Abstract
The cause of the L-dopa–induced dyskinesia (LID) has been ascribed to G-protein coupled receptor (GPCR) supersensitivity and uncontrolled downstream signaling. It is now supposed that β-arrestin2 affects GPCR signaling through its ability to scaffold various intracellular molecules. We used the rAAV (recombinant adeno-associated virus) vectors to overexpress and ablation of β-arrestin2. L-dopa-induced changes in expression of signaling molecules and other proteins in the striatum were examined by western blot and immunohistochemically. Our data demonstrated that via AAV-mediated overexpression of β-arrestin2 attenuated LID performance in 6-OHDA-lesioned rodent models. β-arrestin2 suppressed LID behavior without compromising the antiparkinsonian effects of L-dopa. Moreover, we also found that the anti-dyskinetic effect of β-arrestin2 was reversed by SKF38393, a D1R agonist. On the contrary, the rat knockdown study demonstrated that reduced availability of β-arrestin2 deteriorated LID performance, which was counteracted by SCH23390, a D1R antagonist. These data not only demonstrate a central role for β-arrestin2/GPCR signaling in LID, but also show the D1R signal pathway changes occurring in response to dopaminergic denervation and pulsatile administration of L-dopa.
Highlights
Parkinson’s disease (PD) is characterized by the serious dopaminergic neurons deficiency in the substantia nigra (SN) of the midbrain, leading to bradykinesia, muscular rigidity and rest tremor et al [1]
The rat knockdown study demonstrated that reduced availability of β-arrestin2 deteriorated L-dopa–induced dyskinesia (LID) performance, which was counteracted by SCH23390, a D1R antagonist
We found the TH levels were decreased by more than 90% in the lesioned hemisphere of 6-OHDA-lesioned rats treated or not with L-dopa when compared with the sham group (n=4 for each group, P
Summary
Parkinson’s disease (PD) is characterized by the serious dopaminergic neurons deficiency in the substantia nigra (SN) of the midbrain, leading to bradykinesia, muscular rigidity and rest tremor et al [1]. After prolonged and pulsatile exposure to L-dopa, PD patients eventually develop a variety of abnormal involuntary movements, termed Ldopa-induced dyskinesia (LID), which represent a major treatment limitation and reduce the quality of life of PD patients [3]. The underlying cellular and molecular key events that result in LID remains unclear . LID is closely correlated with pathological changes in dopaminergic transmissions in the striatum [5]. A large body of evidence showed that increased activity of dopamine D1-receptors (D1R) was imperative for LID development [6]. Darmopil et al demonstrated that the D1R was critical for the development of LID in mice and the underlying molecular changes in the denervated striatum while the D2R had little or no involvement [9]. Pharmacological or genetic interventions aimed at reducing abnormal sensitizing D1R maybe a potential alternative approach to control the LID
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