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Published on: February 23, 2015
Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma
Jacek M Kwiecien1, Wojciech Dabrowski2, Bryce J Kwiecien-Delaney3
1Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada.
Abstract:
Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163-, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the first week post-SCI, should limit inflammatory damage, shorten its duration and result in neuroprotection. By sustained subdural infusion we administered Serp-1, a Myxoma virus-derived immunomodulatory protein previously shown to improve neurologic deficits and inhibit macrophage infiltration in the COI in rats with the balloon crush SCI. Firstly, in a 7 day long study, we determined that the optimal dose for macrophage inhibition was 0.2 mg/week. Then, we demonstrated that a continuous subdural infusion of Serp-1 for 8 weeks resulted in consistently accelerated lowering of pro-inflammatory macrophages in the COI and in their almost complete elimination similar to that previously observed at 16 weeks in untreated SCI rats. The macrophage count in the COI is a quantitative test directly related to the severity of destructive inflammation initiated by the SCI. This test has consistently demonstrated anti-inflammatory effect of Serp-1 interpreted as neuroprotection, the first and necessary step in a therapeutic strategy in neurotrauma.
Insights
Serp-1 protein administration after spinal cord injury (SCI) significantly reduced destructive inflammation by eliminating pro-inflammatory macrophages. This targeted approach offers potential neuroprotection and limits secondary damage in SCI recovery.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Spinal cord injury (SCI) triggers severe inflammation involving macrophage infiltration.
- This inflammation contributes to secondary damage and cavity formation at the injury site.
- Targeting macrophage activity is a potential strategy for neuroprotection in SCI.
Purpose of the Study:
- To evaluate the efficacy of Serp-1 in inhibiting macrophage infiltration post-SCI.
- To determine the optimal dosage and duration of Serp-1 administration.
- To assess the neuroprotective effects of Serp-1 by quantifying macrophage reduction.
Main Methods:
- Administered Serp-1 via sustained subdural infusion in a rat balloon crush SCI model.
- Determined optimal Serp-1 dosage (0.2 mg/week) in a 7-day study.
- Monitored macrophage counts in the cavity of injury (COI) over an 8-week treatment period.
Main Results:
- Serp-1 administration accelerated the reduction of pro-inflammatory macrophages in the COI.
- Achieved near-complete elimination of macrophages by 8 weeks of Serp-1 treatment.
- Macrophage count reduction correlated with Serp-1's anti-inflammatory and neuroprotective effects.
Conclusions:
- Sustained Serp-1 infusion effectively reduces inflammation post-SCI by inhibiting macrophage infiltration.
- Serp-1 demonstrates significant neuroprotective potential, offering a promising therapeutic avenue for SCI.
- Targeting macrophage-mediated inflammation is a critical step in developing effective SCI treatments.
