Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging.
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.
Cicchetti
F
F
Neuroregeneration Laboratory, MRC119, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Brownell
A L
AL
Williams
K
K
Chen
Y I
YI
Livni
E
E
Isacson
O
O
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
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