title: 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.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Cheng-long
authors.initials: CL
authors.lastname: Xie
authors.affiliation: The center of Traditional Chinese Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Su-fang
authors.initials: SF
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China.
authors.forename: Ming-Lu
authors.initials: ML
authors.lastname: Yuan
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China.
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Che
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gan
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Song
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China.
authors.forename: Wei-En
authors.initials: WE
authors.lastname: Yuan
authors.affiliation: Department of Neurology, Xinhua Hospital affiliated to the Medical School of Shanghai Jiaotong University, 200092, 1665 Kongjiang Road, Shanghai, China.
authors.forename: Zhen-Guo
authors.initials: ZG
authors.lastname: Liu
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001545:Benserazide / Q000627:therapeutic use*; D015153:Blotting, Western; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015259:Dopamine Agents / Q000627:therapeutic use; D004338:Drug Combinations; D020820:Dyskinesias / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D005455:Fluorescent Antibody Technique; D019344:Lactic Acid; D007980:Levodopa / Q000627:therapeutic use / Q000633:toxicity*; D008863:Microspheres; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018663:Adrenergic Agents; D015259:Dopamine Agents; D004338:Drug Combinations; C489131:Mapt protein, rat; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; C005177:benserazide, levodopa drug combination; C075995:down-regulator of transcription 1; D016875:tau Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; D017868:Cyclic AMP-Dependent Protein Kinases