title: Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging.
abstract: We investigated the microglial response to progressive dopamine neuron degeneration using in vivo positron emission tomography (PET) imaging and postmortem analyses in a Parkinson's disease (PD) rat model induced by unilateral (right side) intrastriatal administration of 6-hydroxydopamine (6-OHDA). Degeneration of the dopamine system was monitored by PET imaging of presynaptic dopamine transporters using a specific ligand (11)C-CFT (2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane). Binding of (11)C-CFT was markedly reduced in the striatum indicating dopaminergic degeneration. Parallel PET studies of (11)C-PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3 isoquinoline carboxamide) (specific ligand for activated microglia) showed increased binding in the striatum and substantia nigra indicative of a microglial response. Postmortem immunohistochemical analyses were performed with antibodies against CR3 for microglia/macrophage activation. Using a qualitative postmortem index for microglial activation we found an initially focal, then widespread microglial response at striatal and nigral levels at 4 weeks postlesion. These data support the hypothesis that inflammation is a significant component of progressive dopaminergic degeneration that can be monitored by PET imaging.
authors.affiliation: Neuroregeneration Laboratory, MRC119, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
authors.forename: F
authors.initials: F
authors.lastname: Cicchetti
authors.forename: A L
authors.initials: AL
authors.lastname: Brownell
authors.forename: K
authors.initials: K
authors.lastname: Williams
authors.forename: Y I
authors.initials: YI
authors.lastname: Chen
authors.forename: E
authors.initials: E
authors.lastname: Livni
authors.forename: O
authors.initials: O
authors.lastname: Isacson
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000970:Antineoplastic Agents / Q000494:pharmacology; D030161:Avian Proteins; D051926:Basigin; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D004298:Dopamine / Q000378:metabolism*; D004660:Encephalitis / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D005911:Gliosis / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D007546:Isoquinolines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D017072:Neostriatum / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D013378:Substantia Nigra / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D013565:Sympatholytics / Q000494:pharmacology; D014055:Tomography, Emission-Computed; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D030161:Avian Proteins; D001798:Blood Proteins; C102624:Bsg protein, Gallus gallus; C079432:Bsg protein, rat; D002250:Carbon Radioisotopes; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D013565:Sympatholytics; D051926:Basigin; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; C037850:PK 11195