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Research Article

Lithium delays progression of amyotrophic lateral sclerosis

Francesco Fornai, Patrizia Longone, Luisa Cafaro, Olga Kastsiuchenka, Michela Ferrucci, Maria Laura Manca, Gloria Lazzeri, Alida Spalloni, Natascia Bellio, Paola Lenzi, Nicola Modugno, Gabriele Siciliano, Ciro Isidoro, Luigi Murri, Stefano Ruggieri, and Antonio Paparelli
PNAS February 12, 2008 105 (6) 2052-2057; first published February 4, 2008; https://doi.org/10.1073/pnas.0708022105
Francesco Fornai
*Department of Human Morphology and Applied Biology, and
†Istituto Neurologico Mediterraneo, Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed, 86077 Pozzilli (IS), Italy;
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  • For correspondence: f.fornai@med.unipi.it
Patrizia Longone
§Molecular Neurobiology Unit, Santa Lucia Foundation, 00179 Rome, Italy; and
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Luisa Cafaro
†Istituto Neurologico Mediterraneo, Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed, 86077 Pozzilli (IS), Italy;
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Olga Kastsiuchenka
*Department of Human Morphology and Applied Biology, and
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Michela Ferrucci
*Department of Human Morphology and Applied Biology, and
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Maria Laura Manca
¶Department of Neuroscience, Clinical Neurology, University of Pisa 56100 Pisa, Italy;
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Gloria Lazzeri
*Department of Human Morphology and Applied Biology, and
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Alida Spalloni
§Molecular Neurobiology Unit, Santa Lucia Foundation, 00179 Rome, Italy; and
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Natascia Bellio
‖Department of Medical Sciences, University of Novara, 28100 Novara, Italy
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Paola Lenzi
*Department of Human Morphology and Applied Biology, and
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Nicola Modugno
†Istituto Neurologico Mediterraneo, Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed, 86077 Pozzilli (IS), Italy;
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Gabriele Siciliano
¶Department of Neuroscience, Clinical Neurology, University of Pisa 56100 Pisa, Italy;
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Ciro Isidoro
‖Department of Medical Sciences, University of Novara, 28100 Novara, Italy
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Luigi Murri
¶Department of Neuroscience, Clinical Neurology, University of Pisa 56100 Pisa, Italy;
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Stefano Ruggieri
†Istituto Neurologico Mediterraneo, Istituto Di Ricovero e Cura a Carattere Scientifico Neuromed, 86077 Pozzilli (IS), Italy;
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Antonio Paparelli
*Department of Human Morphology and Applied Biology, and
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  1. Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 21, 2007 (received for review August 24, 2007)

This article has a Correction. Please see:

  • Correction for Fornai et al., Lithium delays progression of amyotrophic lateral sclerosis - October 09, 2008
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Abstract

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

Footnotes

  • ↵‡To whom correspondence should be addressed. E-mail: f.fornai{at}med.unipi.it
  • 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.

  • Received August 24, 2007.
  • © 2008 by The National Academy of Sciences of the USA

Freely available online through the PNAS open access option.

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Lithium delays progression of amyotrophic lateral sclerosis
Francesco Fornai, Patrizia Longone, Luisa Cafaro, Olga Kastsiuchenka, Michela Ferrucci, Maria Laura Manca, Gloria Lazzeri, Alida Spalloni, Natascia Bellio, Paola Lenzi, Nicola Modugno, Gabriele Siciliano, Ciro Isidoro, Luigi Murri, Stefano Ruggieri, Antonio Paparelli
Proceedings of the National Academy of Sciences Feb 2008, 105 (6) 2052-2057; DOI: 10.1073/pnas.0708022105

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Lithium delays progression of amyotrophic lateral sclerosis
Francesco Fornai, Patrizia Longone, Luisa Cafaro, Olga Kastsiuchenka, Michela Ferrucci, Maria Laura Manca, Gloria Lazzeri, Alida Spalloni, Natascia Bellio, Paola Lenzi, Nicola Modugno, Gabriele Siciliano, Ciro Isidoro, Luigi Murri, Stefano Ruggieri, Antonio Paparelli
Proceedings of the National Academy of Sciences Feb 2008, 105 (6) 2052-2057; DOI: 10.1073/pnas.0708022105
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