Rosenberg et al using [ 14 C] sucrose efflux (Rosenberg et al, 1993), and Chiu et al using gadoliniumenhanced MRI (Chiu et al, 2017). Very early BBB injury is not a surprising consequence of the breakdown of collagen type IV, a key stabilizing component of the basement membrane (Baeten and Akassoglou, 2011).…”

Section: Discussionsupporting

confidence: 92%

Rapid loss of perihematomal cell viability in the collagenase intracerebral hemorrhage model

et al. 2019

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The effective time window of any therapeutic in an experimental stroke model is limited by the rate of injury progression. Intracerebral hemorrhage in rodents is commonly induced by striatal injection of either autologous blood or bacterial collagenase, which digests local blood vessels. During time window studies of the heme oxygenase-1 inducer hemin, which is protective when administered within 1-3 hours in both models, the rate of perihematomal injury was directly compared after striatal blood or collagenase injection. Surprisingly, about 80% of the loss of perihematomal cell viability as measured by MTT reduction assay occurred within 6 hours of collagenase injection. In contrast, significant viability loss was not observed at this time point after autologous blood injection, but rather it progressed over the subsequent four days to a level similar to that produced by collagenase. Consistent with these observations, systemic hemin therapy reduced blood-brain barrier disruption and perihematomal cell injury when initiated at 6 hours after striatal injection of blood but not collagenase. These results indicate that the rate of early cell injury differs markedly in the collagenase and blood injection ICH models, which may contribute to inconsistent results in time window studies. The blood injection model may be more appropriate for prolonged time window studies of a neuroprotective agent.

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Section: Discussionsupporting

confidence: 92%

Rapid loss of perihematomal cell viability in the collagenase intracerebral hemorrhage model

et al. 2019

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“…87 This particular detrimental mechanism may be involved in the cognitive impairment that is seen after ICH. Although we have evidence that suppression of astrocytic activity decreases hematoma volume, BBB destruction, and improves neurologic outcomes, 88 therapeutic targets as it relates to astrocytes have not been explored and warrant further investigation.…”

Section: Astrocytesmentioning

confidence: 99%

Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets

et al. 2020

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Spontaneous intracerebral hemorrhage (ICH) is a catastrophic illness causing significant morbidity and mortality. Despite advances in surgical technique addressing primary brain injury caused by ICH, little progress has been made treating the subsequent inflammatory cascade. Pre-clinical studies have made advancements identifying components of neuroinflammation, including microglia, astrocytes, and T lymphocytes. After cerebral insult, inflammation is initially driven by the M1 microglia, secreting cytokines (e.g., interleukin-1β [IL-1β] and tumor necrosis factor-α) that are involved in the breakdown of the extracellular matrix, cellular integrity, and the blood brain barrier. Additionally, inflammatory factors recruit and induce differentiation of A1 reactive astrocytes and T helper 1 (Th1) cells, which contribute to the secretion of inflammatory cytokines, augmenting M1 polarization and potentiating inflammation. Within 7 days of ICH ictus, the M1 phenotype coverts to a M2 phenotype, key for hematoma removal, tissue healing, and overall resolution of inflammation. The secretion of anti-inflammatory cytokines (e.g., IL-4, IL-10) can drive Th2 cell differentiation. M2 polarization is maintained by the secretion of additional anti-inflammatory cytokines by the Th2 cells, suppressing M1 and Th1 phenotypes. Elucidating the timing and trigger of the anti-inflammatory phenotype may be integral in improving clinical outcomes. A challenge in current translational research is the absence of an equivalent disease animal model mirroring the patient population and comorbid pathophysiologic state. We review existing data and describe potential therapeutic targets around which we are creating a bench to bedside translational research model that better reflects the pathophysiology of ICH patients.

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“…*p < 0.05, **p < 0.01, and ***p < 0.001, compared to controls at the same time points (ANOVA followed by Newman-Keuls test), n = 3-4. Data are shown as mean ± SD PKO mice show abnormal microglial activation at the recovery phase after ICH ICH induces reactive astrogliosis and microglial activation [65][66][67]. To determine if loss of mural cell-derived laminin affects these processes, reactive astrogliosis and microglial activation were examined by GFAP and Iba1 staining, respectively.…”

Section: Pko Mice Show Enhanced Inflammatory Cell Extravasation Aftermentioning

confidence: 99%

Loss of mural cell-derived laminin aggravates hemorrhagic brain injury

Gautam

Nirwane

et al. 2020

J Neuroinflammation

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Background: Mural cells synthesize and deposit laminin to the basement membrane. To investigate the function of mural cell-derived laminin, we generated a mutant mouse line lacking mural cell-derived laminin (termed PKO). In a previous study, we showed that the PKO mice were grossly normal under homeostatic condition, but developed blood-brain barrier (BBB) breakdown with advanced age (> 8 months), suggesting that these mutants are intrinsically weak. Based on these findings, we hypothesized that PKO mice have exacerbated injuries in pathological conditions. Methods: Using collagenase-induced intracerebral hemorrhage (ICH) as an injury model, we examined various stroke outcomes, including hematoma volume, neurological function, neuronal death, BBB integrity, paracellular/ transcellular transport, inflammatory cell infiltration, and brain water content, in PKO mice and their wildtype littermates at young age (6-8 weeks). In addition, transmission electron microscopy (TEM) analysis and an in vitro ICH model were used to investigate the underlying molecular mechanisms. Results: Compared to age-matched wildtype littermates, PKO mice display aggravated stroke outcomes, including larger hematoma size, worse neurological function, increased neuronal cell death, enhanced BBB permeability, increased transcytosis, and elevated inflammatory cell infiltration. These mutants also exhibit high baseline brain water content independent of aquaporin-4 (AQP4). In addition, mural cell-derived laminin significantly reduced caveolin-1 without affecting tight junction proteins in the in vitro ICH model. Conclusions: These results suggest that mural cell-derived laminin attenuates BBB damage in ICH via decreasing caveolin-1 and thus transcytosis, regulates brain water homeostasis, and plays a beneficial role in ICH.

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Inhibition of astrocytic activity alleviates sequela in acute stages of intracerebral hemorrhage

Cited by 24 publications

References 54 publications

Rapid loss of perihematomal cell viability in the collagenase intracerebral hemorrhage model

Rapid loss of perihematomal cell viability in the collagenase intracerebral hemorrhage model

Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets

Loss of mural cell-derived laminin aggravates hemorrhagic brain injury

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