08 Aug 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