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 2

Genetic deficiency of the miR-15a/16–1 cluster reduces brain tissue loss and neuronal death in mice after TBI.

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Genetic deficiency of the miR-15a/16–1 cluster reduces brain tissue loss...
MAP2 immunostaining was conducted in miR-15a/16-1–KO and WT mice 30 days after TBI to measure brain tissue loss. (A) Representative images of MAP2 immunostaining. Scale bar: 0.5 cm. (B and C) Quantitative analysis of volume or cross-sectional areas in brain tissue loss. Neuronal loss was examined by CV histological staining and NeuN immunofluorescence staining 30 days after TBI. (D) Coordinates and perilesional brain regions for CV and NeuN staining. (E) Representative images of CV staining in the pericontusional CTX, CA1, and CA3 regions. Scale bars: 100 μm. (F–H) Quantitative analysis of CV-stained cells in the pericontusional CTX, CA1, and CA3 regions. (I) Representative images of NeuN immunostaining in the pericontusional CTX, CA1, and CA3 regions. (J–L) Quantitative analysis of NeuN-immunopositive cells in the pericontusional CTX, CA1, and CA3 regions. Data are presented as mean ± SD, n = 6/group. Statistical analyses were performed by 1-way ANOVA and Tukey’s post hoc test. *P < 0.05, **P < 0.01, and ***P < 0.001 versus TBI + WT group. (M) Correlation analysis between sensorimotor or cognitive outcomes and CV-stained/NeuN+ neurons in the pericontusional CTX, CA1, and CA3 regions (n = 6/group, Pearson correlation analysis).