Shape of receptor predicts side effects of Parkinson’s drug

Whether or not a Parkinson’s patient will develop crippling side effects from using the drug levodopa is predicted by a certain variant of a nerve cell receptor. Groningen and Russian pharmacologists made this discovery and will publish their results in the journal Translational Psychiatry.

Patients suffering from Parkinson’s disease usually use the drug levodopa. Some, however, develop side effects: immediately after taking the medication, they begin to make wild, uncontrolled movements with their arms and legs. As muscle activity is subsequently strongly inhibited, this side effect (called dyskinesia) is also known as the ‘on-off phenomenon’.

Dyskinesia

When dyskinesia is a side effect, patients are put on other medication, but other drugs also have side effects and the dyskinesia never fully passes.
University of Groningen researchers wanted to know why some patients were afflicted by dyskinesia while others were not. Such knowledge might help in preventing side effects in future.

Huntington’s disease

Another neurological disorder, Huntington’s disease, is also characterized by dyskinesia. The disease is hereditary and the first symptoms often crop up at the age of forty or so. Previous research had already shown that the shape of the N-methyl-D-aspartate (NMDA) receptor amongst other factors determines at what age someone will become ill. ‘In Huntington’s disease a certain type of nerve cell dies off in the brain and a certain variant of the NMDA receptor accelerates this process’, says Anton Loonen, professor of Pharmacotherapy in Psychiatric Patients, who led the research project from Groningen.

Predicting

When the Groningen pharmacologists and researchers from the university hospital in Tomsk, Siberia (MHRI) investigated which variant of the NMDA receptor it was that Siberian Parkinson’s patients with dyskinesia had, it turned out to always be the same one. Although the results will have to be confirmed in a non-Siberian patient group, it is expected that in future physicians will be able to predict whether or not patients will easily suffer dyskinesia due to levodopa use, based on the receptor in question being present or not. Loonen: ‘The patient will then be able to take other medication from the outset. We also hope to develop a substance capable of blocking the NMDA receptor, so levodopa can be used without its side effects.’

Surprise

The results of the research were a surprise, as the pharmacologists initially thought that the NMDA receptor played a role in dyskinesia related to schizophrenia medication. This turned out not to be the case. However, to their surprise, in the group of Parkinson’s patients acting as control group in the experiment there did turn out to be a connection between the NMDA receptor variant and dyskinesia as a side effect of levodopa. ‘We had two different statisticians independently study the data, and both came up with this connection. We could hardly believe our eyes’, says Loonen.

Further information

- The University of Groningen researchers work in the Pharmacy department. The study was funded by profits from lectures and workshops the department itself organized, without any outside funding from government or the pharmaceutical industry.

Note for the press

- Contact: Prof. Anton Loonen, tel. 050-363 7576, a.j.m.loonen rug.nl.
- Reference: NMDA receptor genotypes associated with the vulnerability to develop dyskinesia, S. A. Ivanova, A. J. M. Loonen, P. Pechlivanoglou, M. B. Freidin, A. F. Y. Al Hadithy, E. V. Rudikov, I. A. Zhukova, N. V. Govorin, V. A. Sorokina, O. Y. Fedorenko, V. M. Alifirova, A. V. Semke, J. R. B. J. Brouwers and B. Wilffert; Translational Psychiatry (2012) 2, e67 doi:10.1038/tp.2011.66