Lithium delays progression of amyotrophic
lateral sclerosis
http://www.pnas.org/cgi/reprint/0708022105v1.pdf


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

http://www.pnas.org/cgi/reprint/0708022105v1.pdf

Lithium slows ALS progression
Medical Studies/Trials
Published: Monday, 4-Feb-2008
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Daily doses of lithium, a drug used to treat bipolar disorder, have been found to delay progression of amyotrophic lateral sclerosis (ALS) in an Italian study of 44 people with the disease.
No other treatment to date has shown such a dramatic effect on this paralyzing and fatal disease of adults, which affects some 30,000 Americans.

Francesco Fornai at the University of Pisa (Italy), with colleagues at the University of Novara (Italy) and the Santa Lucia Foundation in Rome, announced their results online today in Proceedings of the National Academy of Sciences.

At the end of a 15-month trial that began in October 2005, about 30 percent of the patients that took riluzole, a drug known to have modest benefit in ALS, had died, while all those receiving riluzole plus lithium had survived. The disease progressed markedly in the riluzole-only group but progressed very slowly in the riluzole-plus-lithium group.

"Although the number of study participants is small, the results are very intriguing," said Dr. Valerie Cwik, MDA medical director and vice president of Research. "MDA has already had conversations with researchers in the United States to follow up on these results with a larger, confirmatory study."

Sixteen trial participants were randomly selected to receive 50 milligrams a day of riluzole plus two daily doses of 150 milligrams of lithium carbonate. (If necessary, doses were adjusted up to 450 milligrams a day during the study to maintain targeted blood levels.)

The remaining 28 participants were randomly assigned to receive riluzole only.

The two groups were carefully matched with respect to the number of patients with bulbar ALS, the most rapidly progressive form, and pulmonary function.

A parallel study in mice with a genetic form of ALS suggested that lithium works by increasing autophagy, a process in which worn-out or abnormal cellular components are destroyed, and boosting the number of mitochondria, the energy-producing units of cells.

Lithium must be taken under a doctor's supervision and with frequent monitoring of blood levels. Early signs of lithium toxicity include diarrhea, vomiting, drowsiness, weakness and lack of coordination. Later signs include giddiness, blurred vision, ringing in the ears and a large output of dilute urine.

http://www.als-mda.org/