Loss of microRNA-15a/16-1 function promotes neuropathological and functional recovery in experimental traumatic brain injury
Chao Zhou, Shun Li, Na Qiu, Ping Sun, Milton H. Hamblin, C. Edward Dixon, Jun Chen, Ke-Jie Yin
Chao Zhou, Shun Li, Na Qiu, Ping Sun, Milton H. Hamblin, C. Edward Dixon, Jun Chen, Ke-Jie Yin
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Research Article Inflammation Therapeutics

Loss of microRNA-15a/16-1 function promotes neuropathological and functional recovery in experimental traumatic brain injury

Abstract

The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir–treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.

Authors

Chao Zhou, Shun Li, Na Qiu, Ping Sun, Milton H. Hamblin, C. Edward Dixon, Jun Chen, Ke-Jie Yin

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Figure 8

Genetic deletion and pharmacological inhibition of miR-15a/16–1 function reduces the inflammatory burden in posttrauma brains.

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Genetic deletion and pharmacological inhibition of miR-15a/16–1 function...
(A–E) miR-15a/16-1–KO and WT mice were subjected to experimental TBI or sham operation. A panel of 40 inflammatory mediators was examined in mouse brains at 3 days after CCI surgery. (A) A heatmap showing the mean expression levels of 40 inflammatory mediators in posttrauma brains from experimental groups. (B–E) Quantitative analysis of 40 brain inflammatory mediators in experimental groups. Data are presented as mean ± SD, n = 4/group. Statistical analyses were performed by 1-way ANOVA and Tukey’s test or Kruskal-Wallis test & Dunn’s test. &,*P < 0.05, &&,**P < 0.01, and &&&,***P < 0.001, where & represents TBI + WT versus Sham + WT group and * represents TBI + KO versus TBI + WT group. (F–J)C57BL/6J mice were subjected to experimental TBI and intranasally treated with the miR-15a/16–1 antagomir or control antagomir at 2 hours after surgery. A panel of 40 inflammatory mediators was measured in mouse brains at 3 days after CCI surgery. (F) A heatmap showing the mean expression levels of 40 inflammatory mediators in posttrauma brains from experimental groups. (G–J) Quantitative analysis of 40 brain inflammatory mediators in experimental groups. Data are presented as mean ± SD, n = 4/group. Statistical analyses were performed by 1-way ANOVA and Tukey’s test or Kruskal-Wallis test and Dunn’s test. &,*P < 0.05, &&,**P < 0.01, and &&&,***P < 0.001 where & represents TBI + control antagomir versus Sham + control antagomir group and * represents TBI + miR-15a/16-1 antagomir versus TBI + control antagomir group.