D-4F increases microRNA-124a and reduces neuroinflammation in diabetic stroke rats
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Ruizhuo Ning1,2,*, Poornima Venkat1,*, Michael Chopp1,3, Alex Zacharek1, Tao Yan4, Xu Cui1, Don Seyfried1 and Jieli Chen1,4
1Department of Neurology, Henry Ford Hospital, Detroit, MI, USA
2Department of Neurology, First Hospital Harbin, Harbin, China
3Department of Physics, Oakland University, Rochester, MI, USA
4Gerontology Institute, Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
*These authors have contributed equally to this work
Jieli Chen, email: firstname.lastname@example.org
Keywords: stroke; diabetes mellitus; apolipoprotein-A1; microRNA-124a; neuroinflammation
Received: April 21, 2017 Accepted: August 15, 2017 Published: September 08, 2017
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.
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