Stabilizing microtubules with L-AP4 reduces rotenone toxicity

Wed, 19 Apr 2006 20:00:37 PST

( from http://www.rxpgnews.com ) Researchers at the University at Buffalo affiliated with the New York State Center of Excellence in Bioinformatics and Life Sciences have identified a novel agent that can protect neurons involved in Parkinson's disease from being destroyed by the pesticide rotenone.

The agent, called L-AP4, activates a critical group of receptors called group III metabotropic glutamate receptors and may be a promising drug target. Currently there is no known cure for Parkinson's disease.

Long-term studies have shown that environmental toxins play a critical role in the development of Parkinson's disease, and it has been shown recently in research with rats that administering rotenone, a naturally occurring substance widely used as a pesticide, destroys dopamine-producing neurons and causes symptoms of Parkinson's disease in this animal model.

In the April 19 issue of The Journal of Neuroscience, UB researchers lead by Jian Feng, Ph.D., report that activation of group III metabotropic glutamate receptors reverses a cascade of events triggered by rotenone that destroys dopamine neurons.

Feng, UB associate professor of physiology and biophysics, and colleagues earlier demonstrated that microtubules, the intracellular highways for transporting dopamine and many vital cellular components, are critical for the survival of dopamine neurons, which are responsible for controlling body movement.

They showed that rotenone kills dopamine neurons by destroying microtubules, and that stabilizing microtubules greatly reduces the toxicity of rotenone.

In this new study, Feng's group has found that activation of group III metabotropic glutamate receptors by drugs such as L-AP4 triggers a chain of events that leads to microtubule stabilization. This cascade, called the MAP kinase pathway, activates several enzymes that regulate the stability of microtubules.

The primary symptoms of Parkinson's disease are tremors, slowness in movements, and impaired balance and coordination. At least 500,000 people are believed to suffer from Parkinson's disease in the United States, and about 50,000 new cases are reported annually, according to the National Institutes of Health. These figures are expected to increase as the population ages: The average age of onset is about 60. The disorder appears to be slightly more common in men than women.

How rotenone destroys the dopamine neurons

Thu, 25 Aug 2005 05:19:38 PST

( from http://www.rxpgnews.com ) Neuroscientists from the University at Buffalo have described for the first time how rotenone, an environmental toxin linked specifically to Parkinson's disease, selectively destroys the neurons that produce dopamine, the neurotransmitter critical to body movement and muscle control.

Microtubules, intracellular highways that transport dopamine to the brain area that controls body movement, are the crucial target, they report.

Damage to microtubules prevents dopamine from reaching the brain's movement center, causing a back-up of the neurotransmitter in the transport system, the researchers found. The backed-up dopamine accumulates in the body of the neuron and breaks down, causing a release of toxic free radicals, which destroy the neuron.

The study appeared in the Aug. 9 issue of the Journal of Biological Chemistry.

"This study shows how an environmental toxin affects the survival of dopamine neurons by targeting microtubules that are critical for the survival of dopamine-producing neurons," said Jian Feng, Ph.D., assistant professor of physiology and biophysics in the UB School of Medicine and Biomedical Sciences and senior author on the study.

"Based on these findings, we have identified several ways to stabilize microtubules against the onslaught of rotenone. These results ultimately may lead to novel therapies for Parkinson's disease."

At least 500,000 people are believed to suffer from Parkinson's disease in the United States, and about 50,000 new cases are reported annually, according to the National Institutes of Health. These figures are expected to increase as the population ages: The average age of onset is about 60. The disorder appears to be slightly more common in men than women.

Feng and colleagues in the Department of Physiology and Biophysics have concentrated their research on the cellular mechanisms of the disease. They are interested specifically in understanding why rotenone destroys neurons that produce dopamine, while sparing neurons that produce other neurotransmitters.

Using cultures of rat neurons, the researches subjected neurons that produce various types of neurotransmitters to agents that mimic the action of rotenone. These results showed that dopaminergic neurons were destroyed while others survived.

They then topped off the treatment by adding the drug taxol, which stabilizes microtubules and prevents their breakdown. Findings showed that by protecting microtubules, the toxic effect of rotenone on dopamine-producing neurons was greatly reduced.

"Based on these findings, we believe that microtubules are a critical target of PD environmental toxins such as rotenone," said Feng. "Since many microtubule-depolymerizing agents are compounds naturally produced in many plants, our research points to the need to examine their possible link to Parkinson's disease. In addition, PD has a higher incidence in rural areas and is associated with pesticides and insecticides frequently used in farming practices."

The research also opens up novel avenues for the development of PD therapies by targeting microtubules, he said. Feng and colleagues in his laboratory are working actively towards this goal.

RxPG News : Rotenone

Stabilizing microtubules with L-AP4 reduces rotenone toxicity

How rotenone destroys the dopamine neurons