gms | German Medical Science

Objective: Traumatic spinal cord injury (SCI) remains a devastating event with no neuroprotective treatment currently available. Disruption of the blood-spinal cord barrier (BSCB) with subsequent edema formation and neuroinflammation contributes to the disease’s seriousness. It has been linked to the release of the neuropeptide Substance-P (SP). In our current study, we, therefore, aimed to antagonize the binding of SP to its neurokinin-1 (NK1) receptor with N-acetyl-L-tryptophan (NAT) in a rodent SCI model.

Methods: 66 female Wistar rats were subjected to either a thoracic clip-contusion/compression SCI at the T10 level or sham surgery (laminectomy). After trauma application, an osmotic micropump was additionally implanted, and infusion of NAT or Vehicle into the intrathecal space over the spinal cord lesion was initiated. The Basso, Beattie, Bresnahan (BBB) score, the Gridwalk test, and the CatWalk gait analysis were performed to assess functional recovery. After infusion of NAT/Vehicle for 1, 3, or 7 days, animals were sacrificed, immunohistological analyses were conducted, and results were statistically compared between groups (p < 0.05 was considered significant).

Results: In immunohistological analyses, the inhibition of SP via NAT in the injured spinal cord showed no significant effects on macrophages’ infiltration and their polarization towards the M1- or the M2-subtype 7 days after SCI. However, the invasion of T-lymphocytes was significantly reduced with the NAT treatment. Furthermore, a reduced leakage of Fibrinogen and an attenuated expression of ß-Catenin was found, indicating a significant effect of NAT on the integrity of the BSCB. Correspondingly, a trend towards reduced spinal cord edema could be observed 7 days after the injury. Fine motor recovery measured by the Gridwalk test was not significantly affected after intrathecal NAT infusion for 7 days. However, animals in the NAT group showed a significantly increased BBB score and significantly improved recovery in the CatWalk gait analysis.

Conclusion: In our study, the intrathecal administration of the NK1 receptor antagonist NAT led to increased integrity of the BSCB in the acute phase after thoracic SCI, potentially attenuating aspects of neuroinflammation, reducing edema formation, and improving functional recovery. Our findings suggest that NAT might have neuroprotective properties, which should be further assessed in the context of SCI.