Sci. Aging Knowl. Environ., 23 June 2004
Vol. 2004, Issue 25, p. nf61
[DOI: 10.1126/sageke.2004.25.nf61]


Stem Cell Savior

Compound shelters neuron precursors during Parkinson's disease treatment

Mitch Leslie

Stem cells are like the first players picked in the NBA draft--everyone expects wonders from them. A new study reveals a compound that might help stem cells live up to their promise in treating Parkinson's disease (PD). By reducing damage inflicted by a traditional PD treatment, the drug might allow patients to benefit from the standard therapy and stem cells.

The tremors and rigid muscles of PD result from a mass die-off of neurons in a brain region called the substantia nigra, which supplies the brain with the neurotransmitter dopamine (see Parkinson's Disease Case Study). For 40 years, doctors have dosed PD patients with L-dopa, a compound that the brain converts to dopamine. However, long-term L-dopa use often spurs wild movements and other unpleasant side effects (see "Everything in Moderation"). As an alternative, researchers hope they can coax transplanted stem cells to specialize into dopamine-producing neurons and ameliorate the disease. In animal studies, however, stem cells ease but don't eliminate symptoms, hinting that stem cell transplant patients might still have to swallow L-dopa. That possibility concerns researchers, because some studies suggest that L-dopa poisons neurons--and therefore might also slay stem cells.

To find out, Liu and colleagues cultured neural stem cells from newborn mice and doused them with L-dopa. Small amounts of L-dopa improved survival, but hiking the dose killed cells. The researchers next determined whether pergolide, a drug that doctors sometimes prescribe for PD, shielded the stem cells. At moderate doses of L-dopa, it did.

The researchers also wanted to determine why stem cells died. They tested whether the cells were undergoing apoptosis, or programmed suicide. Compared with untreated cells, about seven times as many cells splashed with L-dopa were in the throes of apoptosis. Adding pergolide cut cell suicides by about one-third. The team also checked for several molecules that help orchestrate apoptosis, including caspase-3 and cytochrome c. L-dopa treatment provoked a surge in cytochrome c and the active forms of caspase-3; for each one, pergolide reduced the size of the increase. Together, the results indicate that L-dopa kills stem cells by provoking apoptosis. Pergolide counters the effect, probably by serving as an antioxidant, the researchers conclude. Thus, pergolide might fight L-dopa's propensity to rub out transplanted stem cells.

The study suggests that pergolide spares stem cells, at least in this simple system, says neuroscientist Ronald McKay of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. But researchers don't understand the effects of pergolide and L-dopa on stem cells and neurons in the brain, he says, and L-dopa might even benefit rather than kill adult stem cells in animals. For example, McKay notes, a study published last week in Nature Neuroscience suggests that in rodents, precursor cells need dopamine to mature. We need careful studies in humans and animals to determine whether pergolide confers lasting protection, he says. If it does, the drug might help stem cells perform like Michael Jordan, rather than, er--um, who was that guy who was picked first in 1989?

June 23, 2004
  1. W.-G. Liu et al., Neuroprotection by pergolide against levodopa-induced cytotoxicity of neural stem cells. Neurochem. Res., 10 June 2004 [e-pub ahead of print]. [Journal Home Page] [Until paper appears in print, see "Articles in Advance."]
  2. G. U. Höglinger et al., Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat. Neurosci., 13 June 2003 [e-pub ahead of print]. [Abstract/Full Text]
Citation: M. Leslie, Stem Cell Savior. Sci. Aging Knowl. Environ. 2004 (25), nf61 (2004).

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