Neuroprotection and acute spinal cord injury: A reappraisal

Abstract

Summary: It has long been recognized that much of the posttraumatic degeneration of the spinal cord following injury is caused by a multi-factorial secondary injury process that occurs during the first minutes, hours, and days after spinal cord injury (SCI). A key biochemical event in that process is reactive oxygeninduced lipid peroxidation (LP). In 1990 the results of the Second National Acute Spinal Cord Injury Study (NASCIS II) were published, which showed that the administration of a high-dose regimen of the glucocorticoid steroid methylprednisolone (MP), which had been previously shown to inhibit post-traumatic LP in animal models of SCI, could improve neurological recovery in spinal-cord-injured humans. This resulted in the registration of high-dose MP for acute SCI in several countries, although not in the U.S. Nevertheless, this treatment quickly became the standard of care for acute SCI since the drug was already on the U.S. market for many other indications. Subsequently, it was demonstrated that the non-glucocorticoid 21-aminosteroid tirilazad could duplicate the antioxidant neuroprotective efficacy of MP in SCI models, and evidence of human efficacy was obtained in a third NASCIS trial (NASCIS III). In recent years, the use of high-dose MP in acute SCI has become controversial largely on the basis of the risk of serious adverse effects versus what is perceived to be on average a modest neurological benefit. The opiate receptor antagonist naloxone was also tested in NASCIS II based upon the demonstration of its beneficial effects in SCI models. Although it did not a significant overall effect, some evidence of efficacy was seen in incomplete (i.e., paretic) patients. The monosialoganglioside GM1 has also been examined in a recently completed clinical trial in which the patients first received high-dose MP treatment. However, GM1 failed to show any evidence of a significant enhancement in the extent of neurological recovery over the level afforded by MP therapy alone. The present paper reviews the past development of MP, naloxone, tirilazad, and GM1 for acute SCI, the ongoing MP-SCI controversy, identifies the regulatory complications involved in future SCI drug development, and suggests some promising neuroprotective approaches that could either replace or be used in combination with high-dose MP.

Corticosteroids Reduce Glial Fibrillary Acidic Protein Expression in Response to Spinal Cord Injury in a Fetal Rat Model of Dysraphism

“…In the USA, the National Acute Spinal Cord Injury Study (NASCIS II and NASCIS III) found that high doses of methylprednisolone administered during the first 8 h after trauma are associated with significant clinical improvement in patients with spinal cord injury, though less so in patients with paraplegia or quadriplegia [33]. In animal models, clinical improvement with corticoids is not necessarily followed by recovery of histological damage [34].…”

“…For example, Merola et al [35] observed no change in GFAP expression in adult rats with complete spinal cord injury receiving methylprednisolone. Hence, the neuroprotective mechanism of corticoids may not be mediated by astrocytes, although other anti-inflammatory events may be involved [33]. …”

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

“…The secondary injury is caused by ischemia/reperfusion, electrolyte imbalance, free radical damage, ischemia, excitotoxicity, apoptosis, and inflammation, [3][4][5][6] which all contribute to neuronal cell death, astrocyte activation and proliferation. 7,8 Rapid proliferation of astrocytes is benefited from abnormal modulation of cell cycle.…”

Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury

“…For example, in cats, the observed dose-response is an inverted U-shaped curve, with higher doses (e.g., 60 mg͞kg) being ineffective (reviewed by Hall and Springer in ref. 10). Other species, e.g., rodents, have received less attention, but the results suggest a different outcome, with only a small window of opportunity for reducing tissue injury and with no improvement in motor outcome (11).…”