By David N. Leff

EPO (erythropoietin), the blood-building anti-anemia drug, wears two hats ¿ one white, one black. Now it¿s trying on a third chapeau ¿ protecting the brain from stress, trauma and disease.

After the FDA blessed Amgen Inc.¿s erythropoietin in 1989, EPO started out as the drug of choice for correcting the blood-trashing anemia of kidney dialysis. As it got up steam in ensuing years, its white-hat use has extended to other anemias, caused by HIV treatment, cancer chemotherapy, surgery, kidney failure and drug toxicity.

Meanwhile, almost from Day One, EPO¿s black-hat inside track gave competitive athletes the undetectable blood-doping surge they¿d been looking for to enhance performance and endurance by sharply boosting their oxygen capacity.

Oxygen was key to the hormone¿s own performance. EPO¿s main 24/7 gig was to sense the body¿s ever-changing demand for O2 ¿ mainly by replenishing the red blood cells that carry the life-giving fuel from the kidneys, which make EPO, to every organ, tissue and cell. (See BioWorld Today, Sept. 15, 2000, p. 1.)

A healthy red blood cell (RBC) patrols its oxygen-delivery beat for about 120 days before going out of business. The resulting hypoxia ¿ drop in O2 ¿ signals the kidney cells to replace the used-up RBCs. But besides that normal routine, there are many other causes of hypoxia, especially in the brain, which is the RBC¿s best customer for a steady-state oxygen supply.

Cerebral stresses that starve the brain cells of oxygen include ischemic stroke ¿ which by definition crimps the blood supply to parts of the brain ¿ or a sudden hike in nitric oxide, with resulting free oxygen radicals, to name just a few. So it¿s no surprise that neurons in the central nervous system eagerly lap up erythropoietin on demand. But the brain is a long way from the kidneys. What¿s more, erythropoietin is a bulky molecule, not likely to transit the blood-brain barrier readily. So neuroscientists have recently begun to suspect brain cells of secreting their own EPO fixes.

EPO Receptors Bind Only Neurons In Brain

A paper in today¿s Nature, dated August 9, 2001, bears the title: ¿Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NFkB signaling cascades.¿ Its senior author is clinical and research neurologist Stuart Lipton, director of the Burnham Institute¿s Center for Neuroscience and Aging in La Jolla, Calif.

¿There are actually EPO-binding receptors in the brain,¿ Lipton told BioWorld Today, ¿and lo and behold, we found them only on neurons ¿ not on any other brain cells. They¿re not on the astrocytes, the supporting cells of the brain. Our paper goes on and characterizes the Jak-Stat signaling pathway that the EPO receptor activates. Stat,¿ he explained, ¿is the transcription factor that¿s being turned on.

¿We found,¿ Lipton continued, ¿that there was cross-talk ¿ one pathway turning on another ¿ in which Jak2 activated the well-known cell-protective NFkB pathway. So we already knew that NFkB can turn on a series of protective genes. And we actually know what those genes are. Some of them help prevent apoptosis ¿ programmed cell death ¿ which is prevalent in many neurodegenerative diseases.

¿Another important finding of this paper,¿ he added, ¿concerns stroke. The same transcription factor that makes EPO in the kidney also responds in the brain to similar kinds of stresses ¿ hypoxia, trauma, reactive oxygen species, nitric oxide. It activates this pathway that we characterized, because it¿s a predominant pathway for neuroprotection.

¿We believe, therefore,¿ Lipton observed, ¿that it is important in a phenomenon neurologists have known about for a number of years called hypoxic ischemic preconditioning. That is, if you have a little stroke today, and a huge stroke a few day later, we know that you¿re relatively protected by that initial ischemic attack. It would be interesting to know that mechanism, because if we could recapitulate it we might be able to prevent a lot of stroke damage.

¿There are probably multiple mechanisms for this preconditioning phenomenon,¿ Lipton continued. ¿We believe now that erythropoietin is one of the major ones, because hypoxia turns on EPO, which then turns on this neuroprotective pathway. Can we harness that? Whoever designed the brain was very smart to make these protective pathways. Our argument now is that we can harness the natural pathway, using EPO. The reason that¿s so important,¿ he pointed out, ¿is that all of the neuroprotective compounds that have been developed to date ¿ and 99.999 percent of the drugs tested for use in the brain fail ¿ not because they don¿t work, but because they¿re not safe.¿

Lipton made the point, ¿Here is a way to really jump-start brain therapy: To take a drug we know is approved as safe, EPO for one, and try to figure out how it works in the brain so we can produce better drugs for brain protection. The actual protective pathways here are important, and not just in stroke. It¿s been known for some time that essentially any neurologic disease activates a final common pathway to cell injuries and death. If we can stop the pathway, it might not cure the disease, but it can certainly stave off its ravages for a good long time. This includes Alzheimer¿s and Lou Gehrig¿s diseases ¿ amyotrophic lateral sclerosis ¿ and all the classical neurodegenerative diseases, even extending to the eyes, such as glaucoma, and spinal cord trauma.¿

Disease-Smartened Mice First, Then Patients

¿Some of the big pharmaceutical companies,¿ Lipton observed, ¿have been developing EPO-mimetic drugs that cross the blood-brain barrier, and we¿re hoping to test some of those. I think EPO itself should be tested in patients as a brain protectant, but the way to do this is first test it in very good animal models of several of these major neurological diseases ¿ such as stroke, Alzheimer¿s, Huntington¿s, multiple sclerosis and Parkinson¿s diseases.

¿We have mice that mimic many of the features of those ailments. The fact that EPO is a known drug that¿s safe should greatly expedite its testing in humans. Normally, developing a drug is 10 or 20 years away from getting it into people, but we have EPO, which is already in people in the U.S., so it¿s much easier to test it for another indication.¿