Neuroprotection and Acute Spinal Cord Injury: A Reappraisal

Edward D. Hall, Joe E. Springer

Research output: Contribution to journalArticlepeer-review

359 Scopus citations

Abstract

It has long been recognized that much of the post-traumatic 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 oxygen-induced 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.

Original languageEnglish
Pages (from-to)80-100
Number of pages21
JournalNeuroRx
Volume1
Issue number1
DOIs
StatePublished - Jan 2004

Bibliographical note

Funding Information:
The clinical testing of MP in either NASCIS I or II was much easier than the typical scenario of new drug development, due to the fact that MP had already been successfully developed, approved by the U.S. Food and Drug Administration (FDA), and marketed over several years for a wide variety of anti-inflammatory conditions. MP in multiple oral, intramuscular, and intravenous formulations was approved in the early 1960s, and the drug was actually off-patent in the U.S. by the time of the initiation of the NASCIS trials. Furthermore, in regards to the testing of high doses of the steroid in SCI patients, there was already considerable clinical experience with the i.v. administration of doses as high or higher than 30 mg/kg in several clinical studies concerned with the potential use of MP in various critical care indications. The safety of this high-dose treatment for a short period had already been established, even in severely compromised patients. Therefore, the approval of the Investigational New Drug Application for testing in human SCI did not pose a significant hurdle. Moreover, the trials were not initiated or controlled by the drug's original sponsor (The Upjohn Company, Kalamazoo, MI), but rather by the NASCIS group headed by Dr. Michael Bracken (Epidemiology and Public Health, Yale University, New Haven, CT). Although Upjohn provided the supplies of their already marketed MP formulation (Solu Medrol) and the aqueous vehicle (placebo) in support of NASCIS I and II, the trials were funded solely with peer-reviewed grant support from the NINDS. NASCIS III was also NIH-supported although Upjohn, in addition to providing MP at no cost, shouldered some of the monitoring costs relevant to tirilazad which was still under pre-marketing clinical development. However, the clinical data analysis was carried out at Yale University, completely independent of The Upjohn Company.

Keywords

  • Spinal cord injury
  • apoptosis
  • methylprednisolone
  • naloxone
  • neuroprotection
  • secondary injury

ASJC Scopus subject areas

  • Pharmacology (medical)

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