8 August 2001. Pretreatment with the hormone erythropoietin (EPO) can protect
neurons in models of neurodegenerative and stroke-related cell death, according
to a paper in today's Nature. The authors, Stuart Lipton of the Burnham Institute
in La Jolla, California, and Murat Digicaylioglu of Harvard University, have also
found that this neuroprotection is mediated by cross-talk between two distinct
signaling pathways, the NF-KB and Jak2 cascades.
EPO, a kidney cytokine, is best known for its role in regulating the production
of red blood cells; in this context, exogenous EPO is already used safely as
therapy for some forms of anemia. But it has also been demonstrated that EPO
is upregulated in the brain in response to inflammation or hypoxia/ischemia
and in neurodegenerative disorders. Of particular interest to Alzheimer's researchers
was the demonstration that EPO can protect cultured hippocampal neurons from
programmed cell death instigated by glutamate exitotoxicity (Morishita et al.).
In their current article, Lipton and Digicaylioglu demonstrate that pretreatment
with EPO can block apoptosis caused by glutamate's overactivation of NDMA receptors
and the subsequent production of the free radical nitric oxide (NO). In particular,
they show that this protection is mediated by the transcription factor NF-KB.
This protein is part of a well-characterized signaling cascade that upregulates
transcription of apoptosis-inhibiting proteins in response to inflammation or
oxidative or nitrosative stress. A surprising finding was the role of the Jak2
cascade, which typically responds to hormones and growth factors in non-neural
cells. In neurons, Jak2 activation (by EPO-EPO receptor binding) induces NF-KB
to upregulate anti-apoptotic proteins.
"Most drugs touted to protect nerve cells have failed in clinical trials of
stroke or other neurodegenerative diseases because of side effects and lack
of safety in humans. In this case, we have found the pathway to nerve cell protection
using a known drug, EPO, that is already widely used in people for other indications
with a fine safety record. Nonetheless, more work needs to be done in clinical
trials to insure that EPO will work in this manner in humans" said Lipton.
In addition to the obvious therapeutic possibilities, Ulrich Siebenlist, of
the National Institute of Allergy and Infectious Diseases (USA), points out
in an accompanying News and Views article that cell biologists studying signaling
cascades may have more work cut out for them if it turns out that there is significant
cross-talk between seemingly independent pathways.-Hakon Heimer.
Reference:Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature. 2001 Aug 9;412(6847):641-7. Abstract
Siebenlist U. Signal transduction. Barriers come down. Nature 2001 Aug 9;412:601-2. Abstract