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Postby dignan » Sat Feb 27, 2010 6:05 pm

Another astrocyte-related abstact I thought I'd throw into this thread...

Astrocytes as potential targets to suppress inflammatory demyelinating lesions in multiple sclerosis.

Neurochem Int. 2010 Feb 20. [Epub ahead of print]
De Keyser J, Laureys G, Demol F, Wilczak N, Mostert J, Clinckers R.
Department of Neurology, University Hospital Brussel, Vrije Universiteit Brussel, Brussels, Belgium; Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

A hallmark of multiple sclerosis (MS) is the occurrence of focal inflammatory demyelinating lesions in the central nervous system. The prevailing view that activated anti-myelin T cells inherently mediate these lesions has been challenged after observations that these T cells, which are part of the normal immune repertoire, can also intermittently become activated in healthy people and subjects with other diseases.

Astrocytes in the white matter of subjects with MS are deficient in ss(2) adrenergic receptors. Stimulation of ss(2) adrenergic receptors increases cAMP, leading to activation of protein kinase A (PKA). ss(2) adrenergic receptor deficiency will reduce the suppressive action of PKA on coactivator class II transactivator (CIITA), which is a key regulator of interferon gamma-induced major histocompatibility (MHC) class II molecule transcription. The expression of MHC class II may deviate astrocytes to function as facultative antigen presenting cells, which can then initiate the inflammatory cascade.

In a proof of concept study in MS subjects it was shown that fluoxetine, which activates PKA in astrocytes, reduced the development of focal inflammatory lesions. If confirmed and extended by additional studies, suppressing the antigen presenting capacity of astrocytes could be a novel therapeutic option for the treatment of MS.
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Postby dignan » Sat Jun 12, 2010 10:05 am

Another very interesting study on the role of astrocytes. Nothing is ever simple or easy with MS research, but this looks like a promising line of enquiry.

Primary loss and dysfunction of astrocytes may trigger demyelination, as seen in neuromyelitis optica, an inflammatory disease of the central nervous system. In most patients affected by this disease, injury to astrocytes is initiated by the action of autoantibodies targeting aquaporin 4 (AQP-4), a water channel on astrocytes. We show here
that damage of astrocytes and subsequent demyelination can also occur in the absence of autoantibody-mediated mechanisms. Following injection of lipopolysaccharide into the white matter initial microglia activation is followed by a functional disturbance of astrocytes, mainly reflected by
retraction of astrocytic foot processes at the glia limitans and loss of AQP-4 and connexins, which are involved in the formation of gap junctions between astrocytes and oligodendrocytes. Demyelination and oligodendrocyte degeneration in this model follows astrocyte pathology.
Similar structural abnormalities were also seen in a subset of active lesions in multiple sclerosis. Our studies suggest that astrocyte injury may be an important early step in the cascade of lesion formation in brain inflammation.

for the full study: ... lltext.pdf
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Postby dignan » Sat Sep 11, 2010 10:24 am

More Aussie research on astrocytes:

Mult Scler. 2010 Sep 7. [Epub ahead of print]
Neuromyelitis optica: a demyelinating disease characterized by acute destruction and regeneration of perivascular astrocytes.

Parratt JD, Prineas JW.

The Institute of Clinical Neurosciences, Department of Medicine, The University of Sydney/The Brain & Mind Research Inst., University of Sydney, NSW, Australia.

Background: A serum antibody directed against astrocytes is present in a high proportion of patients with neuromyelitis optica (NMO). The pathogenicity of the antibody is uncertain because no consistent astrocyte lesion is known to occur in NMO.

Objective: To determine whether there is an astrocyte lesion in NMO and if this differs from astrocyte changes in multiple sclerosis (MS).

Methods: Astrocyte pathology in early (still-myelinated) lesions and subacute NMO and MS lesions was examined immunohistochemically and in sections stained for astrocytes using routine histological techniques.

Results: Demyelination in early NMO lesions is accompanied by oligodendrocyte apoptosis in a pattern identical to that seen in MS and this is preceded by an abrupt destruction of perivascular astrocytes. Reparative astrogliosis is effected by a population of unipolar, new astrocytes. Evidence of a different type of astrocyte lesion was found in MS.

Discussion: The findings add to experimental evidence that the antibody is pathogenic. They also raise the possibility that demyelination in MS may be a bystander effect of an astrocyte lesion, i.e. that MS is not a disease primarily of myelin and oligodendrocytes.
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