Original article Subdural infusion of dexamethasone inhibits leukomyelitis after acute spinal cord injury in a rat model

Abstract

A b s t r a c t Trauma in spinal cord injury often results in massive damage to the white matter and in damage to myelin that results in a severe phagocyte-rich infiltration apparently directed at removing immunologically toxic myelin debris. In the epidural balloon crush injury to the rat cranial thoracic spinal cord, the dorsal column was crushed, which at one week post-op resulted in its obliteration by a severe infiltration by a virtually pure population of macrophages that internalized all damaged myelin. A week-long subdural infusion of dexamethasone, a stable synthetic corticosteroid, resulted in remarkable inhibition of the macrophage infiltration of the crush cavity and in the lack of removal of myelin debris by phagocytosis. In this study we demonstrated that spinal cord injury results in a severe inflammatoryresponse directed at massively damaged myelin, and we inhibited this response with a subdural infusion of a powerful anti-inflammatory drug, dexamethasone.

Safe Use of Epidural Corticosteroid Injections: Recommendations of the WIP Benelux Work Group

“…Intrathecally administered dexamethasone weakens glutamate dehydrogenase and glutamate downregulation, as well as antinociceptive tolerance in rats in the long term . Subdural administration during 1 week of dexamethasone in a rat model of spinal cord injury resulted in the inhibition of a serious inflammatory response to the damaged myelin . In another study, intrathecally administered dexamethasone worsened thermal hyperalgesia and mechanical allodynia in rats with a chronic constriction injury.…”

The Serpintine Solution

“…Certainly in the absence of NSP in mice, cerebral arterial occlusion leads to larger stroke sizes suggesting a protective mechanism for NSP in this model. A pilot, 7-day subdural infusion of Serp-1 in the vicinity of the SCI resulted in remarkable inhibition of inflammation seen histologically as inhibition of macrophage infiltration similar to that observed in subdural administration of high dose of dexamethasone, [51]. Administration of dexamethasone however, resulted in severe steroid toxicity in recipient rats while Serp-1 was well tolerated, emphasizing the need to study this protein as a neuroprotective therapy administered chronically, suitable for inhibition and elimination of the destructive inflammation in the white matter injury, not only in spinal cord and brain injuries but also in stroke.…”

“…The white matter inflammation that lasts 12-16 weeks in the rat model of SCI, the most severe inflammatory reaction in the body, appears to get out of control of anti-inflammatory mechanisms that typically inhibit and eliminate the inflammation in any extra-neural tissue within 2-3 weeks, resulting in a quiescent scar [51]. Is the supply of serpins exhausted in the white matter injury and thus a powerful antiinflammatory mechanism removed?…”

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.…”