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A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis ¹

Neuroinflammation Research Laboratories, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA

²Correspondence: Neuroinflammation Research Laboratories, Mount Sinai School of Medicine, Department of Psychiatry, One Gustave L. Levy Place, Box 1230, New York, NY 10029, USA. E-mail: giulio.pasinetti{at}mssm.edu

SPECIFIC AIMS

We report the effects of the preferential cyclooxygenase (COX)-2 inhibitor nimesulide on motor impairment in the G93A superoxide dismutase (SOD1-G93A) mouse model of amyotrophic lateral sclerosis (ALS). Prophylactic dietary supplementation with nimesulide beginning at 7 wk of age resulted in a significant delay in the onset of motor impairment and reduced COX-2-mediated induction of proinflammatory prostaglandin in the cervical spinal cord toward normal/control levels. This evidence provides strong support for the therapeutic use of COX-2 inhibitors in ALS.

PRINCIPAL FINDINGS

1. Motor ability as a function of the therapeutic efficacy of nimesulide
To measure the onset and progression of ALS type symptomatology in SOD1-G93A transgenic mice, we conducted two independent but similar tests of muscle strength, balance, and coordination: the accelerating Rotarod and the grid walking test. We found that SOD1-G93A transgenic mice fed normal diet exhibited a mean onset of motor impairment at 108 days of age in the Rotarod test (Fig. 1 A) and 113 days in the grid walking test (Fig. 1B ). However, dietary supplementation with nimesulide imparted a significant delay in the onset of ALS-type symptomatology and preserved motor skill integrity up to 120 days of age in the Rotarod test and 124 days in the grid walking test. After this period of therapeutic delay, motor activity of SOD1-G93A mice fed the nimesulide diet declined to levels similar to that of SOD1-G93A mice fed a normal diet. Wild-type groups displayed optimum performance scores of 180 s (Rotarod) and 0 foot misses (grid walking test) throughout the testing period.

View larger version (30K): [in this window] [in a new window]   Figure 1. Nimesulide (NIM) treatment delays the onset of motor impairment in SOD1-G93A mutant mice. A) Effects of nimesulide on Rotarod performance and B) grid walking test. Red circles denote SOD1-G93A mice fed a normal diet; blue diamonds = SOD1-G93A nimesulide-fed mice; black squares = WT littermates fed a normal diet; green triangles (overlapping the black squares) = WT nimesulide-fed mice. There was improved performance with nimesulide supplementation at most time points between 109 and 125 days of age (in brackets). A, B) *P < 0.05 (t test) compared with SOD1-G93A female transgenic mice fed a normal diet (n=6 per group).

2. PG-E2 levels as a function of the therapeutic efficacy of nimesulide
Consistent with previous evidence, in parallel studies we found that the absolute concentration of PG-E2 content in the cervical spinal cord of SOD1-G93A mice (control diet) relative to WT group exhibited a > threefold elevation (Fig. 2 ). Most important, we found that prophylactic treatment of SOD1-G93A (and WT) mice with nimesulide in the diet coincided with significantly decreased PG-E2 content, similar to WT controls.

View larger version (21K): [in this window] [in a new window]   Figure 2. Nimesulide and PG-E2 content in the serum and spinal cord of end-stage ALS type motor impairment. A) Bar graphs representing nimesulide content in serum and spinal cord were assessed in the same mice; average age of mice used in this study was 140 days of age (time of death); no detectable nimesulide was found in mice fed a normal diet, as expected. B) Bar graphs represent the spinal cord content of PG-E2 levels in WT or SOD1-G93A mice fed a normal or a nimesulide-supplemented diet. Data (means±SE) are from 3–6 female mice per group; ***P < 0.001, *P < 0.01 vs. wild-type group; **P < 0.001 vs. SOD1 (Newman-Keuls post hoc test).

CONCLUSIONS AND SIGNIFICANCE

Increasing anecdotal evidence suggests that, based on anti-inflammatory properties, COX-2 inhibitors may delay neuroinflammation in ALS and be useful in lessening the symptoms of motor dysfunction in this disease. In the present study we provide the first experimental evidence that prophylactic treatment of SOD1-G93A mice with the preferential COX-2 inhibitor nimesulide significantly delays the onset of motor dysfunction in the SOD1-G93A transgenic mice relative to SOD1-G93A mice fed a normal diet. Nimesulide is a preferential COX-2 inhibitor with potent antioxidant properties that we have previously shown to be well tolerated in geriatric patients for periods of > 2 years. The delay of ALS symptomatology in the SOD 1 mutant mice observed here was achieved at tolerable doses of nimesulide (that reached micromolar concentrations in the brain) and resulted in significantly decreased levels of PG-E2 content in the spinal cord. These studies suggest that inhibition of COX-2, which blocks PG-E2 production, may therapeutically delay the onset of motor neuron symptomatology in ALS patients.

In view of the ongoing clinical trial of the selective COX-2 inhibitor Celebrex sponsored by the Northeast ALS consortium, these data provide significant support for the therapeutic application of NSAIDs to ALS. However, nimesulide did not alter the onset of end stage disease (bilateral hind limb paralysis) or the weight loss associated with the SOD1-G93A transgenic mice, suggesting that additional pathophysiologic mechanisms in ALS need to be addressed in order to more comprehensively treat this disease. Further, given the prophylactic nature of this study, it may also be the case that NSAIDS will need to be administered very early in the disease process in order to achieve optimal efficacy, as has been suggested in recent experimental studies with aspirin and creatine. Nonetheless, we think this study provides significant validation for the ongoing trial of Celebrex, and clearly emphasizes the need for further study of these compounds in inflammatory neurodegeneration.

If the hypothesis that COX-2 plays an important role in neurodegeneration (see Fig. 3 ) in ALS is indeed correct, then CNS penetration with selective or preferential COX-2 may be successful in inhibitors altering the clinical progression of ALS in humans. Experimental studies in animal models, cell culture models of ALS-type neurodegeneration, and studies of postmortem ALS brain have all implicated COX-2 as an important therapeutic target in ALS, and our findings with nimesulide further underscore this implication. These studies provide strong support for ongoing clinical studies of COX-2 inhibitors and advocate further exploration of additional NSAID compounds (e.g., mixed COX-1/-2 inhibitors) in the treatment and management of ALS.

View larger version (25K): [in this window] [in a new window]   Figure 3. Schematic diagram.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0876fje; to cite this article, use FASEB J. (February 5, 2003) 10.1096/fj.02-0876fje

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