On the move to stimulate cell plasticity in the substantia nigra in Parkinson's disease

Abstract

Background. Parkinson's disease (PD) is the second mostcommon neurodegenerative disorder affecting over 1% ofindividuals over 50 years of age. A major neuropathologicalfeature to PD is the progressive degeneration of dopaminergicneurons in substantia nigra leading to a dramatic reduction ofdopamine levels in the striatum. The study by Steiner andcoworkers published in this issue of Experimental Neurology(Steiner et al., this issue) examined functional and morpholog-ical effects of housing rats with unilateral neurotoxin-inducedlesions of the nigrostriatal pathway in an enriched environmentinvolving physical activity. Enriched environment typicallyinvolves housing rodents in large groups with access toappealing “toys”, e.g., ladders, tubes and boxes. The additionalphysical activity consisted of the rats walking on a rotarod for10–20minonce daily(Steineretal., thisissue).Inthe unilateralrat model of PD, a combination of altered housing conditionsand daily physical activity induced an increase in the number ofbromodeoxyuridine (BrdU)-labeled, newborn cells in thesubstantia nigra. The lesion itself, induced by intrastriatalinjections of the neurotoxin 6-hydroxydopamine, did not affectthe rate of cell proliferation in the substantia nigra, which is atvariance with some earlier studies that have reported increasesfollowing nigral lesions (Kay and Blum, 2000; Mohapel et al.,2005; Shan et al., 2006; Zhao et al., 2003). The majority of theBrdU-positive, newborn cells were also positive for NG2, glialfibrillary acid protein (GFAP) or the microglial marker Iba1.The chondroitin sulfate proteoglycan NG2 is expressed on thesurface of neural cells whose role in the brain is not fullyestablished. The NG2 positive cells have been called “poly-dendrocytes” (Nishiyama et al., 2002) and have also beensuggestedtobeoligodendrocyteprecursors.In contrast, noneofthe newborn, BrdU-stained cells in the substantia nigraexpressed the markers for neuroblasts and neurons that werestudied, i.e., doublecortin, NeuN and tyrosine hydroxylase.Around one third of the BrdU-labeled cells were not labeled byany of the phenotype-specific markers that were examined.Earlier studies have reported the occurrence of angiogenesis inthe substantia nigra following dopamine-denervating lesions(Barcia et al., 2005; Carvey et al., 2005). It is therefore possiblethat newborn cells with an unidentified phenotype were ofvascular origin, although endothelial markers were not exa-mined in this study. Steiner and collaborators also report thatenriched environment combined with physical activity im-proves recovery of motor function in one of the studied groups.Their conclusion is based on that there was a significant re-duction in amphetamine-induced rotation in rats studied after 7weeks compared to a similar group tested at 4 weeks after le-sion, and that the difference was only significant in rats sub-jected to exercise in combination with enriched environment.This behavioral recovery was not, however, striking. Also therats housed under normal conditions exhibited a trend forspontaneous normalization of rotational asymmetry between 4and7weekspost-lesion (seeFig.2in(Steineret al.,this issue)).Therefore, despite the clearly significant changes in cellularplasticity in the substantia nigra, there was not a clearly signi-ficant impact of the housing conditions and physical activity onfunctional recoveryofthelesion-induceddeficits asassessedbyrotational behavior. Further studies using behavioral tests thatdo not involve drug treatment (e.g., spontaneous rotation,forelimb use for stepping or reaching) may help to determinewhether the enriched environmental conditions employed by