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 5

Long-term intranasal delivery of the miR-15a/16–1 antagomir promotes neurobehavioral recovery and reduces brain tissue loss and neuronal death in mice after TBI.

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Long-term intranasal delivery of the miR-15a/16–1 antagomir promotes neu...
C57BL/6J mice were subjected to experimental TBI and intranasal treatment of 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. Sensorimotor function was examined in experimental mice at the indicated time points (–1, 3, 5, 7, 14, 21, and 28 days after surgery). (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) The forepaw foot-fault rate and hindpaw foot-fault rate in the foot-fault test. Cognitive function was evaluated by the 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 the MWM test. (J) Latency to enter the dark box. Data are presented as mean ± SD, n = 10/group. Statistical analyses were performed by 1-way/2-way ANOVA and Tukey’s post hoc test. MAP2 and NeuN immunostaining were performed to examine brain tissue/neuronal loss. (K and L) Representative images of MAP2 immunostaining and quantitative analysis of brain tissue loss volume (n = 10/group, unpaired t test). (M) Representative images of NeuN immunostaining in the pericontusional CTX, CA1, and CA3 regions. Scale bar: 100 μm. (N–P) Quantitative analysis of NeuN+ cells in the pericontusional CTX, CA1, and CA3 regions (n = 6/group, 1-way ANOVA & Tukey’s test). *P < 0.05 and ***P < 0.001 versus TBI + control antagomir group. (Q) Correlation analysis between sensorimotor or cognitive outcome and CV-stained or NeuN+ neurons in the pericontusional CTX, CA1, and CA3 regions (n = 6/group, Pearson correlation analysis).