gms | German Medical Science

Introduction: Multiple trauma patients frequently suffer from a combination of traumatic brain injury (TBI) and fractures. The release of Substance P (SP), a neuropeptide in primary sensory neurons, is significantly increased after TBI. The neurokinin 1 receptor (NK1-R) located on osteoblasts and on osteoclasts is suggested to represent one of the main targets for SP. Therefore it might be assumed that this interaction has a significant impact on fracture healing. We hypothesize that the blockage of NK1 R by the non-peptide SR140333 results in an impaired fracture healing.

Material and Methods: A femur fracture was created by a blunt guillotine device in anesthetized Sprague Darwley rats (250g BW). Rats were divided into 12 groups (3d, 7d, 14d, 28d and 48d; 3 month for gait analysis; 6 animals/ group). SR140333 was given subcutaniously over the time course of the first 2 weeks once per day. RT-PCRs were performed for analysis of expression of osteocalcin, collagen 1 and 2 of bone and callus material from the fracture site (3d; 7d; 14d). Load to failure was assessed at 6 and 42 weeks after trauma by biomechanical testing. At 6 weeks after trauma µCT scanning of the fractured femur was performed in order to determine bone and callus density and diameter.

Results: Results showed a significantly impaired fracture healing for the SR140333 treated groups. After SR14033 application all NK1-R antagonist treated groups had significantly reduced expression levels of osteocalcin (1 week p0.05= 0.0002), collagen 1 (1 week p0.05= 0.00148; 2 weeks p0.05= 0.00028) and collagen 2 (p0.05= 0.000041) in the first 14 days after trauma compared to non-treated control groups. Biomechanical testing at 6 weeks (sham 142.95 N vs. treated 69.78 N) and at 3 months (176.2 N vs. 72.5 N) revealed significantly lower load to failure values in the SR14033-treated animals. µCT scanning showed a decrease of both, callus diameter (6.1 mm (control) vs. 5.8 mm (treated)) and density (control 4826 mean voxel intensity (mvi) (bone) to 4487 mvi (callus) vs. treated: 4592 mvi (bone) to 4387 mvi (callus) comparing the control and the treated femora.

Discussion and Conclusion: Blockade of the interaction between SP and NK1-R significantly impairs fracture healing. Therefore, it might be assumed that this interaction might represent a promising therapeutic target for treatment of disturbances of fracture healing after multiple trauma.