Abstract
D-4F is an apolipoprotein-A1 mimetic peptide that promotes anti-inflammatory effects. MicroRNA-124 is the most abundant brain-specific microRNA and has anti-inflammatory effects. In this study, we investigated the therapeutic efficacy and mechanisms of D-4F treatment of stroke in type one diabetes mellitus (T1DM) rats. Male Wistar rats were induced with T1DM, subjected to embolic middle cerebral artery occlusion and treated with PBS or D-4F (1 mg/kg i.p.) at 2, 24 and 48 hours after stroke (n=8/group). A battery of function tests, brain blood barrier (BBB) integrity, white matter changes and microRNA expression were evaluated in vivo and in vitro. D-4F treatment in T1DM-stroke rats significantly improves functional outcome, decreases BBB leakage, increases tight junction protein expression, decreases white matter damage and inflammatory factor expression, while increasing anti-inflammatory M2 macrophage polarization in the ischemic brain. D-4F significantly increases microRNA-124a expression, and decreases matrix metalloproteinase-9, tumor necrosis factor-α and toll-like receptor-4 gene expression in the ischemic brain, and in primary cortical neuronal and microglial cultures. Inhibition of microRNA-124 in cultured primary cortical neurons and microglia attenuates D-4F induced anti-inflammatory effects and M2 macrophage polarization. D-4F treatment of T1DM-stroke increases microRNA-124 expression, promotes anti-inflammatory effects and M2 macrophage polarization, which may contribute to D-4F-induced improvement in neurological function, and BBB and white matter integrity.
Highlights
Diabetes mellitus (DM) patients suffer from a 3-4 fold higher risk of stroke and a worse vascular prognosis compared to non-DM patients [1, 2]
For the first time to our knowledge, we demonstrate that D-4F treatment of Type one DM (T1DM) rats subjected to stroke significantly increases miR-124a expression in the ischemic brain and in cultured primary cortical neuron (PCN) and microglial cells, decreases inflammatory factor expression, promotes M2 macrophage polarization, increases tight junction protein expression, decreases brain blood barrier (BBB) leakage, decreases white matter (WM) damage, and improves neurological functional outcome at 48 hours after stroke
We found that D-4F treatment in T1DM rats subjected to stroke significantly decreases BBB leakage, increases tight junction protein expression, and reduces inflammatory factor expression such as matrix metalloproteinase 9 (MMP9), tumor necrosis factor-α (TNFα) and Nuclear factor kappalight-chain-enhancer of activated B cells (NFκB) in the ischemic brain, as well as improves functional outcome compared to phosphate buffered saline (PBS) treated T1DM stroke rats at 48 hours after stroke
Summary
Diabetes mellitus (DM) patients suffer from a 3-4 fold higher risk of stroke and a worse vascular prognosis compared to non-DM patients [1, 2]. Stroke rodents suffer increased inflammatory effects in the ischemic brain, exacerbated proinflammatory responses, and increased release of cytotoxic enzymes, which together increase BBB leakage and brain hemorrhage [3, 4]. DM rats treated with tPA suffer from increased lesion volume, blood brain barrier (BBB) leakage, brain hemorrhagic transformation as well as worse functional outcome [3, 5,6,7]. MiR-124a is highly expressed by resident microglia in the CNS, mediates microglial quiescence in the CNS, and has anti-inflammatory effects [11, 12]. MiR-124 promotes macrophage polarization by decreasing the proinflammatory M1 phenotype and increasing the anti-inflammatory M2 phenotype [16]
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