Abstract
Protecting white matter is one of the key treatment strategies for spinal cord injury (SCI), including alleviation of myelin loss and promotion of remyelination. Rapamycin has been shown neuroprotective effects against SCI and cardiotoxic effects while enhancing autophagy. However, specific neuroprotection of rapamycin for the white matter after cervical SCI has not been reported. Therefore, we aim to evaluate the role of rapamycin in neuroprotection after hemi-contusion SCI in mice. Forty-six 8-week-old mice were randomly assigned into the rapamycin group (n = 16), vehicle group (n = 16), and sham group (n = 10). All mice of the rapamycin and vehicle groups received a unilateral contusion with 1.2-mm displacement at C5 followed by daily intraperitoneal injection of rapamycin or dimethyl sulfoxide solution (1.5 mg⋅kg–1⋅day–1). The behavioral assessment was conducted before the injury, 3 days and every 2 weeks post-injury (WPI). The autophagy-related proteins, the area of spared white matter, the number of oligodendrocytes (OLs) and axons were evaluated at 12 WPI, as well as the glial scar and the myelin sheaths formed by Schwann cells at the epicenter. The 1.2 mm contusion led to a consistent moderate–severe SCI in terms of motor function and tissue damage. Rapamycin administration promoted autophagy in spinal cord tissue after injury and reduced the glial scar at the epicenter. Additionally, rapamycin increased the number of OLs and improved motor function significantly than in the vehicle group. Furthermore, the rapamycin injection resulted in an increase of Schwann cell-mediated remyelination and weight loss. Our results suggest that rapamycin can enhance autophagy, promote Schwann cell myelination and motor function recovery by preserved neural tissue, and reduce glial scar after hemi-contusive cervical SCI, indicating a potential strategy for SCI treatment.
Highlights
MATERIALS AND METHODSSpinal cord injury (SCI) is a devastating disease that can lead to permanent motor and sensory dysfunction
We demonstrated that rapamycin administration promotes the recovery of motor function and alleviates myelin loss after spinal cord injury (SCI)
The rapamycin treatment increased the area of spared white matter at 12 weeks post-injury (WPI) and reduced the glial scar formation and the loss of spinal cord tissues
Summary
Spinal cord injury (SCI) is a devastating disease that can lead to permanent motor and sensory dysfunction. The protection of white matter is mainly to reduce myelin loss and promote remyelination in the acute and chronic SCI phases, respectively. Inflammation and peroxidation in the secondary pathology following SCI often contributed to the death of OLs (Connor and Menzies, 1996; Thorburne and Juurlink, 1996; Almad et al, 2011) and caused the loss of myelin sheath. The myelin loss can cause abnormal transmission of electrical signals and degeneration of the axons, which will further aggravate the motor and sensory dysfunction. Alleviating myelin loss and promoting endogenous remyelination are an important strategy for the treatment of SCI
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