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Neurotrophic Support (neurotrophic + support)

Distribution by Scientific Domains

Life Sciences	50%

Selected Abstracts

Analysis of Gene Expression in Parkinson's Disease: Possible Involvement of Neurotrophic Support and Axon Guidance in Dopaminergic Cell Death

BRAIN PATHOLOGY, Issue 1 2009
Koen Bossers
Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. We have studied alterations in gene expression in the substantia nigra, the caudate nucleus and putamen of four PD patients and four matched controls using custom designed Agilent microarrays. To gain insight into changes in gene expression during early stages of dopaminergic neurodegeneration, we selectively investigated the relatively spared parts of the PD substantia nigra, and correlated gene expression changes with alterations in neuronal density. We identified changes in the expression of 287 transcripts in the substantia nigra, 16 transcripts in the caudate nucleus and four transcripts in the putamen. For selected transcripts, transcriptional alterations were confirmed with qPCR on a larger set of seven PD cases and seven matched controls. We detected concerted changes in functionally connected groups of genes. In the PD substantia nigra, we observed strong evidence for a reduction in neurotrophic support and alterations in axon guidance cues. As the changes occur in relatively spared parts of the PD substantia nigra, they suggest novel disease mechanisms involving neurotrophic support and axon guidance in early stages of cellular stress events, ultimately leading to dopaminergic cell death in PD. [source]

Inter-relationship of cytokine production and NOS2 expression in microglia

JOURNAL OF NEUROCHEMISTRY, Issue 2002
C. Dello Russo
Under normal conditions, glial cells provide neurotrophic support, but can contribute to damage during neurodegenerative disorders such as multiple sclerosis and Alzheimer's disease. Once activated, glia produce and release inflammatory mediators and potentially neurotoxic substances (including cytokines, NO, and prostanoids) whose interactions could lead to sustained inflammation. We investigated the relationship between cytokine production and NO release using enriched cultures of rat microglia. Preliminary data suggest that low concentrations of endotoxin LPS (1,10 ng/mL) activated microglia by a complex mechanism involving NF,B activation, cAMP increase and PKA activation, and IL-1, production and release. We characterized this system using pharmacological activators and inhibitors of NF,B and PKA, and IL-1r, to reduce IL-1, effects. Norepinephrine (NE) dose-dependently inhibited LPS-induced NOS2 expression and NO generation, via activation of ,-2 adrenergic receptors (,2-ARs) and elevation of cAMP. Similarly, NE dose-dependently blocked LPS-dependent IL-1, production. The addition of PKA inhibitors did not reverse the suppressive effects of NE on NO production, but did reverse its effects on IL-1,. Addition of IL-1r, also reduced NO production, and exogenous IL-1, reversed the inhibitory effects of NE. These data suggest that effects of NE on LPS-dependent NO release is, at least in part, mediated by blocking of IL-1, secretion. At the same time, results with inhibitors suggest that PKA activation is necessary for LPS effects. Together, these results point to the existence of autocrine and paracrine regulatory mechanisms of microglia activation. The relationship between cytokines and NO could be an important mechanism of sustained and disruptive microglia activation. [source]

Glial cell line-derived neurotrophic factor-responsive and neurotrophin-3-responsive neurons require the cytoskeletal linker protein dystonin for postnatal survival

THE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 2 2001
Julie A. Carlsten
Abstract We have investigated the fate of different neurotrophin-responsive subpopulations of dorsal root ganglion neurons in dystonia musculorum (dt) mice. These mice have a null mutation in the cytoskeletal linker protein, dystonin. Dystonin is expressed by all sensory neurons and cross links actin filaments, intermediate filaments, and microtubules. The dt mice undergo massive sensory neurodegeneration postnatally and die at around 4 weeks of age. We assessed the surviving and degenerating neuronal populations by comparing the dorsal root ganglion (DRG) neurons and central and peripheral projections in dt mice and wildtype mice. Large, neurofilament-H-positive neurons, many of which are muscle afferents and are neurotrophin-3 (NT-3)-responsive, were severely decreased in number in dt DRGs. The loss of muscle afferents was correlated with a degeneration of muscle spindles in skeletal muscle. Nerve growth factor (NGF)-responsive populations, which were visualized using calcitonin gene-related peptide and p75, appeared qualitatively normal in the lumbar spinal cord, DRG, and hindlimb skin. In contrast, glial cell line-derived neurotrophic factor (GDNF)-responsive populations, which were visualized using the isolectin B-4 and thiamine monophosphatase, were severely diminished in the lumbar spinal cord, DRG, and hindlimb skin. Analysis of NT-3, NGF, and GDNF mRNA levels using semiquantitative reverse transcriptase-polymerase chain reaction revealed normal trophin synthesis in the peripheral targets of dt mice, arguing against decreased trophic synthesis as a possible cause of neuronal degeneration. Thus, the absence of dystonin results in the selective survival of NGF-responsive neurons and the postnatal degeneration of many NT-3- and GDNF-responsive neurons. Our results reveal that the loss of this ubiquitously expressed cytoskeletal linker has diverse effects on sensory subpopulations. Moreover, we show that dystonin is critical for the maintenance of certain DRG neurons, and its function may be related to neurotrophic support. J. Comp. Neurol. 432:155,168, 2001. © 2001 Wiley-Liss, Inc. [source]