Antiinflammatory actions of RORalpha in astrocytes
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melatonin levels are so high (and probably toxic) in Parkinson's.
<http://www.sciencedaily.com/releases/2009/12/091215164115.htm>
RORalpha, the Orchestrator of Neuron Protection
How do the brain cells called astrocytes ensure the protection of
neurons? By studying the protagonists in the protection and satisfactory
functioning of neurons, scientists at the Laboratoire Neurobiologie des
Processus Adaptatifs (CNRS/UPMC) have found a mechanism that clarifies
the role of astrocytes. Crucial to this mechanism, RORalpha protein is
revealed as an essential regulator of inflammatory factors. This
discovery constitutes a new path for research on novel drugs in the
event of cerebral lesions (e.g. neurodegenerative diseases or trauma).
These findings were published in the advance edition of PNAS on 1
December 2009.
Astrocytes form part of the glial cells and play a key role in the
functioning, well-being and protection of neurons. They react to neuron
status and are implicated in the inflammatory response. Inflammation is
a complex immune phenomenon that balances the activating and inhibitory
actions of a finely-tuned set of molecules. Neuronal inflammation can
cause disturbances and hamper the functioning of nerves.
Focusing on glial cells, the scientists hypothesized that there was a
contribution of the RORalpha protein in the reaction of these cells to
neuronal death. RORalpha is known as a receptor specialized in
controlling the expression of genes in the nucleus that exert an
anti-inflammatory effect. Until now, it was thought that this protein
was exclusively localized in neurons and not in astrocytes.
This discovery thus demonstrates the expression of RORalpha in
astrocytes and its role in regulating interleukin-6 (IL-6), an essential
mediator of inflammation. In the brain, IL-6 is mainly produced by
astrocytes, this production being up-regulated under inflammatory
conditions. This molecule has demonstrated neuro-protective properties
in several in vivo and in vitro models, but under certain conditions it
may also have neurotoxic effects.
The unexpected finding was that RORalpha exerts an ambivalent action on
IL-6 production. In astrocytes in an inflammatory situation, RORalpha is
up-regulated. It indirectly blocks IL-6 production, preventing any
toxicity. However, under normal physiological conditions where the
astrocyte is not stimulated, RORalpha activates IL-6 production at
concentrations that are beneficial at a basal level. This ambivalence of
both RORalpha and IL-6 thus permits astrocytes to react rapidly to
attack so as to ensure favorable conditions under all circumstances in
the microenvironment of neurons. In vivo, RORalpha is thus the molecular
heart of a complex IL-6 regulation mechanism that occurs in the
astrocyte to the benefit of neurons.
These results are of particular interest in the context of neuronal
death. Indeed, whether this is chronic -- as in neurodegenerative
diseases -- or acute -- following a trauma, neuron loss is always
associated with a reaction by glial cells. RORalpha is thus a new path
that could be followed to search for new drugs for use in these
pathological situations.