Former acclaimed cyclist, Lance Armstrong, was thrown back into the limelight in 2012, when his seven Tour de France medals were rescinded due to use of a cocktail of performance-enhancing drugs over the course of his cycling career. In addition to Armstrong, athletes of endurance sports have reveled in the performance-enhancing benefits of one of these drugs in particular, the synthetic hormone, Erythropoietin.
Originally identified as a kidney-derived stimulator of erythrocyte precursor cell proliferation and differentiation, EPO’s biological role had since expanded, and its pleiotropic effects are currently being studied. Recent trials have displayed the hormone’s profound effects on cognitive performance, begging the question: could EPO hold the key for future clinical treatment and prevention of brain injury?
Image courtesy of hematology.org
Since it’s discovery in 1987, synthetic EPO has been commonly used worldwide to treat patients with anemia. Not long thereafter its discovery, athletes realized they too could exploit EPO’s ability to increase oxygen carrying capacity to muscles, and it was employed as a quick-and-easy (and previously undetectable) alternative to the traditional blood-transfusion doping method.
As deception in cycling became prevalent, it undermined the advances made in studies of EPO’s connection to the Central Nervous System (CNS). As Armstrong was vigorously preparing to win his first Tour De France gold medal in 1999, researchers found EPO and its receptor (EPOR) to be expressed at very high levels in the developing CNS of fetuses. In contrast, there is a sheer drop in expression upon birth, and gradual decline throughout ones life. This finding was used as inspiration for two recent studies done in 2011, and in August of this year. The former showed that EPO can have a lasting increase in brain performance if administered early in development. The latter, published in JAMA, showed that baby’s born very prematurely – therefore, at a high risk of incomplete brain development and brain damage – and who are given EPO immediately after birth, had a significantly reduced risk of long-term brain injury.
In the past decade, multiple studies have also documented EPO’s potential clinical application for patients who develop brain damage related disease’s later in life. This includes people with schizophrenia, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.
How does EPO engender protection and a*brainpower boost?
It does so through its ability to act as a neuroprotector and specifically; research alludes to five main brain potential properties. These include: protection of neurons from glutamate neurotoxicity (thus, neuroplasticity), prevention of cellular inflammation, promotion of angiogenesis and neurogenesis, and antioxidant effects. With the exception of multiple sclerosis, the enigmatic causes of Alzheimer’s disease, Parkinson’s disease, and Schizophrenia make it hard to pinpoint exactly which EPO brain potential property is relevant for treatment; however, they all have a common theme in the onset of each, oxidative stress.
Since the mechanisms that lead to oxidative stress, and the tissue destruction that occurs after the fact has been well documented, why aren’t there readily available drugs to mitigate the process? Well, there have been preclinical studies of drugs that act on a singular part of the process, and were labeled, “significant breakthroughs”, only to be deemed futile when brought to clinical trial. Treatment with EPO is different because it is an all encompassing-symptom approach.
Practical Future Direction
It is important to mention that a few preclinical and clinical trials on EPO’s effectiveness have produced contrary results.** According to a recent randomized clinical trial published in JAMA, “In Patients with closed head injury, the administration of erythropoietin (did not result) in improved neurological outcome at 6 months,” the author concludes.
I propose this disparity is due to different methodology used. Comparing this clinical trial to the aforementioned successful trials, there is a significant variant in dose-amount of EPO administered in each treatment. At a lower intravenously administered dose, EPO may not be able to cross the Blood Brain Barrier; this theory was explored with different drugs, in a 2012 review by Dr. William M Pardrige.
Safety concerns have been raised about several potentially detrimental side effects of EPO-therapy, including blood clots, heart disease, and stroke. These concerns may be exacerbated when even higher doses of the synthetic hormone are used. Further research is necessary to find a safe and effective dose to be ubiquitously used throughout clinical trials.
Safer alternatives to the traditionally used synthetic EPO drugs are currently being researched. These EPO variants don’t stimulate hematopoiesis while still retaining the neuroprotective effects.
Another approach is to elude the high-dose capacity necessary to cross the BBB altogether. This was addressed in a preclinical study of a nasally delivered EPO variant, called Neuro-EPO, and proved to be effective. The author states, “In conclusion, the intranasal application of Neuro-EPO has a better neuroprotective effect than intravenously (administered) EPO, evidenced by the significant improvement of neurological, cognitive, and histological status*in the animal model of stroke employed.”
Overall, it is clear that the present data indicates the enormous potential of EPO and only time will tell if this nuance of Lance Armstrong’s legacy holds the key to treat and prevent brain injury.
References:
Cruz YR, Támos YM, Adriana CM, Cernuda AM, Martines SN, Quevedo AG, Teste IS, Rodriguez JC. (2010) Treatment with nasal neuro-EPO improves the neurological, cognitive, and histological state in a gerbil model of focal ischemia. The Scientific World J. 10:2288-2300.
Derya S, et al. (2011) Expression of Constitutively Active Erythropoietin Receptor in Pyramidal Neurons of Cortex and Hippocampus Boosts Higher Cognitive Functions in Mice. BMC Biology 9:27. doi:10.1186/1741-7007-9-27.
Leuchter R, et al. (2014) Association Between Early Administration of High-Dose Erythropoietin in Preterm Infants and Brain MRI Abnormality at Term-Equivalent Age.*JAMA 312(8):817-824. doi:10.1001/jama.2014.9645.
Macur J (2012) Details of Doping Scheme Pain Armstrong as Leader. NY Times. http://www.nytimes.com/2012/10/11/s...inst-lance-armstrong.html?pagewanted=all&_r=0
Pardridge WM (2012) Drug transport across the blood–brain barrier. J Cereb Blood Flow Metab 32(11):1959–1972.
Robertson CS, et al. (2014) Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury: A Randomized Clinical Trial.*JAMA 312(1):36-47. doi:10.1001/jama.2014.6490.
Originally identified as a kidney-derived stimulator of erythrocyte precursor cell proliferation and differentiation, EPO’s biological role had since expanded, and its pleiotropic effects are currently being studied. Recent trials have displayed the hormone’s profound effects on cognitive performance, begging the question: could EPO hold the key for future clinical treatment and prevention of brain injury?
Image courtesy of hematology.orgSince it’s discovery in 1987, synthetic EPO has been commonly used worldwide to treat patients with anemia. Not long thereafter its discovery, athletes realized they too could exploit EPO’s ability to increase oxygen carrying capacity to muscles, and it was employed as a quick-and-easy (and previously undetectable) alternative to the traditional blood-transfusion doping method.
As deception in cycling became prevalent, it undermined the advances made in studies of EPO’s connection to the Central Nervous System (CNS). As Armstrong was vigorously preparing to win his first Tour De France gold medal in 1999, researchers found EPO and its receptor (EPOR) to be expressed at very high levels in the developing CNS of fetuses. In contrast, there is a sheer drop in expression upon birth, and gradual decline throughout ones life. This finding was used as inspiration for two recent studies done in 2011, and in August of this year. The former showed that EPO can have a lasting increase in brain performance if administered early in development. The latter, published in JAMA, showed that baby’s born very prematurely – therefore, at a high risk of incomplete brain development and brain damage – and who are given EPO immediately after birth, had a significantly reduced risk of long-term brain injury.
In the past decade, multiple studies have also documented EPO’s potential clinical application for patients who develop brain damage related disease’s later in life. This includes people with schizophrenia, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.
How does EPO engender protection and a*brainpower boost?
It does so through its ability to act as a neuroprotector and specifically; research alludes to five main brain potential properties. These include: protection of neurons from glutamate neurotoxicity (thus, neuroplasticity), prevention of cellular inflammation, promotion of angiogenesis and neurogenesis, and antioxidant effects. With the exception of multiple sclerosis, the enigmatic causes of Alzheimer’s disease, Parkinson’s disease, and Schizophrenia make it hard to pinpoint exactly which EPO brain potential property is relevant for treatment; however, they all have a common theme in the onset of each, oxidative stress.
Since the mechanisms that lead to oxidative stress, and the tissue destruction that occurs after the fact has been well documented, why aren’t there readily available drugs to mitigate the process? Well, there have been preclinical studies of drugs that act on a singular part of the process, and were labeled, “significant breakthroughs”, only to be deemed futile when brought to clinical trial. Treatment with EPO is different because it is an all encompassing-symptom approach.
Practical Future Direction
It is important to mention that a few preclinical and clinical trials on EPO’s effectiveness have produced contrary results.** According to a recent randomized clinical trial published in JAMA, “In Patients with closed head injury, the administration of erythropoietin (did not result) in improved neurological outcome at 6 months,” the author concludes.
I propose this disparity is due to different methodology used. Comparing this clinical trial to the aforementioned successful trials, there is a significant variant in dose-amount of EPO administered in each treatment. At a lower intravenously administered dose, EPO may not be able to cross the Blood Brain Barrier; this theory was explored with different drugs, in a 2012 review by Dr. William M Pardrige.
Safety concerns have been raised about several potentially detrimental side effects of EPO-therapy, including blood clots, heart disease, and stroke. These concerns may be exacerbated when even higher doses of the synthetic hormone are used. Further research is necessary to find a safe and effective dose to be ubiquitously used throughout clinical trials.
Safer alternatives to the traditionally used synthetic EPO drugs are currently being researched. These EPO variants don’t stimulate hematopoiesis while still retaining the neuroprotective effects.
Another approach is to elude the high-dose capacity necessary to cross the BBB altogether. This was addressed in a preclinical study of a nasally delivered EPO variant, called Neuro-EPO, and proved to be effective. The author states, “In conclusion, the intranasal application of Neuro-EPO has a better neuroprotective effect than intravenously (administered) EPO, evidenced by the significant improvement of neurological, cognitive, and histological status*in the animal model of stroke employed.”
Overall, it is clear that the present data indicates the enormous potential of EPO and only time will tell if this nuance of Lance Armstrong’s legacy holds the key to treat and prevent brain injury.
References:
Cruz YR, Támos YM, Adriana CM, Cernuda AM, Martines SN, Quevedo AG, Teste IS, Rodriguez JC. (2010) Treatment with nasal neuro-EPO improves the neurological, cognitive, and histological state in a gerbil model of focal ischemia. The Scientific World J. 10:2288-2300.
Derya S, et al. (2011) Expression of Constitutively Active Erythropoietin Receptor in Pyramidal Neurons of Cortex and Hippocampus Boosts Higher Cognitive Functions in Mice. BMC Biology 9:27. doi:10.1186/1741-7007-9-27.
Leuchter R, et al. (2014) Association Between Early Administration of High-Dose Erythropoietin in Preterm Infants and Brain MRI Abnormality at Term-Equivalent Age.*JAMA 312(8):817-824. doi:10.1001/jama.2014.9645.
Macur J (2012) Details of Doping Scheme Pain Armstrong as Leader. NY Times. http://www.nytimes.com/2012/10/11/s...inst-lance-armstrong.html?pagewanted=all&_r=0
Pardridge WM (2012) Drug transport across the blood–brain barrier. J Cereb Blood Flow Metab 32(11):1959–1972.
Robertson CS, et al. (2014) Effect of Erythropoietin and Transfusion Threshold on Neurological Recovery After Traumatic Brain Injury: A Randomized Clinical Trial.*JAMA 312(1):36-47. doi:10.1001/jama.2014.6490.