Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma

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.

The Role of Astrogliosis in Formation of the Syrinx in Spinal Cord Injury

“…Since astrogliosis appears to play central role in the removal of edema in the SCI, experiments leading to the enhancement of astrogliosis [ 23 ] should address a novel therapeutic approach; the enhancement of the spinal cord tissue reaction designed to accelerate the removal of edema fluid. A more immediate pharmacological approach to eliminating edema may be the use of anti-inflammatories to inhibit [ 7 , 9 , 11 ] and eliminate [ 100 ] inflammation from the COI and thus inhibit vasogenic edema. The breakdown of the BSCB or of the BBB due to severe inflammation following the initial traumatic event [ 6 ] is a complex process involving proteolytic cleavage of the endothelial tight junctions and breakdown of the capillary basement membrane [ 101 ] leading to an uncontrolled leakage of fluid and solutes to the perivascular CNS parenchyma [ 102 , 103 ].…”

“…It is also evident that successful inhibitory treatment of the severe, destructive inflammation in the COI will require an infusion of effective doses well beyond 1-2 weeks [ 6 - 8 , 11 ], not likely achievable with high doses of dexamethasone due to its severe toxicity [ 7 ], indicating the need for non-toxic compounds with powerful anti-inflammatory activity with the ability to also inhibit inflammatory edema following the SCI and also, following brain trauma and stroke. Serp-1 and M-T7 infused subdurally fulfill this requirement and recently completed study determined that constant infusion of Serp-1 at 0.2 mg/week for 8 weeks [ 100 ] resulted in lowering the numbers of macrophages in the COI to levels seen in untreated SCI until 16 weeks post-SCI [ 6 ] indicating a neuroprotective therapeutic effect. Whether inhibition of inflammation in the COI will result in inhibition of vascular damage and accelerate the evacuation of vasogenic edema remains an important question.…”

Early CSF Biomarkers and Late Functional Outcomes in Spinal Cord Injury. A Pilot Study

“…The biomarkers profile, observed in the CSF, collected within 24 h from the injury, also reflects inflammation as the prevalent pathogenic mechanism at this stage of this progressive pathology, that will chronically evolve in neurodegeneration and demyelination. Inflammation is a major player in the so-called "secondary degeneration", that expands the initial damage, sustaining the chronic evolution of the lesion [35], and a recognized, effective target for early pharmacological intervention [36,37]. However, being the traumatic lesion itself, such as the tissue and systemic reaction, a highly personalized process, appropriate biomarker discovery strategy should be based on serial sampling of biological fluids, from injury to stabilization.…”

Credibility of the Neutrophil-to-Lymphocyte Count Ratio in Severe Traumatic Brain Injury

“…Several studies focus on methods to intensify the protective effects of inflammation. Recent publications show positive effects of several drugs such as minocycline, melatonin, statins, subdural infusion of serpine-1, mesenchymal stem cells therapy [124][125][126][127][128][129]. All of these therapies can modulate a neuroinflammatory response, which may affect NLR.…”