MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease. Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.
Nigrostriatal dopaminergic neurons undergo sprouting around the margins of a striatal wound. The mechanism of this periwound sprouting has been unclear. In this study, we have examined the role played by the macrophage and microglial response that follows striatal injury. Macrophages and activated microglia quickly accumulate after injury and reach their greatest numbers in the first week. Subsequently, the number of both cell types declines rapidly in the first month and thereafter more slowly. Macrophage numbers eventually cease to decline, and a sizable group of these cells remains at the wound site and forms a long-term, highly activated resident population. This population of macrophages expresses increasing amounts of glial cell line-derived neurotrophic factor mRNA with time. Brain-derived neurotrophic factor mRNA is also expressed in and around the wound site. Production of this factor is by both activated microglia and, to a lesser extent, macrophages. The production of these potent dopaminergic neurotrophic factors occurs in a similar spatial distribution to sprouting dopaminergic fibers. Moreover, dopamine transporter-positive dopaminergic neurites can be seen growing toward and embracing hemosiderin-filled wound macrophages. The dopaminergic sprouting that accompanies striatal injury thus appears to result from neurotrophic factor secretion by activated macrophages and microglia at the wound site.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons in the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Here, we show that the proapoptotic protein Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neuronal apoptosis. In adult mice, there is an up-regulation of Bax in the SNpc after MPTP administration and a decrease in Bcl-2. These changes parallel MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking Bax are significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that Bax plays a critical role in the MPTP neurotoxic process and suggests that targeting Bax may provide protective benefit in the treatment of Parkinson's disease. P arkinson's disease (PD) is a common neurodegenerative disorder whose cardinal clinical features include tremor, slowness of movement, stiffness, and postural instability (1). These disabling symptoms are primarily due to a profound deficit in striatal dopamine content that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the consequent loss of their projecting nerve fibers in the striatum (2, 3). Although several approved drugs do alleviate PD symptoms, their chronic use often is associated with debilitating side effects (4), and none seem to dampen the progression of the disease. Moreover, the development of effective neuroprotective therapies is impeded by our limited knowledge of the mechanism by which SNpc dopaminergic neurons die in PD. Thus far, however, significant insights into the pathogenesis of PD have been achieved by the use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which replicates in humans and nonhuman primates a severe and irreversible PD-like syndrome (5). In several mammalian species, MPTP reproduces most of the biochemical and pathological hallmarks of PD, including the dramatic degeneration of dopaminergic neurons (5).Mounting evidence indicates that highly regulated cell deathassociated molecular pathways could participate in the relentless demise of neurons in degenerative diseases (6, 7), including PD (8). In keeping with this, Bax (9) has emerged as a pro-cell death driving force within the central decision point constituted by the Bcl-2 family that modulates the activation of downstream effectors of cell death such as caspases (7). It is also clear that Bax is required for the death of several types of neurons in the peripheral and central nervous systems during both normal development and pathological situations (10-18). In light of its critical role within the programmed cell death machinery and its importance in neuronal death, Bax appears as a particularly appealing target for therapeutic interventions aimed at hampering neurodegeneration. Consistent with a potential pivotal role for Bax in SNpc neuronal death, here we show that Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neu...
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