Genetic Ablation of Transcription Repressor Bach1 Reduces Neural Tissue Damage and Improves Locomotor Function after Spinal Cord Injury in Mice

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.

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Beneficial effects of modest systemic hypothermia on locomotor function and histopathological damage following contusion-induced spinal cord injury in rats

Journal of Neurosurgery Spine ◽

10.3171/spi.2000.93.1.0085 ◽

2000 ◽

Vol 93 (1) ◽

pp. 85-93 ◽

Cited By ~ 28

Author(s):

Chen Guang Yu ◽

Omar Jimenez ◽

Alexander E. Marcillo ◽

Brian Weider ◽

Kurt Bangerter ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Tissue Damage ◽

Content Type ◽

Locomotor Function ◽

Beneficial Effects ◽

Cord Injury ◽

Systemic Hypothermia ◽

C 30 ◽

Fine Print

Object. Local spinal cord cooling (LSCC) is associated with beneficial effects when applied following ischemic or traumatic spinal cord injury (SCI). However, the clinical application of LSCC is associated with many technical difficulties such as the requirement of special cooling devices, emergency surgery, and complicated postoperative management. If hypothermia is to be considered for future application in the treatment of SCI, alternative approaches must be developed. The objectives of the present study were to evaluate 1) the relationship between systemic and epidural temperature after SCI; 2) the effects of modest systemic hypothermia on histopathological damage at 7 and 44 days post-SCI; and 3) the effects of modest systemic hypothermia on locomotor outcome at 44 days post-SCI. Methods. A spinal cord contusion (12.5 mm at T-10) was produced in adult rats that had been randomly divided into two groups. Group 1 rats (seven in Experiment 1; 12 in Experiment 2) received hypothermic treatment (epidural temperature 32–33°C) 30 minutes postinjury for 4 hours; Group 2 rats (nine in Experiment 1; eight in Experiment 2) received normothermic treatment (epidural temperature 37°C) 30 minutes postinjury for 4 hours. Blood pressure, blood gas levels, and temperatures (epidural and rectal) were monitored throughout the 4-hour treatment period. Twice weekly assessment of locomotor function was performed over a 6-week survival period by using the Basso-Beattie-Bresnahan locomotor rating scale. Seven (Experiment 1) and 44 (Experiment 2) days after injury, animals were killed, perfused, and their spinal cords were serially sectioned. The area of tissue damage was quantitatively analyzed from 16 longitudinal sections selected from the central core of the spinal cord. Conclusions. The results showed that 1) modest changes in the epidural temperature of the spinal cord can be produced using systemic hypothermia; 2) modest systemic hypothermia (32–33°C) significantly protects against locomotor deficits following traumatic SCI; and 3) modest systemic hypothermia (32–33°C) reduces the area of tissue damage at both 7 and 44 days postinjury. Although additional research is needed to study the therapeutic window and long-term benefits of systemic hypothermia, these data support the possible use of modest systemic hypothermia in the treatment of acute SCI.

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Rapamycin Promotes Autophagy and Reduces Neural Tissue Damage and Locomotor Impairment after Spinal Cord Injury in Mice

Journal of Neurotrauma ◽

10.1089/neu.2011.1919 ◽

2012 ◽

Vol 29 (5) ◽

pp. 946-956 ◽

Cited By ~ 112

Author(s):

Akira Sekiguchi ◽

Haruo Kanno ◽

Hiroshi Ozawa ◽

Seiji Yamaya ◽

Eiji Itoi

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Tissue Damage ◽

Neural Tissue ◽

Cord Injury ◽

Locomotor Impairment

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Changes in Expression of Receptor-Interacting Protein Kinase 1 in Secondary Neural Tissue Damage Following Spinal Cord Injury

Neuroscience Insights ◽

10.1177/2633105520906402 ◽

2020 ◽

Vol 15 ◽

pp. 263310552090640

Author(s):

Haruo Kanno ◽

Hiroshi Ozawa ◽

Kyoichi Handa ◽

Taishi Murakami ◽

Eiji Itoi

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Death ◽

Tissue Damage ◽

Time Course ◽

Apoptotic Cell ◽

Neural Tissue ◽

Apoptotic Cell Death ◽

Neural Cells ◽

Cord Injury

Introduction: Necroptosis is a form of programmed cell death that is different from apoptotic cell death. Receptor-interacting protein kinase 1 (RIPK1) plays a particularly important function in necroptosis execution. This study investigated changes in expression of RIPK1 in secondary neural tissue damage following spinal cord injury in mice. The time course of the RIPK1 expression was also compared with that of apoptotic cell death in the lesion site. Methods and Materials: Immunostaining for RIPK1 was performed at different time points after spinal cord injury. The protein expressions of RIPK1 were determined by western blot. The RIPK1 expressions in various neural cells were investigated using immunohistochemistry. To investigate the time course of apoptotic cell death, TUNEL-positive cells were counted at the different time points. To compare the incidence of necroptosis and apoptosis, the RIPK1-labeled sections were co-stained with TUNEL. Results: The RIPK1 expression was significantly upregulated in the injured spinal cord. The upregulation of RIPK1 expression was observed in neurons, astrocytes, and oligodendrocytes. The increase in RIPK1 expression started at 4 hours and peaked at 3 days after injury. Time course of the RIPK1 expression was similar to that of apoptosis detected by TUNEL. Interestingly, the increased expression of RIPK1 was rarely observed in the TUNEL-positive cells. Furthermore, the number of RIPK1-positive cells was significantly higher than that of TUNEL-positive cells. Conclusions: This study demonstrated that the expression of RIPK1 increased in various neural cells and peaked at 3 days following spinal cord injury. The temporal change of the RIPK1 expression was analogous to that of apoptosis at the lesion site. However, the increase in RIPK1 expression was barely seen in the apoptotic cells. These findings suggested that the RIPK1 might contribute to the pathological mechanism of the secondary neural tissue damage after spinal cord injury.

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