The decrement in dopamine levels exceeds the loss of dopaminergic neurons in Parkinson's disease (PD) patients and experimental models of PD. This discrepancy is poorly understood and may represent an important event in the pathogenesis of PD. Herein, we report that the ratelimiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is a selective target for nitration following exposure of PC12 cells to either peroxynitrite or 1-methyl-4-phenylpyridiniun ion (MPP ؉ ). Nitration of TH also occurs in mouse striatum after MPTP administration. Nitration of tyrosine residues in TH results in loss of enzymatic activity. In the mouse striatum, tyrosine nitration-mediated loss in TH activity parallels the decline in dopamine levels whereas the levels of TH protein remain unchanged for the first 6 hr post MPTP injection. Striatal TH was not nitrated in mice overexpressing copper͞zinc superoxide dismutase after MPTP administration, supporting a critical role for superoxide in TH tyrosine nitration. These results indicate that tyrosine nitration-induced TH inactivation and consequently dopamine synthesis failure, represents an early and thus far unidentified biochemical event in MPTP neurotoxic process. The resemblance of the MPTP model with PD suggests that a similar phenomenon may occur in PD, inf luencing the severity of parkisonian symptoms.Parkinson's disease (PD) is a common neurodegenerative disorder characterized by disabling motor abnormalities attributed to a profound deficit in dopamine (1). The decline in dopamine level has been thought to arise solely from the severe loss of dopaminergic neurons in the nigrostriatal pathway. However, the dopamine deficit in the affected regions of the brain significantly exceed the loss of dopaminergic neurons (2, 3), suggesting that dopamine synthesis is impaired before cellular demise. Support for this hypothesis comes from studies of experimental models of PD demonstrating that the reduction in dopamine metabolism-related markers such as tyrosine hydroxylase (TH) and dopamine transporter is far greater than the loss of neuronal cell bodies (4-6). Because the severity of PD symptoms correlates with the magnitude of dopamine deficit, elucidating mechanisms that impair dopamine synthesis and metabolism in neurons that undergo selective degeneration in PD may have important therapeutic implications.There is experimental evidence from studies of humans and animals in support of the hypothesis that oxidative stress contributes to the pathogenesis of PD (7). Studies performed in the MPTP model of PD suggest that peroxynitrite, a reactive species formed by the nearly diffusion-limited reaction of nitric oxide with superoxide, may be a mediator of nigrostriatal damage in PD (8-10). The potential role of peroxynitrite in the pathogenesis of PD is further supported by demonstrating that exposure of the monoamine-producing PC12 cells to peroxynitrite induced a dose-dependent alteration in dopamine synthesis that was not due to cell death or the oxidation of dopamine (11)....

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Axonal loss was detected not only in MS eyes with a previous acute optic neuritis, but also in MS eyes with no known optic neuritis episode. Structural abnormalities correlate with functional assessments of the optic nerve.

Although spontaneous remyelination occurs in multiple sclerosis (MS), the extent of myelin repair is often inadequate to restore normal function. Oligodendrocyte precursors remaining in nonremyelinating MS plaques may be restricted by an inhibitory signal. Bone morphogenetic proteins (BMPs) have been implicated as repressors of oligodendrocyte development and inducers of astrogliogenesis. We hypothesized that BMPs are up-regulated in MS lesions and play a role in demyelination and astrogliosis. We examined expression of BMPs in an animal model of MS, chronic experimental autoimmune encephalomyelitis (EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide in C57BL/6 mice. By 14 days postimmunization, compared to those of control mice, the lumbar spinal cords of MOG-peptide EAE mice demonstrated prominent astrogliosis, infiltration of inflammatory cells, and disrupted expression of myelin proteins. Quantitative RT-PCR showed that expression of BMP4, BMP6, and BMP7 mRNA increased 2- to 4-fold in the lumbar spinal cords of animals with symptomatic EAE versus in vehicle-treated and untreated controls on days 14, 21, and 42 postimmunization. BMP2 mRNA expression was not altered. BMP4 mRNA was much more abundant in the spinal cords of all animals than was mRNA encoding BMP2, BMP6, and BMP7. Immunoblot analysis confirmed the increased expression of BMP4 in the EAE animals. Immunohistochemistry revealed increased BMP4 immunoreactivity in areas of inflammation in MOG-peptide EAE animals. BMP4 labeling was mostly limited to macrophages but was sometimes associated with astrocytes and oligodendrocytes. These results indicate that members of the BMP family are differentially expressed in adult spinal cord and are up-regulated during EAE. (c) 2007 Wiley-Liss, Inc.

There are significant differences in RNFL thickness measurements between Cirrus and Spectralis despite a high correlation of measurement between the two instruments. Fourier-domain OCT can be considered a valid device for detecting RNFL atrophy in MS patients.