Molecular Profiling of a 6-Hydroxydopamine Model of Parkinson’s Disease

Abstract

Convection enhanced delivery of 6-hydroxydopamine (6-OHDA) to the rat striatum results in a model of Parkinson's disease. An important feature of this unilateral model is the progressive loss of dopaminergic (DA) neurons over the course of several weeks. To improve the understanding of this model, gene expression changes in the substantia nigra, which contains the DA neuron cell bodies, and the striatum, which contains the DA neuron synaptic terminals, were examined using DNA microarrays. Samples were collected and behavior was analyzed from vehicle and toxin treated animals at 3 days, 1 week, 2 weeks and 4 weeks following 6-OHDA treatment. Tissue DA content was determined and samples from animals which exhibited a substantial depletion of striatal DA were included in the subsequent gene expression analysis. The results of the gene expression analysis indicated that 6-OHDA elicits a vigorous inflammatory response, comprised of several distinct pathways, in the striatum at the earliest time point tested. In contrast, relatively few gene expression changes were observed in the SN at the 3-day time point. In both tissues examined there was evidence for a vigorous inflammatory response at the 1- and 2-week time points, which was substantially diminished by the 4-week time point. Inflammation plays a prominent role in the 6-OHDA model of Parkinson's disease.

Time course of dopamine neuron loss and glial response in the 6‐OHDA striatal mouse model of Parkinson's disease

“…Reductions in TH mRNA levels after 6‐OHDA lesion have been previously reported (Na et al ., ), and during the cell size analysis we again noted a reduction in the level of TH expression on the lesioned side of the brain. We thus attempted to quantify this by comparing the difference in the intensity of TH expression using fluorescent staining in the SNpC on the lesioned side of the brain when compared with the unlesioned side.…”

Neuroimmunological Processes in Parkinson's Disease and their Relation to α-Synuclein: Microglia as the Referee between Neuronal Processes and Peripheral Immunity

“…For example, when 6-OHDA is injected into the striatum, microglial activation appears to be more robust within the striatum than in the SN at 7 and 28 days after the lesion (Armentero et al, 2006). In contrast, others (Na et al, 2010) reported that intrastriatal 6-OHDA resulted in an increase in inflammatory-related gene expression within both the striatum and the SN 7 days post-lesion, an effect that persisted within the SN for 14 days. Taken together, data from multiple studies suggest that inflammatory processes play a secondary but important role in 6-OHDA-induced nigral degeneration.…”

Neurotoxin-Induced Catecholaminergic Loss in the Colonic Myenteric Plexus of Rhesus Monkeys

“…In that regard, rats treated with unilateral intrastriatal 6-OHDA showed temporarily increased levels of reactive nitrogen and oxygen species markers in the striatum, peaking between 25 min to 2 h after neurotoxin, and returning to near-baseline values within 7 days [53]. mRNA microarray and positron emission tomography (PET) with the radioligand [3H]PK11195 (a marker of microglial activation) confirmed these transient inflammatory changes, demonstrating a return to baseline values within 28 days post-6-OHDA [54,55]. …”