Buck Institute research provides further validation that
low-dose lithium could be repurposed as a therapy for the incurable
neurodegenerative disorder
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| Lithium |
July 24, 2015/Novato, CA.
Low-dose lithium reduced
involuntary motor movements – the troubling side effect of the medication most
commonly used to treat Parkinson’s disease (PD) – in a mouse model of the
condition that is diagnosed in about 60,000 Americans each year. The
third in a series of studies from the Andersen lab involving PD and low-dose
lithium, the results add to mounting evidence that low-doses of the
psychotropic drug could benefit patients suffering from the incurable,
degenerative condition.
This study, published online in Brain Research, involved
Parkinsonian mice that were given Carbidopa/Levodopa (sold as Sinemet®),
a drug used to boost levels of the neurotransmitter dopamine, which is lost in
PD. While the medication remains the single most effective agent in the
management of PD symptoms, long-term use causes its own side effects, among
them abnormal involuntary movements or AIMS. Buck professor and senior
scientist Julie Andersen, PhD, says AIMS become problematic for 30 percent of
patients after four to six years of treatment with Sinemet, with 90 percent of
patients suffering from the complication after nine years of chronic use.
“For patients these side effects are just as devastating as the freezing that
is associated with PD.” “In our mice we saw significant behavioral
improvement.”
In this study, Andersen and her team dosed the mice with an
amount of lithium equivalent to about a quarter of what humans receive for the
treatment of psychiatric diseases. Researchers found that lithium boosted the
expression of tyrosine hydroxylase which increases dopamine synthesis via the
inhibition of calpain-1, an enzyme that normally reduces dopamine synthesis.
In earlier studies, Andersen’s team found that low-dose lithium
was protective in two different mouse models of PD. Treatment in mice with a
human mutation for PD began when the animals reached late middle-age, the human
equivalent of about 60, which is the average age of onset of Parkinson’s in
humans. “We clearly saw a prevention of the motor difficulties we would expect
to see in the animals,” said Andersen. “The treatment also protected the area
of the brain that is normally damaged by Parkinson’s.”
Plans for a clinical trial of low-dose lithium for PD patients
are in early stages. “This study suggests potential therapeutic benefit in PD,”
said David K. Simon, MD, PhD, Associate Professor of Neurology at Harvard
Medical School in Boston. Simon chairs the Scientific Review Committee
for the Parkinson’s Study Group, a not-for-profit network of Parkinson’s
Centers.
“One caveat is that other agents that have shown clear efficacy
in this model of PD have subsequently failed to show benefit in clinical
studies in PD (e.g. CoQ10, creatine, and pioglitazone). However, this study
provides additional evidence on top of prior work from Dr. Andersen’s lab and
others that lithium may have therapeutic potential in PD, which is a hypothesis
that should be tested in clinical trials,” he said.
Lithium is a naturally occurring element, not a ‘developed’
molecule like most medications. It was approved by the FDA for the treatment of
bipolar disorder in 1970 and has shown to be effective for treating mood
disorders and suicidal thoughts. Previous studies suggest that at low
doses lithium has a protective effect in other neurodegenerative diseases
including Alzheimer’s and Huntington’s.
Citation: The combination of lithium and L-Dopa/Carbidopa
reduces MPTP-induced abnormal involuntary movements (AIMs) via calpain-1
inhibition in a mouse model: relevance for Parkinson’s disease therapy.
This work was supported by grants from National Institutes of
Health 5P20GM103653-02; RL1 NS062415
Other Buck Institute contributors include: Rebecca R. Riley and
Anand Rane. Corresponding author Y. Hwan Kim, a former member of the Andersen
lab, is now in the Department of Biological Sciences, Delaware State
University, Carol A. Lazzara, from Delaware State University also contributed
to the work.
About the Buck Institute for Research on Aging
The Buck Institute is the U.S.’s
first independent research organization devoted to Geroscience – focused on the
connection between normal aging and chronic disease. Based in Novato, CA, The
Buck is dedicated to extending “Healthspan”, the healthy years of human life
and does so utilizing a unique interdisciplinary approach involving
laboratories studying the mechanisms of aging and those focused on specific
diseases. Buck scientists strive to discover new ways of detecting, preventing
and treating age-related diseases such as Alzheimer’s and Parkinson’s, cancer,
cardiovascular disease, macular degeneration, osteoporosis, diabetes and
stroke. In their collaborative research, they are supported by the most
recent developments in genomics, proteomics, bioinformatics and stem cell technologies.
For more information: www.thebuck.org
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