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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Lithium delays progression of amyotrophic lateral sclerosis
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*Department of Human Morphology and Applied Biology, and ¶Department of Neuroscience, Clinical Neurology, University of Pisa 56100 Pisa, Italy; Istituto Neurologico Mediterraneo, Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed, 86077 Pozzilli (IS), Italy; Molecular Neurobiology Unit, Santa Lucia Foundation, 00179 Rome, Italy; and ||Department of Medical Sciences, University of Novara, 28100 Novara, Italy
Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 21, 2007 (received for review August 24, 2007)
ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS.
autophagy | clinical study | G93A mice | morphological analysis
Author contributions: F.F., P. Longone, C.I., L.M., S.R., and A.P. designed research; O.K., M.F., M.L.M., G.L., A.S., N.B., P. Lenzi, N.M., and G.S. performed research; L.C., M.F., M.L.M., G.L., P. Lenzi, G.S., C.I., L.M., S.R., and A.P. analyzed data; and F.F. and P. Longone wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708022105/DC1.
To whom correspondence should be addressed. E-mail: f.fornai{at}med.unipi.it
© 2008 by The National Academy of Sciences of the USA
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  R. S. Bedlack, N. Maragakis, and T. Heiman-Patterson Lithium may slow progression of amyotrophic lateral sclerosis, but further study is needed PNAS, April 22, 2008; 105(16): E17 - E17. [Full Text] [PDF]
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F. Fornai, G. Siciliano, M. L. Manca, L. Murri, A. Paparelli, and S. Ruggieri Reply to Bedlack et al.: A small pilot study calls for large clinical trials to evaluate the effects of lithium before prescribing the drug for amyotrophic lateral sclerosis PNAS, April 22, 2008; 105(16): E18 - E18. [Full Text] [PDF]
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 New Tricks for an Old Dog: Lithium Effectively Treats ALS Journal Watch Psychiatry, March 17, 2008; 2008(317): 2 - 2. [Full Text]
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