L-DOPA-induced dyskinesia is associated with regional increase of striatal dynorphin peptides as elucidated by imaging mass spectrometry.
Artikel i vetenskaplig tidskrift, 2011

Opioid peptides are involved in various pathophysiological processes, including algesia, epilepsy, and drug dependence. A strong association between L-DOPA-induced dyskinesia (LID) and elevated prodynorphin mRNA levels has been established in both patients and in animal models of Parkinson's disease, but to date the endogenous prodynorphin peptide products have not been determined. Here, matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) was used for characterization, localization, and relative quantification of striatal neuropeptides in a rat model of LID in Parkinson's disease. MALDI IMS has the unique advantage of high sensitivity and high molecular specificity, allowing comprehensive detection of multiple molecular species in a single tissue section. Indeed, several dynorphins and enkephalins could be detected in the present study, including dynorphin A(1-8), dynorphin B, α-neoendorphin, MetEnkRF, MetEnkRGL, PEnk (198-209, 219-229). IMS analysis revealed elevated levels of dynorphin B, α-neoendorphin, substance P, and PEnk (220-229) in the dorsolateral striatum of high-dyskinetic animals compared with low-dyskinetic and lesion-only control rats. Furthermore, the peak-intensities of the prodynorphin derived peptides, dynorphin B and α-neoendorphin, were strongly and positively correlated with LID severity. Interestingly, these LID associated dynorphin peptides are not those with high affinity to κ opioid receptors, but are known to bind and activate also μ- and Δ-opioid receptors. In addition, the peak intensities of a novel endogenous metabolite of α-neoendorphin lacking the N-terminal tyrosine correlated positively with dyskinesia severity. MALDI IMS of striatal sections from Pdyn knockout mice verified the identity of fully processed dynorphin peptides and the presence of endogenous des-tyrosine α-neoendorphin. Des-tyrosine dynorphins display reduced opioid receptor binding and this points to possible novel nonopioid receptor mediated changes in the striatum of dyskinetic rats. Because des-tyrosine dynorphins can only be detected by mass spectrometry, as no antibodies are available, these findings highlight the importance of MALDI IMS analysis for the study of molecular dynamics in neurological diseases.

metabolism

Protein Precursors

Animal

analysis

analysis

Dynorphins

genetics

Disease Models

Spectrometry

Levodopa

metabolism

Neostriatum

adverse effects

Humans

Sprague-Dawley

Drug-Induced

Antiparkinson Agents

Rats

genetics

drug therapy

Female

Mass

Mice

Matrix-Assisted Laser Desorption-Ionization

Enkephalins

metabolism

metabolism

therapeutic use

Rats

adverse effects

Animals

metabolism

Parkinson Disease

Dyskinesia

therapeutic use

Författare

Jörg Hanrieder

Göteborgs universitet

Anna Ljungdahl

Maria Fälth

Sofie Eriksson Mammo

Jonas Bergquist

Malin Andersson

Molecular and Cellular Proteomics

1535-9476 (ISSN) 1535-9484 (eISSN)

Vol. 10 10 M111.009308-

Ämneskategorier

Neurovetenskaper

Neurologi

DOI

10.1074/mcp.M111.009308

PubMed

21737418