Will New Approaches Help to Treat ALS?

Abstract & Commentary

Source: Almer G, et al. Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients. Neurology. 2002;58: 1277-1279.

Editor’s NoteIn this issue of Neurology Alert, Flint Beal, MD, will join me as the co-editor. Dr. Beal is Professor and Chairman of the Department of Neurology at Cornell University Medical College. During my 20 years of editorship, the goal of Neurology Alert has been to present clinicians with the latest information, especially when new treatments appear that will better ameliorate severe disorders. Neuroscience, both fundamental and clinical, now faces the greatest changes of all clinical disciplines, demanding rapid exploration, understanding, and biological treatment. Neurology Alert will continue presenting the most current information to assist the well-informed clinical neurologist. —Fred Plum, MD

Inflammatory mechanisms may participate in the pathogenesis of neurodegenerative diseases including ALS. It has been known for many years that there is a problem with neuroinflammatory reaction in ALS. The classic findings are those of activated microglia that express high levels of a number of inflammatory molecules such as CD11b.

Several recent studies have directly implicated cyclooxygenase 2 (COX-2) activity in ALS pathogenesis. It was initially shown that there was a dramatic increase in COX-2 activity in postmortem spinal cord samples from sporadic ALS patients (Yasojima K, et al. Neurology. 2001;57:952-956). This was demonstrated by measuring prostaglandin PGE2 levels, which are a known product of COX-2. Subsequent work on ALS spinal cord showed a 7-fold upregulation of COX-2 mRNA and a 3.8-fold increase in protein levels (Almer G, et al. Ann Neurol. 2001;49:176-185). The most recent study has examined PGE2 levels in cerebrospinal fluid of ALS patients. It was demonstrated that 82% of the patients had levels that were 2-10-fold higher than levels in normal control subjects.


These findings raise the possibility that the administration of COX-2 inhibitors, which are well tolerated in man, could prove to be a useful therapeutic strategy for ALS. Consistent with this, COX-2 inhibitors were shown to protect organotypic spinal cord cultures from glutamate toxicity. Furthermore, the COX-2 inhibitor celecoxib (Celebrex®) has been shown to significantly extend survival in a transgenic mouse model of ALS that expresses the mutant form of superoxide dismutase that is associated with human ALS (reported at last year’s ANA meeting). In these mice, it has also been demonstrated that there is a marked increase in expression of COX-2, which is seen not only in glial cells but also in the spinal cord anterior horn neurons. There is also substantial other evidence from gene profiling indicating that inflammatory mechanisms may play an important role in this transgenic mouse model of ALS. These findings are preliminary and deserve replication. Nevertheless, the results, when viewed in concert, are very provocative and suggest that COX-2 inhibitors might be useful in slowing the progress of this otherwise devastating illness. In view of this, initial clinical trials are underway using the selective COX-2 inhibitor celecoxib. —M. Flint Beal

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