Inhibition of PDE1-B by Vinpocetine Regulates Microglial Exosomes and Polarization Through Enhancing Autophagic Flux for Neuroprotection Against Ischemic Stroke

Abstract

Exosomes contribute to cell–cell communications. Emerging evidence has shown that microglial exosomes may play crucial role in regulation of neuronal functions under ischemic conditions. However, the underlying mechanisms of microglia-derived exosome biosynthesis are largely unknown. Herein, we reported that the microglial PDE1-B expression was progressively elevated in the peri-infarct region after focal middle cerebral artery occlusion. By an oxygen-glucose-deprivation (OGD) ischemic model in cells, we found that inhibition of PDE1-B by vinpocetine in the microglial cells promoted M2 and inhibited M1 phenotype. In addition, knockdown or inhibition of PDE1-B significantly enhanced the autophagic flux in BV2 cells, and vinpocetine-mediated suppression of M1 phenotype was dependent on autophagy in ischemic conditions. Co-culture of BV2 cells and neurons revealed that vinpocetine-treated BV2 cells alleviated OGD-induced neuronal damage, and treatment of BV2 cells with 3-MA abolished the observed effects of vinpocetine. We further demonstrated that ischemia and vinpocetine treatment significantly altered microglial exosome biogenesis and release, which could be taken up by recipient neurons and regulated neuronal damage. Finally, we showed that the isolated exosome per se from conditioned BV2 cells is sufficient to regulate cortical neuronal survival in vivo. Taken together, these results revealed a novel microglia-neuron interaction mediated by microglia-derived exosomes under ischemic conditions. Our findings further suggest that PDE1-B regulates autophagic flux and exosome biogenesis in microglia which plays a crucial role in neuronal survival under cerebral ischemic conditions.

CircOGDH Is a Penumbra Biomarker and Therapeutic Target in Acute Ischemic Stroke

“…48 Studies have shown that the expression of astrocyte lamina is significantly increased in the ischemic penumbra of MCAO mice. 49 COL4A is a member of type IV collagen family 50 and the most abundant basal lamina protein, 48 which participates in modulating cellular behaviors during the processes of tissue development, damage, and repair. For example, COL4A1 is considered as a monogenic cause of cerebral small vessel disease, including both ischemic stroke and intracerebral hemorrhage.…”

The dual roles of autophagy and the GPCRs-mediating autophagy signaling pathway after cerebral ischemic stroke

“…Intracerebroventricular injection of protein tyrosine phosphatase 1B (PTP1B) inhibitor could alleviate deleterious microglial activation and neuronal injury after ischemic stroke by modulating the ER stress-autophagy axis via PERK signaling in microglia [ 117 ]. Other studies have also confirmed that microglia autophagy can play important roles in promoting neuroinflammation after cerebral ischemia [ 118 ].…”

Microglia Polarization: A Novel Target of Exosome for Stroke Treatment

“…According to the in vivo study, activated microglia in the peri-infarct ischemic region were significantly increased in the first day and peaked at the 14th day after MCAO. The use of vinpocetine promotes microglia M2 polarization by enhancing microglia autophagy, ultimately attenuating neuronal damage caused by OGD treatment ( Zang et al, 2020 ). The exosomes secreted by polarized microglia may also be an effective target for therapeutic modulation of stroke ( Table 2 ).…”