THIS IS THE CLINICAL STUDY DONE IN ITALY W/ LITHIUM:
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*
*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. Su¨ dhof, 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
ALS is a devastating neurodegenerative disorder with no
effective treatment that usually leads to death within 3–5
years from diagnosis (11 months for the bulbar form) (1). ALS
occurrence is primarily (90%) sporadic, while only 10% is
familial (fALS). Approximately 20% of fALS are due to mutations
of the gene coding for the enzyme copper–zinc superoxidedysmutase
(SOD1) (2). Transgenic mice over expressing the
human mutant SOD1 develop a pathology that is very similar to
that seen in ALS patients [see supporting information (SI) Text
for a comparison]. Studies in animal models or in vitro led to the
identification of a variety of alterations in ALS motor neurons
(MN) (1, 3, 4); however, other cells in the spinal cord besidesMN
are affected (5–8). For instance, a class of interneurons die
either before or concomitantly with MN, as found in mice (9, 10)
and postulated in humans for Renshaw-like cells (11). Again,
glial cells participate in the deleterious interplay leading to MN
degeneration (6–8).
After the generation of the SOD1 ALS mouse models,
attempts have been made to find effective treatments. However,
so far, none of these trials has led to effective clinical outcomes.
Lithium is a compound used as a mood stabilizer, which is
neuroprotective in a variety of disease models (12, 13), such as
brain ischemia (14) and kainate toxicity (15). The ability of
lithium to promote autophagy, through the inhibition of the
inositol-monophosphatase 1 (16–18), together with the protective
effects of autophagy in neurodegeneration (19–22),
prompted us to test the neuroprotective effects of lithium in the
G93A ALS mouse model. Based on the promising data, we
obtained in mice we quickly moved into a clinical trial, which is
now at the end of its second year.
Results
Effects of Lithium on Disease Duration and Survival in G93A Mice.
G93A male mice were treated daily with lithium carbonate (1
mEq/kg, i.p.), starting at 75 days of age. Lithium treatment
prolonged the mean survival time from 110.8 5.0 days (n20)
to 148 4.3 (n 20, 36% of the life span of these mice; Fig.
1a; P 0.001) and, most importantly, increased disease duration
(from a mean of 9 days to 38 days, 300%; Fig. 1b; P 0.05)
compared with the G93A mice treated with saline. Even when
lithium treatment was started at the onset of motor symptoms,
the increase in disease duration was still comparable (data not
shown). More specifically, lithium delayed the onset of paralysis
and limb adduction (Fig. 1c) and significantly improved additional
tests we report in SI Fig. 6, such as rotarod, grip strength,
and stride length.
Effects of Lithium Treatment on Motor Neuron Survival (Lamina IX of
Lumbar and Cervical Spinal Cord and Brainstem Motor Nuclei). These
effects were accompanied by a reduced loss of lumbar MN at 90
days of age (SI Fig. 7). However, at the end of disease (which
occurred later following lithium), the number of alpha-MN
within lumbar lamina IX of the G93A mice treated with lithium
was comparable to that found in the saline-treated mice that had
died previously (SI Fig. 8). However, even at this stage, we
detected a disease modifying effect of lithium. This consisted of
(i) preservation of the size of MN (SI Fig. 8 d and e); (ii)
preservation of MN number and size in those areas [i.e., cervical
spinal cord (SI Fig. 9) or the nucleus ambiguous (SI Fig. 10)],
which degenerate later compared with lumbar lamina IX (23,
24); (iii) decreased astrocytosis (SI Fig. 11); and (iv) decreased
alpha-synuclein, ubiquitin, and SOD1 aggregation (see SI Fig. 6
and Discussion in SI Text).
Effects of Lithium Treatment on the Renshaw-Like Cell Area (Lamina
VII). Lamina VII contains a larger number of interneurons,
defined as Renshaw cells, which form a collateral circuit that
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.
Freely available online through the PNAS open access option.
‡To whom correspondence should be addressed. E-mail: f.fornai@med.unipi.it.
This article contains supporting information online at www.pnas.org/cgi/content/full/
0708022105/DC1.
© 2008 by The National Academy of Sciences of the USA
2052–2057 PNAS February 12, 2008 vol. 105 no. 6 www.pnas.orgcgidoi10.1073pnas.0708022105
No comments:
Post a Comment