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 6

Long-term intranasal delivery of the miR-15a/16–1 antagomir partially preserves white matter integrity in mice after TBI.

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Long-term intranasal delivery of the miR-15a/16–1 antagomir partially pr...
C57BL/6J mice were subjected to experimental TBI and intranasally treated with the miR-15a/16-1 antagomir or control antagomir at 2 hours, 5 days, 10 days, 15 days, 20 days, and 25 days after CCI surgery. White matter integrity was examined by LFB staining and MBP/SMI32 immunostaining 30 days after surgery. (A) Representative images of LFB staining in the perilesional CTX, EC, and STR regions. Scale bar: 100 μm. (B) Coordinates and brain regions for LFB, MBP/SMI32, and Caspr/Nav1.6 staining. (C–E) Quantitative analysis of relative OD values from LFB staining in the pericontusional CTX, EC, and STR regions. (F) Representative images of MBP/SMI32 immunostaining in the pericontusional CTX, EC, and STR regions. Scale bar: 50 μm. (G–I) Quantitative analysis of MBP fluorescence intensity in the pericontusional CTX, EC, and STR regions. (J–L) Quantitative analysis of SMI32 fluorescence intensity in the pericontusional CTX, EC, and STR regions. (M) The node of Ranvier (NOR) was examined by Caspr (red)/Nav1.6 (green) double-immunofluorescence staining. Representative images of Caspr/Nav1.6 immunostaining in the pericontusional EC area. Scale bars: 50 μm (top), 5 μm (bottom). (N–P) Quantitative analysis of the number of NOR (N), paranode length (O), and the length of the paranode gap (P). 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 + control antagomir group. (Q) Correlation analysis of sensorimotor or cognitive outcome and white matter integrity (n = 6/group, Pearson correlation analysis).