MND Factsheet 39 Lithium by dfsiopmhy6

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									                                                         MND Factsheet 39
                                                                  Lithium
                                                                            Last Updated 17/12/2009
17/12/09 Please note, two of the three               assessing the effect the disease is having
human trials have been concluded                     by measuring how someone can function;
early as they have shown no benefits                 and a measure of “Forced Vital Capacity,”
to users and have in fact suggested                  i.e. how much air someone’s lungs can
Lithium might be detrimental at the                  hold and breathe out.
doses taken.
                                                     Preliminary Human Results
Early in 2008 a report from Italy by                 On the face of things the results from the
Francesco      Fornai   and      colleagues          trial were impressive. Fifteen months
revealed how a study of the effects of the           after the start of the trial all of the patients
metal lithium on mice with MND appeared              from the group receiving lithium were still
so successful that it was very quickly               alive and all showed much less disease
followed up by a small clinical trial                progression than their counterparts who
involving patients. The results reported in          received Riluzole only. For example, the
their February 2008 report were based on             patients receiving lithium had on average
data obtained in only the first fifteen              more than 80% of the breath-size they
months of the trial. As yet it is not known          had at the start of the study, while the
if these results are consistent across the           patients receiving only Riluzole (the
whole two years of the study.                        control group) had on average just slightly
                                                     more than 60% of the breath size. On
Preliminary Human Trial                              each of the different scales to measure
44 patients (20 male and 24 female) were             functionality the comparison patients
recruited for the clinical trial and divided         scored markedly worse at the end of the
into two groups. One group of 16 people              fifteen months than the group receiving
received lithium carbonate in addition to            lithium. On completion of the preliminary
Riluzole while the other group of 28                 study almost one third of the comparison
people received Riluzole only. In order              group had died whereas none of the
that the researchers did not inadvertently           patients receiving lithium had died,
influence the patients they did not know             despite a statistical probability that some
who was receiving lithium as well as                 from each group should have died during
Riluzole and who was receiving only                  the study.
Riluzole. None of the groups contained
people who had familial MND and ¼ of                 Important Reservations
each group were patients who had bulbar              However, other researchers have serious
onset MND. (Seven of the 28 and four of              reservations about the quality of the
the control group of 16.)                            information obtained from this clinical
                                                     trial. For example the MND Association
A number of different measures were                  for England Wales and Northern Ireland
used to objectively assess the disease               made the following comments;
progression in the patients recruited to
the clinical trial. Amongst these were               •   “The participants in the trial knew
“functional rating scales,” i.e. ways of                 whether they were taking the trial

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                                       MND Factsheet 39 Lithium

     treatment or whether they were in the                  process called autophagy, in which cells
     control group. This can produce bias                   dismantle parts of themselves to provide
     in the way participants report how they                materials they can re-use. Autophagy
     feel and also means that the placebo                   can sometimes be protective against
     effect can have an influence.                          further damage in diseases that cause
•    The participants were not put into the                 degeneration in the brain and nervous
     treatment and comparison groups at                     system. These facts together prompted
     random - they were chosen for each                     the team to test the protective effects of
     group by the researchers. Random                       lithium in a strain of mice which suffers
     selection is usually performed by a                    from MND.
     computer and prevents bias in
     choosing which patients go into each                   Caution in Interpreting Data
     group.                                                 Care should normally be taken not to
•    A larger proportion of the participants                read too much into the results obtained
     given      lithium     had      disease                from trials involving particular strains of
     characteristics (e.g. age and site of                  mice as the MND they suffer from is
     disease onset) that tend to be                         usually caused by interfering with one of
     associated with slower disease                         their SOD1 genes. Only 2 to 3% of
     progression.”                                          human cases of MND are due to inherited
                                                            mutations of this gene and not all
These criticisms are not trivial nit-picking                mutations to the gene have the same
by others for the sake of it.          They                 degree of disease promoting effects. The
seriously undermine the reliability that                    other 97% of human cases are thought to
can be placed on the results from the                       be due to other inherited genes (about
human trial as it is easy to obtain the                     7% of all cases) or unknown in origin
results you want if you grade and select                    (about 90% of all cases and described as
the people who get the treatment to                         sporadic MND.)
choose those with slower-progressing
disease types and put those with faster-                    Laboratory mice and rats are very highly
progressing disease types into the group                    in-bred to create extremely similar
that don’t get the treatment. Because                       individuals   which      should     give
normal randomisation processes were not                     experimental results that can be
followed and because participants knew                      reproduced over and over again.
whether or not they were taking lithium
we can have no certainty that there was                     How “MND Mice” are “made”
not some degree of bias in the findings                     To create a mouse model for MND a
arising from the selection process.                         known mutation is introduced into a
                                                            SOD1 gene and copies of this mutated
Lithium                                                     gene are, in turn, introduced into some
Lithium carbonate is a compound used as                     mouse embryos.        One of the most
a mood stabiliser in psychiatric disorders,                 commonly used mouse models is the so-
which has been noted to have nerve-                         called “G93A mouse.” What this name
protecting properties in a variety of                       means is that at position 93 on the SOD1
disease models such as brain ischemia                       protein a mutation has been created by
(lack of oxygen) and poisoning by a                         replacing one of the chemicals that
chemical called kainate, which is a potent                  makes up the protein by another. In this
stimulator of the central nervous system.                   case the chemical represented by “G”
Lithium can also promote a cellular                         (Glycine) has been replaced by the
                                                            chemical represented by “A” (Alanine).

    The information in this leaflet is believed to be accurate at the time of production, MND Scotland cannot
     give detailed medical advice, this leaflet should be regarded only as general background information.
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                                    MND Factsheet 39 Lithium

This replacement was brought about by                    onset of limb paralysis and significantly
manipulating the SOD1 gene before it                     improved grip strength when compared to
was introduced into the embryos, thus                    the control mice, which were given salt-
allowing the mutated gene to make the                    water injections to make sure they all got
faulty protein and to be passed on to                    exactly the same treatment, apart from
future generations.                                      the lithium.
The mice that are bred from these
mutated strains all develop symptoms                     The team were so impressed by the
similar to those experienced by MND                      results they discovered in the mice that
patients with a distinctive and predictable              they rapidly moved to the clinical trial
pattern to their disease because of the in-              involving humans.
bred similarities of the mice and the
uniformity of the cause of their MND.                    Mouse Post-Mortem Results
                                                         The analysis in the G93A mice showed
Typically the first signs will appear in the             that lithium delayed cell death amongst
G93A mouse at about 80 days of age                       motor neurones within parts of the spinal
with a weakening of the hind-limbs.                      cord and brain while in some parts of the
Normally by 140 days the disease has                     spinal cord it actually increased motor
run its course and all of the mice are                   neurone survival.      In addition, lithium
dead. For the untreated (control) mice                   treatment helped to remove the build up
used in the trial their life-span was an                 of proteins, such as the SOD1 protein,
average of 111 days and the average                      and other substances that are known to
duration of their MND symptoms just 9                    accumulate when motor neurones are
days.                                                    damaged in MND.           This latter finding
                                                         suggests that an increased removal of the
Effects of Lithium on MND Mice                           mutated SOD1 may contribute to the
When Fornai and colleagues carried out                   improvement observed in G93A mice.
their investigation they started dosing                  The investigators concluded lithium
male mice with lithium at 75 days of age,                affects multiple targets, all of which are
five days before the first MND symptoms                  likely to contribute to the improvement of
normally appear in this strain. They                     MND.
discovered that this treatment extended
the duration of the disease to an average                Further Developments
of 36 days and life-span to an average of                The results of this preliminary trial so
148 days, quite clearly slowing down the                 interested    the     medical    research
progression of the disease and extending                 community that several trials were started
life expectancy.                                         in different countries around the world,
                                                         2/3rds of these trials have been closed
The lithium treatment also delayed the                   early.

Further Information

Fornai and colleagues’ paper       http://www.pnas.org/content/105/6/2052.full.pdf+html
MND Association’s Comments on the above paper
http://www.mndassociation.org/research/research_explained/news_in_research/mnd_asso
ciation.html

Factsheet 22           Riluzole


 The information in this leaflet is believed to be accurate at the time of production, MND Scotland cannot
  give detailed medical advice, this leaflet should be regarded only as general background information.
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