Abstract
BackgroundInflammation is a potential crucial factor in the pathogenesis of subarachnoid hemorrhage (SAH). Circulating microRNAs (miRNAs) are involved in the regulation of diverse aspects of neuronal dysfunction. The therapeutic potential of miRNAs has been demonstrated in several CNS disorders and is thought to involve modulation of neuroinflammation. Here, we found that peripherally injected modified exosomes (Exos) delivered miRNAs to the brains of mice with SAH and that the potential mechanism was regulated by regulation of neuroinflammation.MethodsNext-generation sequencing (NGS) and qRT-PCR were used to define the global miRNA profile of plasma exosomes in aSAH patients and healthy controls. We peripherally injected RVG/Exos/miR-193b-3p to achieve delivery of miR-193b-3p to the brain of mice with SAH. The effects of miR-193b-3p on SAH were assayed using a neurological score, brain water content, blood-brain barrier (BBB) injury, and Fluoro-Jade C (FJC) staining. Western blotting analysis, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR were used to measure various proteins and mRNA levels.ResultsNGS and qRT-PCR revealed that four circulating exosomal miRNAs were differentially expressed. RVG/Exos exhibited improved targeting to the brains of SAH mice. MiR-193b-3p suppressed the expression and activity of HDAC3, upregulating the acetylation of NF-κB p65. Finally, miR-193b-3p treatment mitigated the neurological behavioral impairment, brain edema, BBB injury, and neurodegeneration induced by SAH, and reduced inflammatory cytokine expression in the brains of mice after SAH.ConclusionsExos/miR-193b-3p treatment attenuated the inflammatory response by acetylation of the NF-κB p65 via suppressed expression and activity of HDAC3. These effects alleviated neurobehavioral impairments and neuroinflammation following SAH.
Highlights
Inflammation is a potential crucial factor in the pathogenesis of subarachnoid hemorrhage (SAH)
Exos/miR-193b-3p treatment attenuated the inflammatory response by acetylation of the Nuclear factor-κB (NF-κB) p65 via suppressed expression and activity of Histone deacetylase 3 (HDAC3)
Next-generation sequencing (NGS) permitted identification of a group of plasma exosomal miRNAs that were differentially expressed in SAH patients, yielding six miRNAs that were significantly differentially expressed in SAH patients and control plasma exosome samples: hsamiR-369-3p, hsa-miR-136b-3p, hsa-miR-410-3p, hsa-miR195-5p, hsa-miR-486-3p, and hsa-miR-193b-3p (Table 2)
Summary
Inflammation is a potential crucial factor in the pathogenesis of subarachnoid hemorrhage (SAH). The therapeutic potential of miRNAs has been demonstrated in several CNS disorders and is thought to involve modulation of neuroinflammation. We found that peripherally injected modified exosomes (Exos) delivered miRNAs to the brains of mice with SAH and that the potential mechanism was regulated by regulation of neuroinflammation. Aneurysmal subarachnoid hemorrhage (SAH) typically results from a ruptured aneurysm. It is a clinical syndrome associated with mortality of 45% and morbidity of approximately 6–16 per 100,000 individuals annually worldwide, often in young individuals. The evidence suggests that several pathophysiological disorders during EBI activate inflammatory cascades [6].
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