An in vivo model of anti-inflammatory activity of subdural dexamethasone following the spinal cord injury

Abstract

Current therapies to limit the neural tissue destruction following the spinal cord injury are not effective. Our recent studies indicate that the injury to the white matter of the spinal cord results in a severe inflammatory response where macrophages phagocytize damaged myelin and the fluid-filled cavity of injury extends in size with concurrent and irreversible destruction of the surrounding neural tissue over several months. We previously established that a high dose of 4mg/rat of dexamethasone administered for 1 week via subdural infusion remarkably lowers the numbers of infiltrating macrophages leaving large amounts of un-phagocytized myelin debris and therefore inhibits the severity of inflammation and related tissue destruction. But this dose was potently toxic to the rats. In the present study the lower doses of dexamethasone, 0.125-2.0mg, were administered via the subdural infusion for 2 weeks after an epidural balloon crush of the mid-thoracic spinal cord. The spinal cord cross-sections were analyzed histologically. Levels of dexamethasone used in the current study had no systemic toxic effect and limited phagocytosis of myelin debris by macrophages in the lesion cavity. The subdural infusion with 0.125-2.0mg dexamethasone over 2 week period did not eliminate the inflammatory process indicating the need for a longer period of infusion to do so. However, this treatment has probably lead to inhibition of the tissue destruction by the severe, prolonged inflammatory process.

Prolonged inflammation leads to ongoing damage after spinal cord injury

“…After the initial injury there is an intense macrophage infiltration into damaged and necrotic areas, coinciding with conversion of damaged sites into a cavity of injury (COI), which blocks neuronal regrowth [13][14][15][16]. Axonal regrowth is inhibited by scar [3] and the fluid-filled spaces in the COI lesions [17].…”

Prolonged inflammation leads to ongoing damage after spinal cord injury

“…Damaged myelin has potent immunogenic functions in experimental allergic encephalomyelitis (EAE) [18] and after SCI [19] inducing severe lymphocyte-rich inflammation in EAE and macrophage-rich inflammation in SCI [12,13,17]. As previously reported in Long Evans Shaker (LES) rats lacking myelin [20–22] there is a reduction in inflammation after SCI [15].…”

“…Axonal regrowth is inhibited by scar [2] and the fluid-filled spaces in the COI lesions [15]. The main characteristics of inflammation in SCI are ongoing spinal cord destruction, extraordinarily long duration and conversion of necrotic areas into the COI [12, 13] or arachnoiditis [16]. These changes after SCI are attributed to unique spinal tissue reactions, not observed in extra-neural trauma.…”

“…The longevity of the inflammatory phase seen after SCI indicates that 24-48 hrs of intravenous infusion of high dose anti-inflammatory treatments such as methylprednisolone succinate [23] may provide a partial explanation for why short term high dose steroid infusions are unlikely to be effective as has been demonstrated by a lack of efficacy in prior clinical trials for steroid infusions given early after SCI. High dose steroids additionally cause severe toxicity [1], indicating the need for novel anti-inflammatory compounds of low toxicity that can target central mediators of ongoing inflammation and injury, with potential for sustained long-term administration designed to reduce prolonged inflammation after SCI [13, 24].…”

Local Serpin Treatment via Chitosan-Collagen Hydrogel after Spinal Cord Injury Reduces Tissue Damage and Improves Neurologic Function

“…Indeed, the American Association of Neurological Surgeons and the Congress of Neurological Surgeons published a medical evidence-based guideline with recommendation against the use of methylprednisolone in SCI [16]. Many minimally invasive and regenerative therapeutics are under investigation ranging from regenerative therapy with hydrogel implants, stem cells, growth factors, magnesium and antioxidants, among others, but without proven long term benefits at this time [1,2,[4][5][6][7][11][12][13]17,18]. Chitosan hydrogels with or without growth factors have been proven to promote SCI restoration and axon regeneration in rat and monkey models [19][20][21].…”