Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Abstract

Spinal cord injury (SCI) is a destructive neurological disorder that is characterized by impaired sensory and motor function. Inhibition of bromodomain protein 4 (Brd4) has been shown to promote the maintenance of cell homeostasis by activating autophagy. However, the role of Brd4 inhibition in SCI and the underlying mechanisms are poorly understood. Thus, the goal of the present study was to evaluate the effects of sustained Brd4 inhibition using the bromodomain and extraterminal domain (BET) inhibitor JQ1 on the regulation of apoptosis, oxidative stress and autophagy in a mouse model of SCI. First, we observed that Brd4 expression at the lesion sites of mouse spinal cords increased after SCI. Treatment with JQ1 significantly decreased the expression of Brd4 and improved functional recovery for up to 28 day after SCI. In addition, JQ1-mediated inhibition of Brd4 reduced oxidative stress and inhibited the expression of apoptotic proteins to promote neural survival. Our results also revealed that JQ1 treatment activated autophagy and restored autophagic flux, while the positive effects of JQ1 were abrogated by autophagy inhibitor 3-MA intervention, indicating that autophagy plays a crucial role in therapeutic effects Brd4 induced by inhibition of the functional recovery SCI. In the mechanistic analysis, we observed that modulation of the AMPK-mTOR-ULK1 pathway is involved in the activation of autophagy mediated by Brd4 inhibition. Taken together, the results of our investigation provides compelling evidence that Brd4 inhibition by JQ1 promotes functional recovery after SCI and that Brd4 may serve as a potential target for SCI treatment.

Maltol Promotes Mitophagy and Inhibits Oxidative Stress via the Nrf2/PINK1/Parkin Pathway after Spinal Cord Injury

“…40 mg/kg pentobarbital sodium 4% ( w / v ) was intraperitoneally administered in mice, and laminectomy was performed to remove the part of the vertebra covering the T9-T10 segment of the spinal cord. Then, a 10 g weight steel rod was adopted to damage the exposed spinal cord from 20 mm height, resulting in a moderate contusive SCI model [ 22 , 23 ]. After the surgical operation, the bladders of the mice were manually emptied twice a day until the bladder's function recovered.…”

“…Oxidative Medicine and Cellular Longevity the spinal cord. Then, a 10 g weight steel rod was adopted to damage the exposed spinal cord from 20 mm height, resulting in a moderate contusive SCI model [22,23]. After the surgical operation, the bladders of the mice were manually emptied twice a day until the bladder's function recovered.…”

BRD4 Inhibition Suppresses Senescence and Apoptosis of Nucleus Pulposus Cells by Inducing Autophagy during Intervertebral Disc Degeneration: An In Vitro and In Vivo Study

“…Kornicka et al [49] reported that 5-azacytydine and resveratrol via modulation of autophagy reverse senescence and apoptosis of adipose stem cells. BRD4 reduces apoptosis induced by oxidative stress after spinal cord injury by regulating autophagy [50]. Mu et al [20] showed that BRD4 inhibits autophagy mediated by PINK1/Parkin to prevent high-fat diet-induced diabetic cardiomyopathy.…”

Sesamol Attenuates Neuroinflammation by Regulating the AMPK/SIRT1/NF-κB Signaling Pathway after Spinal Cord Injury in Mice

“…The BMS score of mice ranges from 0 (completely paralysis) to 9 (normal locomotion). For the inclined plane test, mice were placed on a rubber board, and then, the angles at which the mice could not hold its position for 5 sec were defined as the maximum angles, which could be used to evaluate the hind limb strength of mice [ 31 ]. The results of mouse hind limb movements were blindly recorded by two trained investigators.…”