Silencing of long noncoding RNA MEG3 enhances cerebral protection of dexmedetomidine against hypoxic‐ischemic brain damage in neonatal mice by binding to miR‐129‐5p

Abstract

Hypoxic‐ischemic brain damage (HIBD) is a leading cause of neonatal acute mortality and chronic nervous system injury. Recently, it has been found that long noncoding RNAs (lncRNAs) play a significant role in the neurodevelopment and etiopathogenesis of HIBD. Here, the researchers aimed to determine the role of lncRNA maternally expressed gene (MEG3) in the therapeutic effect of dexmedetomidine (DEX) in neonatal mice with HIBD through the regulation of microRNA‐129‐5p (miR‐129‐5p). HIBD models were established in C57/BL6 neonatal mice. Subsequently, the target relationship between MEG3 and miR‐129‐5p was predicted and verified. The neonatal mice were injected with DEX, ad‐shMEG3, and mimics and inhibitors of miR‐129‐5p to identify roles of MEG3 and miR‐129‐5p in therapeutic effects of DEX on neuronal apoptosis and injury, cerebral atrophy, and learning and memory ability of neonatal mice with HIBD. MEG3 directly targeted and inhibited the expression of miR‐129‐5p. Silencing of MEG3 or upregulation of miR‐129‐5p effectively promoted the therapeutic effect of DEX on neonatal mice with HIBD. Silencing of MEG3 or upregulation of miR‐129‐5p reduced the neuronal apoptosis rate and degree of cerebral atrophy, and also enhanced the learning and memory ability of HIBD neonatal mice. Collectively, the key findings obtained from the present study support the notion that MEG3 silencing enhances the therapeutic effect of DEX on neonatal mice with HIBD by binding to miR‐129‐5p.

Dexmedetomidine reduced sevoflurane‐induced neurodegeneration and long‐term memory deficits in neonatal rats

“…According to our previous study, rat pups that receive sevoflurane with 21% oxygen exhibit a profound increase in neurodegeneration compared with those that receive 30% oxygen (Goyagi, 2018). DEX has neuroprotective effects against hypoxic brain and spinal insult (Dahmani et al, 2005; Engelhard et al, 2002; Eser et al, 2008; Goyagi et al, 2009; Goyagi and Tobe, 2014; Ma et al, 2004; Zhu et al, 2013), and in animal neonatal models, particularly in the hypoxic‐ischemic neonatal brain (Ren et al, 2016; Zhou et al, 2018). It is possible that DEX might be protective against the hypoxic effects of 21% oxygen rather than the neurotoxicity induced by sevoflurane here.…”

“…Based on previous studies, DEX can ameliorated the neuroapoptosis and cognitive dysfunction induced by exposure of the developing brain to ketamine (Duan et al, 2014), isoflurane (Li et al, 2014; Sanders et al, 2010, 2009), sevoflurane (Perez‐Zoghbi et al, 2017) and propofol (Lv et al, 2017; Wang et al, 2016; Xiao et al, 2018). Moreover, DEX has neuroprotective effects in the hypoxic‐ischemic neonatal brain (Ren et al, 2016; Zhou et al, 2018) and in an acute hyperoxic neonatal rat model (Endesfelder et al, 2017; Sifringer et al, 2015). In contrast, DEX does not ameliorate the injury induced by sevoflurane, and induces neural apoptosis in neonatal rats (Lee et al, 2017).…”

Dexmedetomidine Postconditioning Alleviates Hypoxia/Reoxygenation Injury in Senescent Myocardial Cells by Regulating lncRNA H19 and m6A Modification

“…The neuroprotective effect of Dex on hippocampal neuronal cells in vitro was associated with miR-223-3p/TIAL1 [21]. Knockdown of the lncRNA MEG3 enhanced the protective effect of Dex against hypoxia-ischemia neonatal brain injury in mice [22]. Dex also attenuated lipopolysaccharide-induced acute lung injury via miR-381 [23].…”

Silencing MEG3 protects PC12 cells from hypoxic injury by targeting miR-21

“…The mechanism for MEG3's function in brain damage has been studied accordingly. It is believed that silence of MEG3 protects neurons against various stimulations associated with hypoxic or ischaemic conditions through regulating miRNAs, like miR-129-5p [12], miR-21 [9], and miR-181b [10]. Among these miRNAs, miR-21 has been widely known as a neuroprotective factor during ischaemicinduced brain damage [13,14].…”