Abstract
L-DOPA-induced dyskinesia is a troublesome complication of L-DOPA pharmacotherapy of Parkinson's disease and has been associated with disturbed brain opioid transmission. However, so far the results of clinical and preclinical studies on the effects of opioids agonists and antagonists have been contradictory at best. Prodynorphin mRNA levels correlate well with the severity of dyskinesia in animal models of Parkinson's disease; however the identities of the actual neuroactive opioid effectors in their target basal ganglia output structures have not yet been determined. For the first time MALDI-TOF imaging mass spectrometry (IMS) was used for unbiased assessment and topographical elucidation of prodynorphin-derived peptides in the substantia nigra of a unilateral rat model of Parkinson's disease and L-DOPA induced dyskinesia. Nigral levels of dynorphin B and alpha-neoendorphin strongly correlated with the severity of dyskinesia. Even if dynorphin peptide levels were elevated in both the medial and lateral part of the substantia nigra, MALDI IMS analysis revealed that the most prominent changes were localized to the lateral part of the substantia nigra. MALDI IMS is advantageous compared with traditional molecular methods, such as radioimmunoassay, in that neither the molecular identity analyzed, nor the specific localization needs to be predetermined. Indeed, MALDI IMS revealed that the bioconverted metabolite leu-enkephalin-arg also correlated positively with severity of dyskinesia. Multiplexing DynB and leu-enkephalin-arg ion images revealed small (0.25 by 0.5 mm) nigral subregions with complementing ion intensities, indicating localized peptide release followed by bioconversion. The nigral dynorphins associated with L-DOPA-induced dyskinesia were not those with high affinity to kappa opioid receptors, but consisted of shorter peptides, mainly dynorphin B and alpha-neoendorphin that are known to bind and activate mu and delta opioid receptors. This suggests that mu and/or delta subtype-selective opioid receptor antagonists may be clinically relevant for reducing L-DOPA-induced dyskinesia in Parkinson's disease.
Highlights
The dopamine (DA) precursor L-DOPA is still the most effective symptomatic treatment in patients with Parkinson’s disease (PD), but with time this treatment often causes troublesome complications, including ‘‘wearing off’’ fluctuations and peak-dose L-DOPA-induced dyskinesia (LID) [1]
In the present study we demonstrate that L-DOPA-induced dyskinesia in a rat model of PD is associated with elevated levels of Dyn B and aNeo in the lateral, but not medial part of substantia nigra
The predominant presence of aNeo and Dyn B in intact substantia nigra (SN) is in accordance with radioimmunoassay measurements from intact rat SN, where levels of alpha-neoendorphin and Dyn B were especially high followed by lower levels of Dyn A(1–8) and leuenkephalin [16,19,20]
Summary
The dopamine (DA) precursor L-DOPA is still the most effective symptomatic treatment in patients with Parkinson’s disease (PD), but with time this treatment often causes troublesome complications, including ‘‘wearing off’’ fluctuations and peak-dose L-DOPA-induced dyskinesia (LID) [1]. With time L-DOPA is still required for adequate symptomatic relief and patients suffer a greater risk of developing LID [2]. Evidence from both clinical studies and experimental models of Parkinson’s disease link LID to disturbed opioid transmission in the basal ganglia [3,4]. No studies have assessed the possible association of LID with the different prodynorphin peptide products and their metabolites in the basal ganglia output structures that includes the substantia nigra (SN)
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