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
View: Text | PDF
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

×

Figure 1

Genetic deletion of the miR-15a/16-1 cluster partially preserves sensorimotor and cognitive functions in mice after TBI.

Options: View larger image (or click on image) Download as PowerPoint
Genetic deletion of the miR-15a/16-1 cluster partially preserves sensori...
Experimental TBI was induced in miR-15a/16-1–KO and WT mice by unilateral controlled cortical impact, followed by a 30 days survival period. Long-term sensorimotor function was evaluated in TBI mice and sham controls at the indicated time points (–1, 3, 5, 7, 14, 21, and 28 days after operation). (A) Time to fall in the rotarod test. (B and C) The time to touch and time to remove the tape in the adhesive tape–removal test. (D and E) Representative forepaw/hindpaw foot-fault images and the forepaw/hindpaw foot-fault rate in the foot-fault test (red circle: foot fault). Long-term cognitive function was examined in TBI mice and sham controls by the Morris water maze (MWM) test (22–27 days) and the passive avoidance test (29–30 days). (F) Representative swimming track plots. (G) Latency to find platform in the learning phase. (H) Time spent in the target quadrant in the memory phase. (I) Average swimming speed in MWM test. (J) Graphic schedule of the passive avoidance test. (K) Latency to enter the dark box. Data are presented as mean ± SD, n = 10–12/group. Statistical analyses were performed by 1-way/2-way ANOVA and Tukey’s post hoc test. *P < 0.05, **P < 0.01, and ***P < 0.001 versus TBI + WT group.