MicroRNA-9 mediated the protective effect of ferulic acid on hypoxic-ischemic brain damage in neonatal rats.

Keli Yao,Ting Lan,Qin Yang,Hong Yu,Yang Yu,Yajuan Li,Giuseppe Pignataro

doi:10.1371/journal.pone.0228825

Abstract

Neonatal hypoxic-ischemic brain damage (HIBD) is prone to cognitive and memory impairments, and there is no effective clinical treatment until now. Ferulic acid (FA) is found within members of the genus Angelica, reportedly shows protective effects on neuronal damage. However, the protective effects of FA on HIBD remains unclear. In this study, using the Morris water maze task, we herein found that the impairment of spatial memory formation in adult rats exposed to HIBD was significantly reversed by FA treatment and the administration of LNA-miR-9. The expression of miRNA-9 was detected by RT-PCR analyses, and the results shown that miRNA-9 was significantly increased in the hippocampus of neonatal rats following HIBD and in the PC12 cells following hypoxic-ischemic injury, while FA and LNA-miR-9 both inhibited the expression of miRNA-9, suggesting that the therapeutic effect of FA was mainly attributed to the inhibition of miRNA-9 expression. Indeed, the silencing of miR-9 by LNA-miR-9 or FA similarly attenuated neuronal damage and cerebral atrophy in the rat hippocampus after HIBD, which was consistent with the restored expression levels of brain-derived neurotrophic factor (BDNF). Therefore, our findings indicate that FA treatment may protect against neuronal death through the inhibition of miRNA-9 induction in the rat hippocampus following hypoxic-ischemic damage.

Highlights

Neonatal hypoxic-ischemic brain damage (HIBD) is a severe disease that can cause irreversible neurological sequelae, such as cerebral palsy, mental deficiency, memory impairment and learning disabilities, and is often characterized by permanent neurological deficits [1, 2]
Protective effect of ferulic acid on hypoxic-ischemic brain damage decreased in the HIBD group compared with the sham group, and the administration of Ferulic acid (FA) significantly suppressed the decrease in hippocampal neurons, the area of cerebral cortex, the size of the hippocampus and the layers of the dentate gyrus (DG) (Fig 1A–1C, P < 0.001 vs. HIBD)
It is urgent to identify drugs that protect against neuronal damage to reduce the neurological disorder induced by HIBD

Summary

Introduction

Neonatal hypoxic-ischemic brain damage (HIBD) is a severe disease that can cause irreversible neurological sequelae, such as cerebral palsy, mental deficiency, memory impairment and learning disabilities, and is often characterized by permanent neurological deficits [1, 2]. In some HIBD patients who receive early diagnosis and hypothermic treatments, still persist serious neurological sequelae. There is no effective clinical treatment for neurological sequelae induced by HIBD [3,4,5]. Effective therapeutic agents which inhibit damage cascades activated after HIBD should be identified. MicroRNAs are some small noncoding RNAs that regulate gene expression and suppression through several mechanisms.

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