L-DOPA-induced dyskinesia is associated with regional increase of striatal dynorphin peptides as elucidated by imaging mass spectrometry
2011 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 10, no 10, M111.009308- p.Article in journal (Refereed) Published
Opioid peptides are involved in various pathophysiological processes, including algesia, epilepsy and drug dependency. 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 Parkinsons disease (PD), 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 PD. 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 B, alpha-neoendorphin, MetEnkRF, MetEnkRGL, PEnk (198-209, 219-229). IMS analysis revealed elevated levels of dynorphin B, alpha-neoendorphin, substance P, and PEnk (220-229) in the dorsolateral striatum of high-dyskinetic animals compared to low-dyskinetic and lesion-only control rats. Here, only peak -intensities of the prodynorphin-derived peptides, dynorphin B and alpha-neoendorphin, were strongly and positively correlated with LID severity. Interestingly, these LID associated dynorphin peptides are not mainly those with high affinity to kappa opioid receptors, but are known to bind and activate also mu- and delta-opioid receptors. In addition, the peak intensities of a putative metabolite of alpha-neoendorphin lacking the N-terminal tyrosine correlated positively with dyskinesia severity. Des-tyrosine dynorphins display reduced opioid receptor binding and this points to possible compensatory non-opioid mediated changes in the striatum. Since des-tyrosine dynorphins can only be detected by mass spectrometry, as no antibodies are currently available, these findings highlight the potential of MALDI-IMS analysis for the study of molecular dynamics in neurological diseases. This is the first MALDI-IMS-based study on neuropeptide analysis in experimental PD and LID. This unique methodological approach facilitated comprehensive investigation of LID-associated prodynorphin-derived peptide products.
Place, publisher, year, edition, pages
2011. Vol. 10, no 10, M111.009308- p.
IdentifiersURN: urn:nbn:se:uu:diva-159672DOI: 10.1074/mcp.M111.009308ISI: 000295773800014PubMedID: 21737418OAI: oai:DiVA.org:uu-159672DiVA: diva2:446123
FunderSwedish Research Council, 522-2006-6414 (MA), 521- 2007-5407 (MA), 342-2004-3944(JB) and 621-2008-3562(JB)