Levodopa/benserazide microsphere (LBM) prevents L-dopa induced dyskinesia by inactivation of the DR1/PKA/P-tau pathway in 6-OHDA-lesioned Parkinson's rats.

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.
Authors	Cheng-long Xie, Wen-Wen Wang, Su-fang Zhang, Ming-Lu Yuan, Jun-Yi Che, Jing Gan, Lu Song, Wei-En Yuan, Zhen-Guo Liu
Journal	Scientific reports (Sci Rep) Vol. 4 Pg. 7506 (Dec 16 2014) ISSN: 2045-2322 [Electronic] England
PMID	25511986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adrenergic Agents Dopamine Agents Drug Combinations Mapt protein, rat Phosphoproteins RNA, Messenger Transcription Factors benserazide, levodopa drug combination down-regulator of transcription 1 tau Proteins Polylactic Acid-Polyglycolic Acid Copolymer Polyglycolic Acid Lactic Acid Levodopa Benserazide Oxidopamine Cyclic AMP-Dependent Protein Kinases
Topics	Adrenergic Agents (toxicity) Animals Benserazide (therapeutic use) Blotting, Western Corpus Striatum (cytology, drug effects, metabolism) Cyclic AMP-Dependent Protein Kinases (genetics, metabolism) Dopamine Agents (therapeutic use) Drug Combinations Dyskinesias (etiology, pathology, prevention & control) Female Fluorescent Antibody Technique Lactic Acid Levodopa (therapeutic use, toxicity) Microspheres Neurons (cytology, metabolism) Oxidopamine (toxicity) Parkinson Disease (etiology, pathology, prevention & control) Phosphoproteins (genetics, metabolism) Polyglycolic Acid Polylactic Acid-Polyglycolic Acid Copolymer RNA, Messenger (genetics) Rats Rats, Sprague-Dawley Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Transcription Factors (genetics, metabolism) tau Proteins (genetics, metabolism)

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