SAN DIEGO—Off-label use of a number of drugs may provide new approaches to treatment of amyotrophic lateral sclerosis (ALS). At the Society for Neuroscience’s 31st Annual Meeting, researchers discussed celecoxib, tamoxifen citrate, and neuronal transplantation as therapeutic strategies.

Results of a study involving an animal model of ALS indicated that the osteoarthritis drug celecoxib merits further study, said Jeffrey Rothstein, MD, PhD, Professor of Neurology and Neuroscience, Department of Neurology, Johns Hopkins University, Baltimore. “Our research shows that [celecoxib] is one of the most potent orally administered agents to date in ALS transgenic mice. The findings indicate that a clinical trial of celecoxib in ALS patients is warranted.”

Dr. Rothstein’s study demonstrated that in 40 animals that received a diet containing the drug, “celecoxib significantly inhibited the COX-2 [cyclooxygenase-2] enzyme in the brain and spinal cord” and the animals lived more than four weeks longer than untreated animals. Riluzole, the only FDA-approved drug for ALS, increased survival of these mice by only two weeks.

Additional research by Dr. Rothstein’s group showed that intraspinal implants of embryoid body-derived cells into green monkey models of ALS caused no harmful effects. In previous work with rats, he found that such transplants slowed the degeneration of motor neurons.

While the pathogenesis of motor neuron loss in ALS is not known, Dr. Rothstein said that it may involve glutamate-mediated excitotoxicity and oxidative damage, while mutations in superoxide dismutase (SOD1) have been found in the familial form of the disease, as well as in the transgenic mouse model.

COX-2 inhibition was tested because cyclooxygenase is the rate-limiting enzyme of prostaglandins, which rapidly stimulate glutamate release, he explained. In addition, the cyclooxygenase reaction results in the formation of free radicals. “Either of these could feed into the toxic cycle of events that propagate motor neuron loss in ALS.” The inducible form of cyclooxygenase, COX-2, has been identified as being present in both motor neurons and astrocytes, he noted.

Off-label use of tamoxifen citrate, widely used in breast cancer treatment, also may provide benefit for ALS patients, according to the results of another study.

Benjamin Brooks, MD, of the Department of Neurology, University of Wisconsin Medical School, Madison, said that the rationale for the study arose serendipitously. He explained that an animal study was conducted after an ALS patient with breast cancer who was taking tamoxifen was able to maintain her muscle strength over a period of 42 months.

A subsequent study of the drug in an ALS mouse model showed that “tamoxifen delayed symptoms in the mice by eight days and prolonged their survival by two weeks.” The mice became symptomatic at 36 days, instead of 28, and survived for 22 days after the appearance of symptoms—considerably longer than the previous eight days.

Dr. Brooks also reported that spinal cord viral titers in the mice, which got their ALS-like symptoms from a neuropathic mutant of a murine leukemia virus, were identical in the tamoxifen and saline-treated mice. This indicates that tamoxifen had a significant beneficial effect without any antiviral effect.

ALS researchers are also looking into transplants. Alison Willing, PhD, of the Departments of Neurosurgery and Anatomy, University of South Florida, Tampa, did intraspinal implants of hNT neurons (derived from the human teratocarcinoma cell line NTera2/D1) at L4 and L5 in SOD1 mice. A delay in progression of motor symptoms of three to four weeks was found, although life span was unaffected. Immunohistochemical analysis of the implanted spinal cords also demonstrated survival of the neurons, she noted.

In earlier research, she had also found that such implants into SOD1 mice before symptoms develop delayed their onset. “While preliminary,” she said, “these studies suggest that such intraspinal implants might well help humans with ALS.”

NR