Abstract
L-3, 4-dihydroxyphenylalanine (L-dopa) is the gold standard for symptomatic treatment of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). In the present study, L-dopa and benserazide were loaded by poly (lactic-co-glycolic acid) microspheres (LBM), which can release levodopa and benserazide in a sustained manner in order to continuous stimulate dopaminergic receptors. We investigated the role of striatal DR1/PKA/P-tau signal transduction in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD. We found that animals rendered dyskinetic by L-dopa treatment, administration of LBM prevented the severity of AIM score, as well as improvement in motor function. Moreover, we also showed L-dopa elicits profound alterations in the activity of three LID molecular markers, namely DR1/PKA/P-tau (ser396). These modifications are totally prevented by LBM treatment, a similar way to achieve continuous dopaminergic delivery (CDD). In conclusion, our experiments provided evidence that intermittent administration of L-dopa, but not continuous delivery, and DR1/PKA/p-tau (ser396) activation played a critical role in the molecular and behavioural induction of LID in 6-OHDA-lesioned rats. In addition, LBM treatment prevented the development of LID by inhibiting the expression of DR1/PKA/p-tau, as well as PPEB mRNA in dyskintic rats.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic Agents / toxicity
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Animals
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Benserazide / therapeutic use*
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Blotting, Western
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Corpus Striatum / cytology
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Dopamine Agents / therapeutic use
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Drug Combinations
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Dyskinesias / etiology
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Dyskinesias / pathology
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Dyskinesias / prevention & control*
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Female
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Fluorescent Antibody Technique
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Lactic Acid
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Levodopa / therapeutic use
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Levodopa / toxicity*
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Microspheres
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Neurons / cytology
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Neurons / metabolism
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Oxidopamine / toxicity*
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Parkinson Disease / etiology
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Parkinson Disease / pathology
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Parkinson Disease / prevention & control*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Polyglycolic Acid
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Polylactic Acid-Polyglycolic Acid Copolymer
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RNA, Messenger / genetics
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Rats
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Rats, Sprague-Dawley
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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tau Proteins / genetics
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tau Proteins / metabolism*
Substances
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Adrenergic Agents
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Dopamine Agents
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Drug Combinations
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Mapt protein, rat
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Phosphoproteins
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RNA, Messenger
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Transcription Factors
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benserazide, levodopa drug combination
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down-regulator of transcription 1
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tau Proteins
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Polylactic Acid-Polyglycolic Acid Copolymer
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Polyglycolic Acid
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Lactic Acid
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Levodopa
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Benserazide
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Oxidopamine
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Cyclic AMP-Dependent Protein Kinases