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The Journal of Neuroscience, March 1, 2006, 26(9):2467-2473; doi:10.1523/JNEUROSCI.5253-05.2006

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Neurobiology of Disease
Thalidomide and Lenalidomide Extend Survival in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Mahmoud Kiaei,¹ Susanne Petri,¹ Khatuna Kipiani,¹ Gabrielle Gardian,¹ Dong-Kug Choi,² Junyu Chen,¹ Noel Y. Calingasan,¹ Peter Schafer,³ George W. Muller,³ Charles Stewart,⁴ Kenneth Hensley,⁴ and M. Flint Beal¹

¹Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, New York 10021, ²Department of Biotechnology, Konkuk University, 380-701, South Korea, ³Celgene Corporation, Summit, New Jersey 07901, and ⁴Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104

Correspondence should be addressed to Dr. Mahmoud Kiaei, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021. Email: mak2026{at}med.cornell.edu

Accumulating evidence suggests that inflammation plays a major role in the pathogenesis of motor neuron death in amyotrophic lateral sclerosis (ALS). Important mediators of inflammation such as the cytokine tumor necrosis factor- (TNF-) and its superfamily member fibroblast-associated cell-surface ligand (FasL) have been implicated in apoptosis. We found increased TNF- and FasL immunoreactivity in lumbar spinal cord sections of ALS patients and G93A transgenic mice. Both increased TNF- and FasL immunostaining in the lumbar spinal cord of the G93A SOD1 transgenic mice occurred at 40–60 d, well before the onset of symptoms and loss of motor neurons. We tested the neuroprotective effect of thalidomide and its analog lenalidomide, pharmacological agents that inhibit the expression of TNF- and other cytokines by destabilizing their mRNA. Treatment with either thalidomide or lenalidomide attenuated weight loss, enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in G93A transgenic mice. Treated G93A mice showed a reduction in TNF- and FasL immunoreactivity as well as their mRNA in the lumbar spinal cord. Both compounds also reduced interleukin (IL)-12p40, IL-1, and IL-1 and increased IL-RA and TGF-1 mRNA. Therefore, both thalidomide and lenalidomide bear promise as therapeutic interventions for the treatment of ALS.

Key words: G93A; SOD1; thalidomide; lenalidomide; TNF-; FasL

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Received Sept. 19, 2005; accepted Jan. 15, 2006.

Correspondence should be addressed to Dr. Mahmoud Kiaei, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021. Email: mak2026{at}med.cornell.edu

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