Neural progenitor cells in the partial progressive 6-OHDA lesion rat model and the post-mortem human brain in Parkinson’s disease

Abstract

The demonstration of endogenous progenitor cells in the adult mammalian brain has raised the exciting possibility that progenitor cells could have potential use in cell replacement therapy for neurodegenerative diseases, such as Parkinson’s disease. Previous studies have shown that progenitor cells in the adult mammalian brain undergo proliferation and neurogenesis in response to neuronal cell loss. In this study, immunohistochemical techniques were used to demonstrate progenitor cell proliferation and differentiation in the subventricular zone (SVZ) adjacent to the striatum/caudate nucleus and in the midbrain regions, in response to dopamine (DA) cell death in the substantia nigra, using the partial progressive 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson’s disease and post-mortem human Parkinson’s disease brains. In the rat model, multiple intraperitoneal injections of the mitotic marker bromodeoxyuridine (BrdU) injected at various time points showed, a significant increase in BrdU positive cells in the SVZ, striatum and the midbrain regions of 6-OHDA-treated rats compared to SHAM controls. Further, the newborn cells were shown to produce glial cells in the striatum of 6-OHDA-treated rats. The normal and Parkinson's disease human brains were stained with a proliferative marker, proliferating cell nuclear antigen (PCNA), to label dividing cells. The results demonstrated a significant 2.1-fold increase of PCNA positive cells in the SVZ adjacent to the caudate nucleus when compared to normal brains. Close inspection of individual human brains demonstrated significant asymmetry between the left and the right hemisphere of one Parkinson’s disease brain treated with deep brain stimulation. Further, the presence of migrating neuroblasts and glial cells was also demonstrated in the Parkinson’s disease human brains. The results in this thesis demonstrate progenitor cell proliferation in response to DA cell loss in the experimental rodent brain and the human Parkinson’s disease brain and further, indicate the regenerative potential of the adult mammalian brain in Parkinson’s disease. The findings from this thesis suggest the potential for the development of novel therapeutic approaches in the treatment of neurodegenerative diseases.