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Fingolimod Inhibits Inflammation but Exacerbates Brain Edema in the Acute Phases of Cerebral Ischemia in Diabetic Mice.

ABSTRACT: Background and Purpose: Diabetes mellitus increases stroke incidence and mortality and hampers functional recovery after stroke. Fingolimod has been shown to improve neurofunctional recovery and reduce brain infarction after ischemic injury in mice without comorbidities. In this work, we investigated the effects of fingolimod in diabetic mice after transient middle cerebral artery occlusion (tMCAO). Methods: Hyperglycemia was induced by a single bolus streptozotocin injection. Adult male ICR mice (n = 86) underwent 1-h tMCAO surgery and received intraperitoneal injection of fingolimod (1 mg/kg) or vehicle immediately after reperfusion. Clark neurological score, brain infarction and edema, blood-brain barrier (BBB) integrity, apoptosis, and inflammation were evaluated at 24 h after tMCAO. Results: Fingolimod treatment reduced the number of infiltrated inflammatory cells and lowered the mRNA level of Tnf?. It also increased the ratio of Bcl-2/Bax. However, fingolimod significantly aggravated brain edema and reduced the expression levels of tight junction proteins ZO-1 and Occludin. The negative impacts of fingolimod on BBB integrity outweighed its beneficial effects in anti-inflammation, which resulted in the lack of improvement in endpoint outcomes at 24 h after tMCAO. Conclusion: Caution should be taken in considering the acute treatment using fingolimod for ischemic stroke with diabetes comorbidity.

SUBMITTER: Li W

PROVIDER: S-EPMC7432267 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Fingolimod Inhibits Inflammation but Exacerbates Brain Edema in the Acute Phases of Cerebral Ischemia in Diabetic Mice.

Li Wanlu W He Tingting T Jiang Lu L Shi Rubing R Song Yaying Y Mamtilahun Muyassar M Ma Yuanyuan Y Zhang Zhijun Z Tang Yaohui Y Yang Guo-Yuan GY Wang Yongting Y

Frontiers in neuroscience 20200811

<b>Background and Purpose:</b> Diabetes mellitus increases stroke incidence and mortality and hampers functional recovery after stroke. Fingolimod has been shown to improve neurofunctional recovery and reduce brain infarction after ischemic injury in mice without comorbidities. In this work, we investigated the effects of fingolimod in diabetic mice after transient middle cerebral artery occlusion (tMCAO). <b>Methods:</b> Hyperglycemia was induced by a single bolus streptozotocin injection. Adul ...[more]

PMID: 32848587

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Project description:BACKGROUND: Vasogenic edema dynamically accumulates in many brain disorders associated with brain inflammation, with the critical step of edema exacerbation feared in patient care. Water entrance through blood-brain barrier (BBB) opening is thought to have a role in edema formation. Nevertheless, the mechanisms of edema resolution remain poorly understood. Because the water channel aquaporin 4 (AQP4) provides an important route for vasogenic edema resolution, we studied the time course of AQP4 expression to better understand its potential effect in countering the exacerbation of vasogenic edema. METHODS: Focal inflammation was induced in the rat brain by a lysolecithin injection and was evaluated at 1, 3, 7, 14 and 20 days using a combination of in vivo MRI with apparent diffusion coefficient (ADC) measurements used as a marker of water content, and molecular and histological approaches for the quantification of AQP4 expression. Markers of active inflammation (macrophages, BBB permeability, and interleukin-1?) and markers of scarring (gliosis) were also quantified. RESULTS: This animal model of brain inflammation demonstrated two phases of edema development: an initial edema build-up phase during active inflammation that peaked after 3 days (ADC increase) was followed by an edema resolution phase that lasted from 7 to 20 days post injection (ADC decrease) and was accompanied by glial scar formation. A moderate upregulation in AQP4 was observed during the build-up phase, but a much stronger transcriptional and translational level of AQP4 expression was observed during the secondary edema resolution phase. CONCLUSIONS: We conclude that a time lag in AQP4 expression occurs such that the more significant upregulation was achieved only after a delay period. This change in AQP4 expression appears to act as an important determinant in the exacerbation of edema, considering that AQP4 expression is insufficient to counter the water influx during the build-up phase, while the second more pronounced but delayed upregulation is involved in the resolution phase. A better pathophysiological understanding of edema exacerbation, which is observed in many clinical situations, is crucial in pursuing new therapeutic strategies.

Dataset Information

Fingolimod Inhibits Inflammation but Exacerbates Brain Edema in the Acute Phases of Cerebral Ischemia in Diabetic Mice.

Publications

Fingolimod Inhibits Inflammation but Exacerbates Brain Edema in the Acute Phases of Cerebral Ischemia in Diabetic Mice.

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