A few weeks ago we looked at the possible benefits of intermittent oxygen deprivation
for people with impaired respiratory function as a result of spinal cord trauma.
A new paper related to boosting breathing capacity came out this week in the Journal of Neuroscience from the same lab that did the above-mentioned hypoxia work, Gordon Mitchell’s group at the University of Wisconsin/Madison. This one, written by Erica A. Dale with help from Irawan Satriotomo is called “Cervical Spinal Erythropoietin Induces Phrenic Motor Facilitation via Extracellular Signal-Regulated Protein Kinase and Akt Signaling
.” That’s a molecular mouthful, indeed, but the basic point is this: the drug erythropoietin, well-known as the blockbuster blood booster EPO, may improve breathing function related to nerve trauma.
The scientists think EPO may also affect motor plasticity, crucially important for upper cervical SCI, stroke and ALS.
EPO is a hormone that controls erythropoiesis, or red blood cell production. It continues to have huge success in the kidney dialysis market, as well as for post-chemo cancer patients. This is the anti-anemia drug cyclist Floyd Landis admitted helped him win the Tour de France. It is also the subject of a fascinating book, Blood Feud
, by Kathleen Sharp, about a whistleblower who describes an appalling level of greed and fraud in the marketing of EPO by Amgen and Johnson & Johnson. Sharp said the companies have made over $60 billion on EPO, mostly paid by the federal government reimbursements. The book is recommended by the New York Times
as a “complex story of a justice-driven drug salesman going up against Big Pharma’s greed and deception… should be required reading for anyone interested in the business of medicine and in Big Pharma’s questionable drug therapies.” Pardon the digression…
EPO also plays a role in wound healing and one that is not fully understood in the brain or spinal cord’s response to trauma. EPO appears to protect nerves exposed to apoptosis (programmed cell death), anoxia (lack of oxygen), and excitotoxicity (over abundance of neurotransmitters such as glutamate). But the body’s response alone isn’t enough to counteract the chaos; scientists for a number of years have been looking at the effects of applying outside doses of EPO in animal models of SCI.
Here, for example, is a review paper published last summer from Alfredo Gorio’s group in Italy summarizing SCI work related to EPO: “Erythropoietin: Recent Developments in the Treatment of Spinal Cord Injury
.” (Note: full text is available, click on the box upper right of webpage).
From the Gorio paper:
The work of many groups demonstrated that the administration of exogenous rhEPO [genetically engineered or recombinant human EPO] in animal models (rats) of traumatic SCI produces substantial neuroprotection and coworkers in two different models of traumatic spinal cord lesion (transient compression or blunt trauma) showed that the single dose administration of rhEPO gives a markedly superior clinical course of recovery of motor function compared with placebo, characterized by an earlier and more complete normalization of function over a 28-day period of study. Moreover, the same authors observed that secondary inflammation was also markedly attenuated by rhEPO administration and associated with reduced cavitation within the cord. These results suggested that beneficial effect of rhEPO treatment occurs within the first week after injury.
According to that paper, there is reason to think EPO will move toward human clinical trials for SCI. EPO, the Italian group suggested, might contribute to recovery after SCI by increasing the number of new neurons. But there are problems to overcome. In an animal stroke model, for example, EPO treatment “exhibits increased cerebral infarct size following arterial occlusion in spite of high levels of EPO within the brain. In addition to adverse effects at the level of injury, serious systemic complications are possible, as, for example, the well-publicized fatal outcomes observed following ‘blood doping’ by athletes.” Said outcomes include heart attack, stroke, and pulmonary embolism.
Gorio added that EPO also reduced scar formation, or astrogliosis. That seems like it might make for a more permissive environment for regeneration. “However, it has been reported that a genetic reduction in reactive astrocytes in a mouse model has been associated with a worse clinical outcome after a stab injury to the spinal cord.” Scientists are looking for ways to modify EPO so its analogues will avoid side effects.
Back to the main topic, and the potential for good news, from the new Mitchell publication:
“An unintended outcome of [this] EPO administration may well have been increased breathing, which can be good or bad depending on the prevailing state of the patient. If breathing is inadequate as a result of cervical injury, then EPO-induced pMF [phrenic motor facilitation] is expected to restore lost breathing function.”