Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury

Abstract

Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs—miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR-128—were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival. Electronic supplementary material The online version of this article (10.1007/s12035-020-02018-w) contains supplementary material, which is available to authorized users.

Social Isolation and Enrichment Induce Unique miRNA Signatures in the Prefrontal Cortex and Behavioral Changes in Mice

“…miR-140-5p and miR-181a-5p, the miRNAs modulated in an enriched context, are miRNAs expressed both in glia and neurons. Although previous work has implicated them in similar pathological processes such as brain ischemia ( Casey et al., 2020 ; Moon et al., 2013 ; Han et al., 2018 ) and Alzheimer disease ( Akhter et al., 2018 ; Ansari et al., 2019 ; Rodriguez-Ortiz et al., 2020 ), their physiological functions remain poorly explored. Increasing evidence suggest that both miR-140-5p ( Ambrozkiewicz et al., 2018 ) and miR-181a-5p ( Chandrasekar and Dreyer, 2009 ; Rodriguez-Ortiz et al., 2020 ; Saba et al., 2012 ) play important roles in neurons and are required for proper cognition ( Gullett et al., 2020 ; Xu et al., 2018 ; Zhang et al., 2017 ).…”

Early Brain microRNA/mRNA Expression is Region-Specific After Neonatal Hypoxic-Ischemic Injury in a Mouse Model

“…One significant hurdle to designing miRNA-based therapies for neonatal HIBI is a lack of data describing the endogenous miRNA expression after neonatal HIBI. To date, there have been two studies that have profiled the serum miRNA changes in human newborns with HIE using high-throughput analyses using the same cohort but two different miRNA detection techniques ( Looney et al, 2015 ; Casey et al, 2020 ). Between the two studies, the investigators identified at least 107 miRNAs that were significantly up- or downregulated in newborns diagnosed with HIE.…”

“…We hypothesized that the miRNA profile would differ between the cortex and striatum/thalamus and that the cerebellar miRNA expression would be distinct from both of the other regions given its relative protection from ischemic injury in this model. As described above, all of the human studies were obtained immediately after delivery (i.e., cord blood) ( Looney et al, 2015 ; Casey et al, 2020 ), but previous studies in the piglet model of neonatal HIBI have demonstrated that many miRNAs do not reach peak dysregulation until around 1 h after injury ( Garberg et al, 2017 ; Casey et al, 2020 ). As such, to allow for comparison with the previous clinical studies (of cord blood at 0 min after injury) but also ensure time for miRNA dysregulation to occur (peak at 60 min after injury), the region-specific miRNA levels assessed in this study were all obtained at 30 min after injury, consistent with the timing used in other similar studies ( Yuan et al, 2010 ; Garberg et al, 2017 ).…”

Febrile Seizure-Related miR-148a-3p Exerts Neuroprotection by Promoting the Proliferation of Hippocampal Neurons in Children with Temporal Lobe Epilepsy

“…Previous studies have pointed out that miR-148a-3p was frequently closely associated with mental abnormality class diseases, such as susceptibility for panic disorder [9]. In hypoxic-ischemic encephalopathy, it was found that miR-148a-3p could be used as a potential biomarker to indicate the injury [10]. Lithium is one of the most widely certified anticonvulsants and mood stabilizers and exhibits significant neuroprotective effects in the treatment of epilepsy, and the neuroprotective effects of lithium have been reported to be achieved through regulating miR-148a-3p in Parkinson's disease [11].…”