Lazaroids: Mechanisms of Action and Implications for Disorders of the CNS

Abstract

Oxygen radical-induced lipid peroxidation to cerebrovascular or brain parenchymal cell membranes has been implicated as a pathophysiological mechanism in both acute and chronic neurodegenerative disorders, including brain and spinal cord trauma, ischemic and hemorrhagic stroke, Alzheimer's and Parkinson's diseases, and amyotrophic lateral sclerosis. As a result, pharmacological strategies have been aimed at antagonizing lipid peroxidative damage in a safe and effective manner. Perhaps the first successful antioxidant neuroprotective approach is high dose treatment with the glucocorticoid steroid methylprednisolone, which has been reported to be effective in improving neurological recovery after blunt spinal cord injury in animals and humans. After a determination that these effects were based upon inhibition of posttraumatic lipid peroxidative reactions rather than steroid receptor interactions, a new class of 21 -aminosteroids ("lazaroids") was discovered. The lazaroids are more effective inhibitors of lipid peroxidation and, at the same time, devoid of glucocorticoid side effect potential. One of them, tirilazad (U-74006F), was found protective in a variety of preclinical neuroprotection models and is currently the subject of Phase Ill clinical trials. Thus far, the compound has been demonstrated to significantly improve 3-month survival and neurological recovery afier subarachnoid hemorrhage in humans. Although tirilazad does penetrate the injured CNS, much of its protective activity is mediated by an action on vascular endothelium. Recently, the 21 -aminosteroids have been followed up with a newer series of non-steroidal compounds, the pyrrolopyrimidines, which possess even greater antioxidant efficacy and brain penetration that may be useful for the treatment of chronic neurodegenerative disorders. NEUROSCIENTIST 3:42-51, 1997.A major role of oxygcn radical-induced cellular injury has been strongly implicatcd in thc pathophysiology of acute CNS traumatic and ischcmic injuries (1-3) and subarachnoid hemorrhage (SAH) (4). Oxidative dcgencration has also been increasingly recognized as a player in Parkinson's discasc (5-7), Alzhcimer's disease (8,9), and motor neuron discascs likc amyotrophic lateral sclerosis (ALS) (10, 11).Proteins, nuclcic acids, and carbohydrates are all susccptiblc to oxygcn radical damage, but pcrhaps the most avid targets of oxygcn radical-induced injury arc ccll mcmbranc lipids, including cholesterol and, in particular, polyunsaturated fatty acids. The process of lipid damagc by oxygcn radicals is known as lipid pcroxidation (LP). CNS tissuc provides an especially scnsitivc target for LP reactions. One reason for this is thc high content of iron found in many brain rcgions, which varics in parallcl with thc rcgional scnsitivity to cx vivo LP (12). In addition, the brain accumulatcs iron as a function of age (13). Figurc I shows the iron-catalpcd reaction Address reprint requests to: Edward D. Hall, Ph.D.. CNS Discascs Rcscarch. Pharmacia 6 : Upjohn. Inc., hlamazoo, MI 49001.mechanisms i...

Neuroprotection and acute spinal cord injury: A reappraisal

“…If in fact the plasticityinhibiting and neurotoxic actions of glucocorticoids are shown to occur in the injured cord coincident with the neuroprotective antioxidant actions this will be yet another example of how MP can constitute a "two-edged sword" in the treatment of acute SCI. In any event, the potential for steroid side effects, inhibition of plasticity mechanisms and even neurotoxic actions underscores the fact that glucocorticoids such as MP are a far-from-ideal approach to dealing with the post-traumatic oxidative stress and LP-related damage and consequent need for antioxidant dosing that continues beyond the first 24 to 48 h. The realization of these limitations was the impetus for the discovery of the non-glucocorticoid steroid tirilazad 56,57 to provide a LP-inhibiting steroid that would be easier to use and be devoid of the detrimental CNS and non-CNS aspects of glucocorticoid steroids. Tirilazad's ability to improve neurological recovery in NASCIS III at least as well as MP (i.e., treatment within 3 h postinjury) while producing fewer side effects 59,60 strongly suggest that it is worthy of additional trials in acute SCI that could ultimately show greater efficacy and safety in comparison to high-dose MP.…”

Antioxidant Therapies for Acute Spinal Cord Injury

“…Despite the possible role of these effects of MP in the injured spinal cord, the principal neuroprotective mechanism appears to be the inhibition of post-traumatic LP that is not mediated via glucocorticoid receptor-mediated activity [91][92][93]. This knowledge prompted the hypothesis that modifying the steroid molecule to enhance the anti-LP effect, while eliminating the glucocorticoid effects of the steriod would result in more targeted antioxidant therapy devoid of the typical side effects of steroid therapy.…”

“…The demonstrated efficacy of a 24-h dosing regimen of MP in human SCI in NASCIS II [83] and the discovery of tirilazad [91][92][93] prompted the conduct of NASCIS III [96,97]. In the NASCIS III trial, 3 groups of patients were evaluated.…”

Drug development in spinal cord injury: What is the FDA looking for?

“…The principal mechanism of the neuroprotective action for MP in the injured spinal cord was determined to be inhibiting post-traumatic LP, rather than it being mediated via glucocorticoid receptor-mediated activity [24][25][26]. This prompted our speculation that modifying the steroid molecule to enhance the anti-LP effect, while eliminating the steroid's glucocorticoid-related effects, would result in more targeted therapy devoid of the typical side effects of steroid therapy.…”

“…The demonstrated efficacy of a 24-hour dosing regimen of MP in human SCI in NASCIS II [18], and the discovery of tirilazad [24][25][26], led to another trial of these agents in human SCI, NASCIS III [27,28]. In the NASCIS III trial, 3 groups of patients were evaluated.…”