title: Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l-DOPA delivery in the 6-OHDA model of Parkinson's disease.
abstract: Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. l-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any l-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic l-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mulas
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Espa
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Fenu
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, via Fiorelli 1, Cagliari, Italy.
authors.forename: Saturnino
authors.initials: S
authors.lastname: Spiga
authors.affiliation: Department of Neurology, AOB "G. Brotzu" General Hospital, via Peretti 2, Cagliari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cossu
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pillai
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Carboni
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Simbula
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Dragana
authors.initials: D
authors.lastname: Jadžić
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Angius
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Spolitu
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Batetta
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Lecca
authors.affiliation: Department of Pharmacology, UT Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giuffrida
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, S.P. N. 8, 09042, Monserrato, Cagliari, Italy. Electronic address: acarta@unica.it.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Carta
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000009:adverse effects; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D004660:Encephalitis / Q000139:chemically induced*; D007839:Functional Laterality / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013565:Sympatholytics / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D013565:Sympatholytics; D014409:Tumor Necrosis Factor-alpha; D007980:Levodopa; D016627:Oxidopamine
keywords: Cytokine; Dyskinesia; Inflammation; Microglia; Parkinson; TNF-alpha; l-DOPA