Browsing by Author "Chang, Fen-Lei"

Now showing 1 - 5 of 5
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    Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge
    (BioMed Central, 2018-03-29) Paraiso, Hallel C.; Kuo, Ping-Chang; Curfman, Eric T.; Moon, Haley J.; Sweazey, Robert D.; Yen, Jui-Hung; Chang, Fen-Lei; Yu, I-Chen; Biology, School of Science
    BACKGROUND: Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer's disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation. METHODS: Primary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2 -/- ) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2 -/- mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF. RESULTS: DMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2 -/- mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation. CONCLUSIONS: DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.
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    Impact of Gabapentin and Pregabalin on Neurological Outcome After Ischemic Stroke
    (2023-04-28) Weber, Michael; Morton, Caleb; Chang, Fen-Lei
    Background: The purpose of this study is to determine whether patients taking either gabapentin or pregabalin at the time of their stroke injury tend to have better outcomes than patients with similar injuries who were not taking one of the two medications. Prior studies have shown potential neuro-protective effects of these two medications. Methods: A retrospective chart review of 115 ischemic stroke patients from 2016-2021 were assessed for patient outcomes using two tools, the NIH Stroke Scale (NIHSS) and the modified Rankin Scale (mRS), in addition to their hospital length of stay. The outcomes of patients taking either gabapentin or pregabalin with stroke diagnoses are compared to patients with stroke diagnoses who were not taking either medication. Kruskal-Wallis and X2 were used for statistical analysis. Results: There was a significantly larger proportion of gabapentin patients that improved compared to patients in the control group when using the mRS tool for patient outcomes (X2; p=0.015). The gabapentin group showed a significantly larger improvement in the NIHSS scores from admission to discharge (Kruskal-Wallis; p=0.0005). Patients on gabapentin had a longer hospital stay than those not taking the medication by 1.7 days (t-test; p=0.041). Discussion: Our data support the potential neuro-protective effect of gabapentin/pregabalin with improved outcomes after an ischemic stroke using two parallel outcome measures of NIHSS and mRS scores. Of interest, patient hospital stays were longer on gabapentin/pregabalin, which may contribute to the improved outcomes. We need larger patient groups to confirm and further study our findings. This often can be facilitated by studies involving larger medical practices, insurance, or payer databases. In addition, further investigation of potential confounders, other pharmaceuticals, other nervous system injury mechanisms, and impact of associated cost and care quality issues should occur.
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    Interferon-b Modulates Inflammatory Response in Cerebral Ischemia
    (American Heart Association, 2016-01-08) Kuo, Ping-Chang; Scofield, Barbara A.; Yu, I-Chen; Chang, Fen-Lei; Ganea, Doina; Yen, Jui-Hung; Department of Microbiology & Immunology, IU School of Medicine
    BACKGROUND: Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti-inflammatory properties and well-characterized safety profile suggest that IFNβ has therapeutic potential for the treatment of ischemic stroke. METHODS AND RESULTS: We investigated the therapeutic effect of IFNβ in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. CONCLUSIONS: Our results demonstrate that IFNβ exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNβ is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator.
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    Isolation of Mouse Cerebral Microvasculature for Molecular and Single-Cell Analysis
    (Frontiers Media, 2020) Paraiso, Hallel C.; Wang, Xueqian; Kuo, Ping-Chang; Furnas, Destin; Scofield, Barbara A.; Chang, Fen-Lei; Yen, Jui-Hung; Yu, I-Chen; Anatomy and Cell Biology, School of Medicine
    Brain microvasculature forms a specialized structure, the blood-brain barrier (BBB), to maintain homeostasis and integrity of the central nervous system (CNS). The BBB dysfunction is emerging as a critical contributor to multiple neurological disorders, including stroke, traumatic brain injury, autoimmune multiple sclerosis, and neurodegenerative diseases. The brain microvasculature exhibits highly cellular and regional heterogeneity to accommodate dynamic changes of microenvironment during homeostasis and diseases. Thus, investigating the underlying mechanisms that contribute to molecular or cellular changes of the BBB is a significant challenge. Here, we describe an optimized protocol to purify microvessels from the mouse cerebral cortex using mechanical homogenization and density-gradient centrifugation, while maintaining the structural integrity and functional activity of the BBB. We show that the isolated microvessel fragments consist of BBB cell populations, including endothelial cells, astrocyte end-feet, pericytes, as well as tight junction proteins that seal endothelial cells. Furthermore, we describe the procedures to generate single-cell suspensions from isolated microvessel fragments. We demonstrate that cells in the single-cell suspensions are highly viable and suitable for single-cell RNA-sequencing analysis. This protocol does not require transgenic mice and cell sorting equipment to isolate fluorescence-labeled endothelial cells. The optimized procedures can be applied to different disease models to generate viable cells for single-cell analysis to uncover transcriptional or epigenetic landscapes of BBB component cells.
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    Peripheral Neuropathy in Long-COVID Patients: Demographic Distribution and Comorbid Risk Factors
    (2024-04-26) Li, Jason; Bohn, Camden; Todd, Noah; Pater, Jessica; Carroll, Jeanne; Henriksen, Brian; Chang, Fen-Lei