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Published on: July 23, 2012
D-4F increases microRNA-124a and reduces neuroinflammation in diabetic stroke rats
Ruizhuo Ning1,2, Poornima Venkat1, Michael Chopp1,3
1Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
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.
Insights
The peptide D-4F improves stroke recovery in type one diabetes by reducing inflammation and enhancing brain repair. It increases microRNA-124, promoting anti-inflammatory M2 macrophage polarization.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Type one diabetes mellitus (T1DM) complicates stroke outcomes.
- Apolipoprotein-A1 mimetic peptide D-4F exhibits anti-inflammatory properties.
- MicroRNA-124 is a brain-specific microRNA with known anti-inflammatory effects.
Purpose of the Study:
- To investigate the therapeutic efficacy of D-4F in a rat model of T1DM with stroke.
- To elucidate the underlying mechanisms of D-4F action, focusing on microRNA-124 and inflammation.
Main Methods:
- T1DM was induced in Wistar rats, followed by embolic middle cerebral artery occlusion.
- Rats were treated with D-4F or PBS, with subsequent evaluation of functional outcomes, blood-brain barrier (BBB) integrity, white matter changes, and microRNA expression.
- In vitro studies used primary cortical neuronal and microglial cultures to assess D-4F's direct effects and the role of microRNA-124 inhibition.
Main Results:
- D-4F treatment significantly improved functional outcomes in T1DM-stroke rats.
- D-4F reduced BBB leakage, white matter damage, and inflammatory markers while promoting M2 macrophage polarization.
- D-4F increased microRNA-124a expression and decreased pro-inflammatory gene expression (MMP-9, TNF-α, TLR-4).
- MicroRNA-124 inhibition attenuated D-4F's anti-inflammatory effects and M2 polarization in vitro.
Conclusions:
- D-4F demonstrates therapeutic potential for stroke in the context of T1DM.
- D-4F's mechanism involves upregulating microRNA-124, which promotes anti-inflammatory M2 macrophage polarization.
- These effects contribute to improved neurological function and preserved BBB and white matter integrity.
