ARTICLE IN BRIEF
Basic scientists are trying to unravel the mechanisms behind levodopa-induced dyskinesia. The new targets of research are the intracellular signaling pathways that become disordered in striatal neurons due to the daily cycles of dopamine flood and drought during treatment with levodopa.
WASHINGTON, DC—The underlying mechanisms causing levodopa-induced dyskinesia are being unraveled by basic scientists, but so far none of the fundamental fixes that have worked in animals are ready for testing in humans, according to presentations made at a symposium during the Society for Neuroscience annual meeting here in November.
Rather than influencing neurotransmitters and their receptors, the new targets of research are the intracellular signaling pathways that become disordered in striatal neurons due to the daily cycles of dopamine flood and drought during treatment with levodopa (L-DOPA).
“At one moment you have too much dopamine, the next moment you don't have anything,” said Eugenia V. Gurevich, PhD, associate professor of pharmacology at Vanderbilt University. “The receptors become super sensitive, but we have found that if we increase the capacity of the intracellular machinery to regulate responsiveness, we can eliminate dyskinesia.”
A program director for Parkinson's Disease research at the NINDS praised the research of Dr. Gurevich and others who presented at the symposium.
“This is very important work, to characterize the intracellular pathways behind dyskinesia and find drug targets to reverse it,” Beth-Anne Sieber, PhD, told Neurology Today.
In 2010, Dr. Gurevich co-authored a paper in Science Translational Medicine focusing on G protein-coupled receptor kinases (GRKs), the proteins that control the responsiveness of striatal neurons to dopamine and other transmitters. After years of treatment with L-DOPA, GRK activity become insufficient to properly regulate the inner workings of striatal neurons in response to dopamine. Using a virus, she and colleagues increased the levels of a subtype, GRK6, in the striatum of both mice and monkeys, thereby relieving dyskinesia without compromising the anti-parkinsonian effect of L-DOPA. (In fact, the treatment raised the effectiveness of a low dose of L-DOPA.) Conversely, reducing the levels of GRK6 increased dyskinesia.
Because gene therapy delivered to brain cells via viral vectors poses unique challenges as a clinical treatment, small-molecule drugs need to be developed that can safely affect GRK6 activity in the striatum, Dr. Gurevich said. She said she hopes that given sufficient resources, her lab will have a drug ready for a pilot clinical trial in three to four years.
“The idea of the symposium was to show how we are trying to look for the root of the problem and fix it,” Dr. Gurevich told Neurology Today. “I wouldn't say we fully understand it even now. It's very complicated intracellular machinery, and we need a lot more effort to really understand it before we can fix it. But we have to try, because we will never be able to really fix the dyskinesia rather than just control it as best we can until we understand it.”
Two other speakers at the symposium described their successes in manipulating other intracellular mechanisms in the striatum. One of them, Riccardo Brambilla, PhD, professor of neuroscience at the San Raffaele Scientific Institute in Milano, Italy, described his research into the Ras-ERK signaling pathway.
“We have shown that it is possible to partially block this signaling pathway in the striatum and to significantly reduce the appearance of abnormal involuntary movements,” Dr. Brambilla told Neurology Today.
He was the senior author of a paper published in the Proceedings of the National Academy of Sciences last December, which showed mice deficient in Ras-GRF1, a crucial mediator of Ras-ERK signaling downstream to dopamine receptors, were significantly resistant to the development of dyskinesia during chronic L-DOPA treatment. In a macaque model, viral vectors designed to block Ras-GRF1 caused a significant reduction in dyskinesia while leaving intact the benefits of L-DOPA. “This last evidence in a primate model of dyskinesia is very important step toward the validation of the therapeutic approach in patients”, Dr Brambilla said.
“Now we are trying to develop some drugs, some molecules which might be able to block this pathway,” Dr. Brambilla said. “We have a couple of candidate peptides which can pass the blood-brain barrier and, at least in mice, significantly reduced dyskinesia. We need to do more experiments to check the right dose and concentration before we can consider a clinical trial.”
The third speaker at the symposium, Gilberto Fisone, PhD, professor of neuroscience at the Karolinska Institute in Stockholm, Sweden, described his research into the mammalian target of rapamycin complex 1 (mTORC1), a multiprotein complex regulated by the Ras-ERK pathway. A paper he published in Science Signaling in July of 2009 showed that inhibiting mTORC1 signaling in mice with rapamycin prevents L-DOPA-induced dyskinesia.
Although currently approved as an immunosuppressant to prevent rejection in organ transplantation, rapamycin appears to exert a neuroprotective effect in a number of neurodegenerative disorders, Dr. Fisone said.
“One important question is whether drugs acting on mTORC1 signaling might have the same anti-dyskinetic effect of rapamycin without causing immune suppression,” he said. “Another question is whether rapamycin or analogues to it can counteract dyskinesia once it has been established. In our initial study, we only showed that the development of dyskinesia is reduced when you give rapamycin at the same time you begin L-DOPA therapy.”
Whereas the drugs already in clinical trials for dyskinesia act upon neurotransmitter receptors, all three of the approaches presented at the symposium target defects occurring within the striatal neurons themselves, Dr. Fisone said.
“This concept of targeting intracellular signalling molecules is already being used in the treatment of cancer, but it has lagged behind in the treatment of disorders of the nervous system,” he said. “We think that acting at the level of intracellular signaling represents an alternative treatment approach for neuropsychiatric and neurodegenerative disorders.”
Ahmed MR, Berthet A, Bychkov E, et al. Lentiviral overexpression of GRK6 alleviates L-DOPA–induced dyskinesia in experimental Parkinson's disease. Science Translat Med 2010; 2 (28): 1-9.
Fasano S, Bezard E, D'Antoni A, et al. Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-DOPA–induced dyskinesia. Proc Natl Acad Sci 2010; 107 (50): 21824-29.
Santini E, Heiman M, Greengard P, et al. Inhibition of mTOR signaling in Parkinson's disease prevents L-DOPA induced dyskinesia. -Science Signaling 2009; 2 (80): 1-10.