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.

Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism

“…For example, mice lacking inducible nitric oxide synthase activity are resistant to MPTP-induced lesions and inhibition of microglial activation reduces MPTP neurotoxicity (Itzhak et al, 1999;Liberatore et al, 1999;Dehmer et al, 2000;Du et al, 2001;Wu et al, 2002). In the striatum and SN of 6-OHDA lesioned rat brains, prominent microglial activation was detectable weeks after the lesion (Cicchetti et al, 2002).…”

Evaluation of Four Pyridine Analogs to Characterize 6-OHDA-Induced Modulation of mGluR5 Function in Rat Brain Using microPET Studies

“…To restrict the effect of 6-OHDA on the dopaminergic neurons, the animals received desipramine (20 mg/kg intraperitoneal) 30 mins before the 6-OHDA injection. A unilateral injection of 6-OHDA (8 mg in 2 mL) was conducted into the medial forebrain bundle on the right side of the rat brain (coordinates: AP À4.5; ML + 1.2; DV À7.6) using a Hamilton syringe (Cicchetti et al, 2002). All experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Policy by the Subcommittee on Research Animals of the Harvard Medical School and Massachusetts General Hospital.…”

Evaluation of Reference Tissue Models for the Analysis of [11C](R)-PK11195 Studies

“…Both [ 11 C](R)-PK11195 and [ 11 C]PK11195 have been used as positron emmision tomography (PET) tracers to study activated microglia in various neurologic disorders. It has been used to study stroke (Ramsay et al, 1992;Pappata et al, 2000;Gerhard et al, 2000Gerhard et al, , 2005a), Alzheimer's disease (Groom et al, 1995; Cagnin et al, 2001a;Versijpt et al, 2003), multiple sclerosis (Banati et al, 2000;Debruyne et al, 2002Debruyne et al, , 2003Versijpt et al, 2005) and various other diseases (Pappata et al, 1991; Banati et al, 1999Banati et al, , 2001Goerres et al, 2001;Cagnin et al, 2001bCagnin et al, , 2004Cicchetti et al, 2002;Gerhard et al, 2003Gerhard et al, , 2004Gerhard et al, , 2005bTurner et al, 2004Turner et al, , 2005Venneti et al, 2004;Henkel et al, 2004;Ouchi et al, 2005). Most studies have used a reference tissue approach to quantify binding, either by applying the simplified reference tissue model (SRTM) (Lammertsma and Hume, 1996) or by using uptake normalized to a reference region.…”