B-RAFV600E Inhibitor Dabrafenib Attenuates RIPK3-Mediated Necroptosis and Promotes Functional Recovery after Spinal Cord Injury

Abstract

The receptor-interacting protein kinase 3 (RIPK3) is a key regulator of necroptosis and is involved in various pathologies of human diseases. We previously reported that RIPK3 expression is upregulated in various neural cells at the lesions and necroptosis contributed to secondary neural tissue damage after spinal cord injury (SCI). Interestingly, recent studies have shown that the B-RAFV600E inhibitor dabrafenib has a function to selectively inhibit RIPK3 and prevents necroptosis in various disease models. In the present study, using a mouse model of thoracic spinal cord contusion injury, we demonstrate that dabrafenib administration in the acute phase significantly inhibites RIPK3-mediated necroptosis in the injured spinal cord. The administration of dabrafenib attenuated secondary neural tissue damage, such as demyelination, neuronal loss, and axonal damage, following SCI. Importantly, the neuroprotective effect of dabrafenib dramatically improved the recovery of locomotor and sensory functions after SCI. Furthermore, the electrophysiological assessment of the injured spinal cord objectively confirmed that the functional recovery was enhanced by dabrafenib. These findings suggest that the B-RAFV600E inhibitor dabrafenib attenuates RIPK3-mediated necroptosis to provide a neuroprotective effect and promotes functional recovery after SCI. The administration of dabrafenib may be a novel therapeutic strategy for treating patients with SCI in the future.

RIPK3: A New Player in Renal Fibrosis

“…The serine/threonine kinase B-Raf V600E inhibitor dabrafenib is the only type I RIPK3 inhibitor approved for clinical use (Rheault et al, 2013;Li et al, 2014;Sugaya et al, 2019). Previous studies have reported that dabrafenib is a selective RIPK3 inhibitor in various models, including human hepatocytes (Li et al, 2014), mouse models of acetaminophen-caused liver injury (Li et al, 2014), and ischemic brain injury (Cruz et al, 2018).…”

Receptor-Interacting Protein Kinase 3 Inhibition Relieves Mechanical Allodynia and Suppresses NLRP3 Inflammasome and NF-κB in a Rat Model of Spinal Cord Injury

“…The previous studies mainly discussed the role of RIPK3-mediated necroptosis in secondary SCI, but few studies further explored the effects of regulating RIPK3 on neuroinflammation and pain. Sugaya et al ( 2019 ) found that RIPK3 modulation prevented necroptosis of various nerve cells at the lesion site and favored neuroprotection. Dabrafenib treatment, one of the RIPK3 inhibitors, also promoted the recovery of motor function and sensory function after SCI.…”

Effects of combination treatment with transcranial magnetic stimulation and bone marrow mesenchymal stem cell transplantation or Raf inhibition on spinal cord injury in rats

“…However, whether the combined use of TMS and BMSCs is more effective compared with either therapy alone in treating SCI is not completely understood. Raf inhibition has also been reported as a potential therapeutic strategy for SCI ( 30 ), but whether the combination of TMS and Raf inhibition displays synergistic effects on SCI recovery requires further investigation. Therefore, the present study aimed to compare the effects of TMS, BMSC transplantation, RafI, TMS+BMSCs and TMS+RafI treatment on SCI in vivo .…”

“…Raf/MEK/ERK signaling is also involved in neuronal apoptosis in the hippocampus following subarachnoid hemorrhage ( 28 ). Previous studies revealed that Raf/MEK/ERK signaling was upregulated in SCI model rats ( 29 ), and that the Raf inhibitor dabrafenib displays potential to facilitate SCI recovery ( 30 ). Therefore, the present study aimed to investigate the feasibility of allogenic BMSCs and Raf inhibition for SCI treatment.…”