New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we provide evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. The number of new neurons generated under physiological conditions in substantia nigra pars compacta was found to be several orders of magnitude smaller than in the granular cell layer of the dentate gyrus of the hippocampus. However, if the rate of neuronal turnover is constant, the entire population of dopaminergic neurons in substantia nigra could be replaced during the lifespan of a mouse. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.
Summary
The observation that human monocytes cultured in the presence of the chemokine CCL18 showed increased survival, led us to profile cytokine expression in CCL18‐stimulated versus control cultures. CCL18 caused significantly increased expression of chemokines (CXCL8, CCL2, CCL3 and CCL22), interleukin‐10 (IL‐10) and platelet‐derived growth factor, but no up‐regulation of M1 cytokines IL‐1β or IL‐12. CCL18‐stimulated monocytes matured into cells with morphological resemblance to IL‐4‐stimulated macrophages, and expressed the monocyte marker CD14 as well the M2 macrophage markers CD206 and 15‐lipoxygenase, but no mature dendritic cell markers (CD80, CD83 or CD86). Functionally, CCL18‐stimulated macrophages showed a high capacity for unspecific phagocytosis and for pinocytosis, which was not associated with an oxidative burst. These findings suggest that CCL18‐activated macrophages stand at the cross‐roads between inflammation and its resolution. The chemokines that are produced in response to CCL18 are angiogenic and attract various leucocyte populations, which sustain inflammation. However, the capacity of these cells to remove cellular debris without causing oxidative damage and the production of the anti‐inflammatory IL‐10 will initiate termination of the inflammatory response. In summary, CCL18 induces an M2 spectrum macrophage phenotype in the absence of IL‐4.
Parkinson's disease is characterized by motor deficits caused by loss of midbrain dopaminergic neurons. Neurotrophic factors and cell transplantation have partially restored function in models of Parkinson's disease, but have had limited effects in humans. Here we show that intracerebroventricular administration of platelet-derived growth factor-BB can offer an alternative strategy to restore function in Parkinson's disease; In animal models of nigrostriatal injury, a two weeks treatment with plateletderived growth factor-BB resulted in long-lasting restoration of striatal dopamine transporter binding sites and expression of nigral tyrosine hydroxylase. It also normalized amphetamine-induced rotational behavior in 6-hydroxydopamine lesioned rats. Platelet-derived growth factor-BB promoted proliferation of neural progenitor cells in the subventricular zone. The effects on dopaminergic neurons and functional recovery could be blocked by co-infusion with a proliferation inhibitor, indicating a link between the proliferative and anti-parkinsonian effects. Based on the current data, we consider platelet-derived growth factor-BB a clinical candidate drug for treatment of Parkinson's disease.
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