X-Message-Number: 12908
Date: Mon, 06 Dec 1999 21:11:25 -0500
From: Jan Coetzee <>
Subject: Neurodegeneration
Lithium as a Treatment
for Neurodegeneration
by Laura Spinney
Lithium treatment dramatically reduces the
destruction of neurons in an animal model of
Huntington's disease, according to findings
presented at the 29th annual meeting of the
Society for Neuroscience in Miami. By
suppressing programmed cell death, it could
also have therapeutic benefits for patients
suffering from a range of neurodegenerative
illnesses, including Alzheimer's.
Huntington's disease is a fatal, inherited
neurodegenerative disease for which there is as
yet no cure. The symptoms include involuntary
movement, psychosis and dementia. Most of the
neuronal death that characterizes the disease
occurs in the striatum, where medium-sized
spiny projection neurons seem to be particularly
vulnerable to apoptosis, or programmed cell
death, while large interneurons tend to survive.
That selective damage is thought to be caused
by the accumulation of excess glutamate, an
excitatory signal, which in turn leads to the
overstimulation of NMDA receptors and
ultimately cell death. It can be recreated in a
rat's brain by injecting either NMDA, or its
receptor agonist quinolinic acid, directly into
the
striatum.
Last year, a team led by De-Maw Chuang, head
of molecular neurobiology at the National
Institute of Mental Health in Bethesda, showed
that lithium could protect cultured neurons
against this kind of glutamate excitotoxicity.
Lithium is widely prescribed for the treatment of
manic depressive illness, although its
mechanism of action is not known, and the
neuroprotective effect they observed in the
cultured cells was achieved with therapeutic
concentrations of the drug. Since excess
glutamate is also at the root of Huntington's
disease, the question Chuang wanted to answer
next was whether lithium could also afford
neuroprotection in an animal model of the
disease.
He and his colleagues injected rats with lithium
chloride once a day for 16 days before treating
them with quinolinic acid. A second experimental
group received a single shot of lithium chloride
one day before the quinolinic acid, and one
immediately after, while the controls were given
equivalent amounts of saline in place of the
lithium. Seven days later the rats were killed and
sections of their striatum analyzed for both
DNA-damaged neurons--an indicator of
apoptosis--and expression of the protein Bcl-2,
which protects cells against apoptosis. In both
experimental groups pre-treatment with lithium
reduced the lesions in the striatum by between
50 and 75% compared to controls. It also led to
a significant increase in expression of Bcl-2 in
both the striatum and the frontal cortex.
Moreover, cell culture studies showed that
lithium reduced the activity of
apoptosis-promoting genes bax and p53, both of
which are activated by glutamate. "Not only did
it promote the good guys, but it suppressed the
bad guys," says Chuang.
His group is now looking for the minimum dose
of lithium that can provide this neuroprotective
effect. Although there was no significant
difference in the results from the two
experimental paradigms--the 16-day and the one
day pre- and post-treatment with lithium--he
believes that the fact that the rats were treated
before the striatal damage was induced was
crucial. And that has implications for human
patients too. The large striatal lesions seen in
the animal model only occur in humans in the
later stages of the disease. "When you begin to
see some behavioral abnormalities, involuntary
agitation for instance, maybe that is the time to
administer lithium," he says.
In related studies, the researchers have shown
that lithium can also ameliorate the
excitotoxicity associated with amyloid peptide, a
component of the plaques that form in the brains
of Alzheimer's patients. And in an animal model
of stroke, where the injury is again thought to be
mediated by NMDA receptor over-excitation,
pretreatment with lithium reduced the area of
brain damage by more than half.
For more information email De-Maw Chuang
Editor's choice links
Neuroprotective effects of chronic lithium on
focal cerebral ischemia in rats.
Nonaka S, Chuang DM
Neuroreport 1998 Jun 22 9:9 2081-4 [MEDLINE],
[full
MEDLINE], [related records]
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