Abstract WP99: Fingolimod Promotes Functional Recovery via Neuroprotection, Angiogenesis and Neurogenesis in Diabetic Stroke Mice

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Abstract

Introduction: Diabetes is a risk factor for stroke. Fingolimod is a small molecule drug approved by FDA in 2010 for the treatment of multiple sclerosis. It has been shown that fingolimod reduced inflammatory infiltration and brain edema, as well as exhibited neuroprotective effects after ischemic stroke. In this work, we investigated the effects of fingolimod on diabetic stroke mice in the acute and post-acute stages.

Methods: Diabetes was induced by streptozotocin (150mg/kg) injection. For acute phase studies, adult male ICR mice underwent 1-hour transient middle cerebral artery occlusion (tMCAO) (n=55), and received intraperitoneal injection of fingolimod (1mg/kg) immediately after reperfusion. Death rate, neurological score, brain infarction, edema, and blood brain barrier permeability were evaluated at 24 hours after MCAO. The number of CD3+ T cells in peripheral blood was analyzed by flow cytometry. Cellular apoptosis, tight junction changes and inflammatory cell infiltration were measured by immunofluorescence staining. To investigate the long-term function of fingolimod, mice (n=25) were treated with fingolimod (1mg/kg) immediately after reperfusion after 1-hour tMCAO. Neurobehavioral outcomes, brain atrophy, neurogenesis, and angiogenesis were evaluated at 14 days after tMCAO.

Results: At 24 hours after tMCAO, mice mortality was reduced by fingolimod treatment. Fingolimod reduced the number of TUNEL positive cells and inflammatory cell infiltration, as well as lowered the mRNA level of inflammatory cytokines including IL-6 and TNF-α. However, it caused aggravated edema which is accompanied by reduced ZO-1 and occludin level, and raised AQP4 expression. In the post-acute stage, fingolimod improved the functional recovery and reduced brain atrophy. The numbers of nestin and DCX/BrdU positive neural progenitor cells in the subventricular zone and CD31/BrdU positive angiogenic microvessels were increased in fingolimod treated group.

Conclusion: Fingolimod reduced the mortality of diabetic stroke mice in the acute phase through neuroprotection and anti-inflammation, and promoted the functional recovery in post-acute phase by promoting neurogenesis and angiogenesis.

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