Liposome-loaded miR-34c-5p attenuates apoptosis and oxidative stress following hypoxia-ischemia brain damage in neonatal mice by targeting Arhgap26.

Abstract

Neonatal hypoxia-ischemia (HI) brain injury is considered a major cause of neonatal mortality and chronic disease morbidity worldwide. Despite its clinical importance, therapeutic options for HI injury remain limited. Here we demonstrated that miR-34c-5p expression peaks at postnatal day 10 in mice. Meanwhile, the miR-34c-5p levels in the lesioned cortex decreased following HI insult in neonatal mice. miR-34c-5p overexpression confers neuroprotective effects by attenuating brain injury and ROS production. These protective mechanisms were mediated through the inhibition of caspase 3 activation, suppression of microglial activation, and downregulation of pro-inflammatory cytokines in the injured cortex. In contrast, miR-34c-5p downregulation markedly aggravated the infarct area after HI injury. Additionally, miR-34c-5p overexpression improved short-term motor coordination and long-term neurological outcomes, including locomotor activity, learning, and memory functions, which were associated with upregulated synaptic protein expression. Importantly, we developed a non-invasive intranasal delivery system using liposome-encapsulated miR-34c-5p mimics, which significantly ameliorated brain injury at 3 days post-HI. Mechanistic studies revealed that miR-34c-5p directly targets the 3' untranslated region of GTPase activating protein 26 (Arhgap26). In conclusion, we identified a non-invasive method for successfully delivering miR-34c-5p to improve functional recovery after HI insult by targeting Arhgap26.