Abstract
Spinal cord injury (SCI) causes a significant physical, emotional, social, and economic burden to millions of people. MicroRNAs are known players in the regulatory circuitry of the neural repair in SCI. However, most microRNAs remain uncharacterized. Here, we demonstrate the neuroprotection of microRNA-145 (miR-145) after SCI in vivo and in vitro. In silico analysis predicted the target gene KDM6A of miR-145. The rat SCI model was developed by weight drop, and lipopolysaccharide- (LPS-) induced PC12 cell inflammatory injury model was also established. We manipulated the expression of miR-145 and/or KDM6A both in vivo and in vitro to explain their roles in rat neurological functional recovery as well as PC12 cell activities and inflammation. Furthermore, we delineated the mechanistic involvement of NOTCH2 and Abcb1a in the neuroprotection of miR-145. According to the results, miR-145 was poorly expressed and KDM6A was highly expressed in the spinal cord tissue of the SCI rat model and LPS-induced PC12 cells. Overexpression of miR-145 protects PC12 cells from LPS-induced cell damage and expedites neurological functional recovery of SCI in rats. miR-145 was validated to target and downregulate the demethylase KDM6A expression, thus abrogating the expression of Abcb1a by promoting the methylation of NOTCH2. Additionally, in vivo findings verified that miR-145 expedites neuroprotection after SCI by regulating the KDM6A/NOTCH2/Abcb1a axis. Taken together, miR-145 confers neuroprotective effects and enhances neural repair after SCI through the KDM6A-mediated NOTCH2/Abcb1a axis.
Highlights
Spinal cord injury (SCI) is recognized as a severe neurological disorder, which results in sensory, motor, and autonomic deficits [1, 2]
We explored the neuroprotective effect of miR-145 on SCI rat models
After overexpressing miR-145 and KDM6A in SCI rats, we found that miR-145 expression in SCI rats was augmented in the presence of miR-145 overexpression alone or its combination with KDM6A overexpression (p < 0:05) (Figure 7(a))
Summary
Spinal cord injury (SCI) is recognized as a severe neurological disorder, which results in sensory, motor, and autonomic deficits [1, 2]. The permanent neurological deficits have been attributed to SCI-induced dysfunction of neural connectivity [3]. 300,000 people suffer from SCI in the United States, and no effective therapies have been developed to reverse the neurological impairments, leading to an urgent call for treatment options to rescue damaged neurons or to enhance neuroplasticity and functional recovery [4]. SCI is accompanied by a wide array of fatal complications during the acute and long-term phases [5]. It is critical to study novel molecular mechanisms in order to induce a neuroprotective condition to prevent the exacerbation of the secondary neurological function injury [7]
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