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.
Highlights
The neurological outcome of spinal cord injury (SCI) is caused by the initial mechanical tissue damage and the consequent cellular and molecular events, known as secondary injury, that increase the lesion size in the injured spinal cord [1,2]
We examine whether the administration of dabrafenib attenuates receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis and secondary injury and improves functional recovery following SCI using a mouse model of thoracic spinal cord contusion injury
To evaluate the effect of dabrafenib treatment on the recovery of the locomotor function, the total scores and subscores of the Basso mouse scale (BMS) were measured for 42 days following SCI (Figure 1A,B)
Summary
The neurological outcome of spinal cord injury (SCI) is caused by the initial mechanical tissue damage and the consequent cellular and molecular events, known as secondary injury, that increase the lesion size in the injured spinal cord [1,2]. Secondary injury has been considered to be mainly caused by apoptosis occurring in the hours to weeks after SCI [3,4]. Over the past few decades, numerous studies have been conducted to identify effective therapeutic strategies to reduce secondary tissue damage following SCI. Most of these studies have mainly focused on the prevention of apoptosis [1]. No clinically useful therapeutic strategy that can inhibit secondary damage has yet been established.
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