To watch the companion video to this series, click here.
To read the previous article in this series, click here.
EPO is a broadly tissue-protective molecule that exerts its effects through complex biological mechanisms that are still being understood. So far, it has been shown to exert protective effects on the heart, liver, in metabolic diseases, and most prominently, in the brain.
EPO, CARDIOVASCULAR, AND METABOLIC HEALTH
EPORs are located in the heart[1], EPO protects cardiomyocytes from toxin-induced mitochondrial dysfunction via SIRT1[2], and EPO administration has been shown to both attenuate cardiac damage from myocardial infarction in rodents[3] and protect the heart from ischemic events[4] . Transgenic mice lacking EPORs mature with developmental defects including a reduced number of cardiac myocytes[5].
EPO has also been shown to offer a protective effect against liver and metabolic diseases. It is shown to limit hepatic lipid accumulation and hepatic steatosis, and this effect appears dependent on sirtuin 1-induced autophagy[6] and upregulation of fibroblast growth factor 21[7], as SIRT1-knockout mice do not experience the effect[8]. Interestingly, mice with EPOR knockout in adipose tissue are obesogenic and insulin resistant[9], and EPO treatment has been shown to attenuate the cognitive dysfunction associated with diabetes[10]. It appears that some of EPO’s metabolic effects may be mediated by its STAT3-dependent activating of uncoupling protein 1 (UCP1)[11], a regular of brown fat thermogenesis.
EPO’s tissue-protective effect may depend on when it is administered. In the context of hypoxia-induced retinopathy, when administered early after the hypoxic event, it can attenuate pathology, but when administered later, it can enhance the pathology[12].
EPO also improves the healing of wounds via its regulation of angiogenesis[13], though as we will see later, this same mechanism is oncogenic.
EPO’S MECHANISMS OF ACTION IN THE BRAIN
Aside from EPO’s effects for anemics and athletes seeking to increase their Vo2 max[14], recall that the hormone began to be investigated in the early 2000’s for its antioxidative, angiogenetic, neurotrophic, anti-inflammatory, blood-brain barrier permeability protection[15], anti-convulsant[16], and antiapoptotic qualities[17] in the human brain.
EPO appears to work antagonistically to the inflammatory cytokines IL1-b, IL-6, and TNF-a (cytokines that are upregulated in neurodegenerative diseases[18]) while it improves activity of the anti-inflammatory interleukin-10[19]. Much of EPO’s effects on the brain appear modulated by its activation of Akt, Wnt, SIRT1, modulation of mTOR (through which it can block autophagy) and inhibition of FoxO proteins, including FoxO3a, and its effects may also be modulated by activation of the AMPK pathway[20].
Though EPORs are only weakly expressed in the adult brain, their expression increases following brain injury[21]. Notably, EPO exerts some of these beneficial results on the brain through a non-hematopoietic method and some also do not depend on its agonism of the EPOR[22].
EPO AND NEUROPROTECTION
EPO is critical to the maintenance of cognitive function, as reductions in EPO produce neuronal degeneration and impaired learning ability in rodents[23]. Transgenic mice lacking EPORs but treated for hematopoiesis exhibit a 2x increase in the apoptotic rate of their brains, and their hippocampal neurons survive poorly compared to the wild-type[24]. EPORs upregulate from the first to seventh day after traumatic brain injury, while EPO remains elevated for a couple of days after injury[25]. Because the receptors remain upregulated longer than the hormone is, there is potential to increase healing and neurogenesis through exogenous EPO administration[26].
EPO administration has been shown to be neuroprotective[27] from epileptic seizures, inflammation, ischemia, traumatic injury, stroke[28], and amyloid b toxicity, one of the causal factors in the development of Alzheimer’s disease[29]. Intranasal administration of EPO, in particular, has proved protective against amyloid b toxicity [30]. Interestingly, it has also been shown to attenuate the neurotoxicity association with administration of L-DOPA, the standard treatment for Parkinson’s disease[31].
THE TROPHIC EFFECTS OF EPO
Impaired EPO signaling to EPORs reduces adult neurogenesis[32]. A 3-week treatment with an EPO analogue on mice has been shown to increase mature hippocampal neuron and oligodendrocyte count by about 20%, likely by stimulating precursor differentiation, rather than having a proliferative or anti-apoptosis effect[33]. rEPO has been shown to promote astrocyte proliferation, likely through an autocrine effect, and this proliferation is thought to enhance the myelin repair potential of matured oligodendrocytes[34].
EPO AND NEUROGENERATIVE DISEASE
There is early evidence of EPO and its analogues delaying the progression of rodent disease models of amyotrophic lateral sclerosis (ALS)[35][36] and attenuating neuronal degeneration in Parkinson’s disease[37][38] and schizophrenia[39]. Interestingly, Alzheimer’s disease patients exhibit increased EPOR expression in their brains[40], while EPO treatments have improved memory and reduced degeneration in animal models of Alzheimer’s disease[41][42].
It has also been shown to improve disease symptomology of schizophrenia and multiple sclerosis. In a human, placebo-controlled trial, schizophrenic patients exhibited improvements in cognition and attenuation of cortical grey matter loss following a 12-week treatment with intravenous (IV) rEPO[43], making EPO the first drug to ever exhibit improvements in schizophrenic cognition. In a year-long study on multiple sclerosis patients, high-dosed EPO (48,000 IU) improved motor function within 12 weeks and cognition while low-dose treatment (8,000 IU) did not[44]. The high-dosed treatment was necessary because of the difficulty for IV EPO to pass the blood-brain and blood-nerve barriers. Note that doses used to treat anemics are less than 500 IU[45].
EPO, COGNITION, AND BEHAVIOR
In transgenic mice with constitutively active EPORs, indicating that they were active without needing to be agonized by EPO, cognition is enhanced[46], and EPO treatment enhanced long-term potentiation and memory in healthy mice[47]. The treatment of pregnant rats with EPO has even been shown to attenuate the damage done to prenatal rats’ working memory, passive avoidance, and anxiety-like behavior from prenatal food restriction[48]. Fascinatingly, EPO treatment has even been shown to improve hippocampal-dependent memory and depressive behavior in humans[49].
This article has summarized EPO’s cardioprotective, hepatoprotective, metabolism enhancing, and neuroprotective effects, its protective effect for neurodegenerative disease, and its cognitive enhancing effect. The next article in this series will survey the state-of-the-art non-erythropoietic analogues and derivatives of EPO developed for the purpose of delivering its cognitive enhancing effect safely.
To read the fourth article in the series, click here.
[1] Depping, R., Kawakami, K., Ocker, H., Wagner, J. M., Heringlake, M., Noetzold, A., ... & Wagner, K. F. (2005). Expression of the erythropoietin receptor in human heart. The Journal of Thoracic and Cardiovascular Surgery, 130(3), 877-e1. [2] Cui, L., Guo, J., Zhang, Q., Yin, J., Li, J., Zhou, W., ... & Carmichael, P. L. (2017). Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. Toxicology letters, 275, 28-38. [3] Zafiriou, M. P., Noack, C., Unsöld, B., Didie, M., Pavlova, E., Fischer, H. J., ... & Zelarayan, L. C. (2014). Erythropoietin responsive cardiomyogenic cells contribute to heart repair post myocardial infarction. Stem Cells, 32(9), 2480-2491. [4] Parsa, C. J., Matsumoto, A., Kim, J., Riel, R. U., Pascal, L. S., Walton, G. B., ... & Koch, W. J. (2003). A novel protective effect of erythropoietin in the infarcted heart. The Journal of clinical investigation, 112(7), 999-1007. [5] Wu, H., Lee, S. H., Gao, J., Liu, X., & Iruela-Arispe, M. L. (1999). Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development, 126(16), 3597-3605. [6] Hong, T., Ge, Z., Meng, R., Wang, H., Zhang, P., Tang, S., ... & Bi, Y. (2018). Erythropoietin alleviates hepatic steatosis by activating SIRT1-mediated autophagy. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1863(6), 595-603. [7] Hong, T., Ge, Z., Zhang, B., Meng, R., Zhu, D., & Bi, Y. (2019). Erythropoietin suppresses hepatic steatosis and obesity by inhibiting endoplasmic reticulum stress and upregulating fibroblast growth factor 21. International journal of molecular medicine, 44(2), 469-478. [8] Hong, T., Ge, Z., Zhang, B., Meng, R., Zhu, D., & Bi, Y. (2019). Erythropoietin suppresses hepatic steatosis and obesity by inhibiting endoplasmic reticulum stress and upregulating fibroblast growth factor 21. International journal of molecular medicine, 44(2), 469-478. [9] Teng, R., Gavrilova, O., Suzuki, N., Chanturiya, T., Schimel, D., Hugendubler, L., ... & Yamamoto, M. (2011). Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production. Nature communications, 2(1), 1-12. [10] Wang, M., Yan, W., Liu, Y., Hu, H., Sun, Q., Chen, X., ... & Chen, L. (2017). Erythropoietin ameliorates diabetes-associated cognitive dysfunction in vitro and in vivo. Scientific reports, 7(1), 1-11. [11] Kodo, K., Sugimoto, S., Nakajima, H., Mori, J., Itoh, I., Fukuhara, S., ... & Hosoi, H. (2017). Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice. PLoS One, 12(3). [12] Chen, J., Connor, K. M., Aderman, C. M., & Smith, L. E. (2008). Erythropoietin deficiency decreases vascular stability in mice. The Journal of clinical investigation, 118(2), 526-533. [13] Haroon, Z. A., Amin, K., Jiang, X., & Arcasoy, M. O. (2003). A novel role for erythropoietin during fibrin-induced wound-healing response. The American journal of pathology, 163(3), 993-1000. [14] Sgrò, P., Sansone, M., Sansone, A., Romanelli, F., & Di Luigi, L. (2018). Effects of erythropoietin abuse on exercise performance. The Physician and sportsmedicine, 46(1), 105-115. [15] Üzüm, G., Diler, A. S., Bahçekapılı, N., & Ziylan, Y. Z. (2006). Erythropoietin prevents the increase in blood–brain barrier permeability during pentylentetrazol induced seizures. Life sciences, 78(22), 2571-2576. [16] Bahçekapılı, N., Akgün-Dar, K., Albeniz, I., Kapucu, A., Kandil, A., Yağız, O., & Üzüm, G. (2014). Erythropoietin pretreatment suppresses seizures and prevents the increase in inflammatory mediators during pentylenetetrazole-induced generalized seizures. International Journal of Neuroscience, 124(10), 762-770. [17] Maiese, K., Li, F., & Chong, Z. Z. (2005). New avenues of exploration for erythropoietin. Jama, 293(1), 90-95. [18] Lofrumento, D. D., Saponaro, C., Cianciulli, A., De Nuccio, F., Mitolo, V., Nicolardi, G., & Panaro, M. A. (2011). MPTP-induced neuroinflammation increases the expression of pro-inflammatory cytokines and their receptors in mouse brain. Neuroimmunomodulation, 18(2), 79-88. [19] Chau, M., Chen, D., & Wei, L. (2011). Erythropoietin attenuates inflammatory factors and cell death in neonatal rats with intracerebral hemorrhage. In Intracerebral Hemorrhage Research (pp. 299-305). Springer, Vienna. [20] Maiese, K. (2016). Regeneration in the nervous system with erythropoietin. Frontiers in bioscience (Landmark edition), 21(3), 561. [21] Grasso, G., Sfacteria, A., Cerami, A., & Brines, M. (2004). Erythropoietin as a tissue-protective cytokine in brain injury: what do we know and where do we go?. The Neuroscientist, 10(2), 93-98. [22] Brines, M., & Cerami, A. (2005). Emerging biological roles for erythropoietin in the nervous system. Nature Reviews Neuroscience, 6(6), 484-494. [23] Sakanaka, M., Wen, T. C., Matsuda, S., Masuda, S., Morishita, E., Nagao, M., & Sasaki, R. (1998). In vivo evidence that erythropoietin protects neurons from ischemic damage. Proceedings of the National Academy of Sciences, 95(8), 4635-4640. [24] Chen, Z. Y., Asavaritikrai, P., Prchal, J. T., & Noguchi, C. T. (2007). Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. Journal of Biological Chemistry, 282(35), 25875-25883. [25] Liao, Z. B., Zhi, X. G., Shi, Q. H., & He, Z. H. (2008). Recombinant human erythropoietin administration protects cortical neurons from traumatic brain injury in rats. European journal of neurology, 15(2), 140-149. [26] Lu, D., Mahmood, A., Qu, C., Goussev, A., Schallert, T., & Chopp, M. (2005). Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. Journal of neurotrauma, 22(9), 1011-1017. [27] Xiong, Y., Lu, D., Qu, C., Goussev, A., Schallert, T., Mahmood, A., & Chopp, M. (2008). Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. Journal of neurosurgery, 109(3), 510-521. [28] Mammis, A., McIntosh, T. K., & Maniker, A. H. (2009). Erythropoietin as a neuroprotective agent in traumatic brain injury. Surgical neurology, 71(5), 527-531. [29] Chong ZZ, Li F, Maiese K. Erythropoietin requires NF-kappaB and its nuclear translocation to prevent early and late apoptotic neuronal injury during beta-amyloid toxicity. Curr Neurovasc Res 2005;2:387–399 [30] T. Maurice, M. H. Mustafa, C. Desrumaux et al., “Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the A𝛽25−−35 non-transgenic mouse model of Alzheimer’s disease [31] Park, K. H., Choi, N. Y., Koh, S. H., Park, H. H., Kim, Y. S., Kim, M. J., ... & Kim, H. T. (2011). L-DOPA neurotoxicity is prevented by neuroprotective effects of erythropoietin. Neurotoxicology, 32(6), 879-887. [32] Chen, Z. Y., Asavaritikrai, P., Prchal, J. T., & Noguchi, C. T. (2007). Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. Journal of Biological Chemistry, 282(35), 25875-25883. [33] Hassouna, I., Ott, C., Wüstefeld, L., Offen, N., Neher, R. A., Mitkovski, M., ... & Vreja, I. C. (2016). Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus. Molecular psychiatry, 21(12), 1752-1767. [34] Sugawa, M., Sakurai, Y., Ishikawa-Ieda, Y., Suzuki, H., & Asou, H. (2002). Effects of erythropoietin on glial cell development; oligodendrocyte maturation and astrocyte proliferation. Neuroscience research, 44(4), 391-403. [35] Grunfeld, J. F., Barhum, Y., Blondheim, N., Rabey, J. M., Melamed, E., & Offen, D. (2007). Erythropoietin delays disease onset in an amyotrophic lateral sclerosis model. Experimental neurology, 204(1), 260-263. [36] Mennini, T., De Paola, M., Bigini, P., Mastrotto, C., Fumagalli, E., Barbera, S., ... & Torup, L. (2006). Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo. Molecular medicine, 12(7-8), 153-160. [37] Genc, S., Akhisaroglu, M., Kuralay, F., & Genc, K. (2002). Erythropoietin restores glutathione peroxidase activity in 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine-induced neurotoxicity in C57BL mice and stimulates murine astroglial glutathione peroxidase production in vitro. Neuroscience letters, 321(1-2), 73-76. [38] Genc, S., Kuralay, F., Genc, K., Akhisaroglu, M., Fadiloglu, S., Yorukoglu, K., ... & Gure, A. (2001). Erythropoietin exerts neuroprotection in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-treated C57/BL mice via increasing nitric oxide production. Neuroscience letters, 298(2), 139-141. [39] Ehrenreich, H., Degner, D., Meller, J., Brines, M., Behe, M., Hasselblatt, M., ... & von Ahsen, N. (2004). Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Molecular psychiatry, 9(1), 42-54. [40] Assaraf, M. I., Diaz, Z., Liberman, A., Miller Jr, W. H., Arvanitakis, Z., Li, Y., ... & Schipper, H. M. (2007). Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment. Journal of neuropathology and experimental neurology, 66(5), 389-398. [41] G. Hamidi, Z. Arabpour, M. Shabrang et al., “Erythropoietin improves spatial learning and memory in streptozotocin model of dementia [42] Lee, S. T., Chu, K., Park, J. E., Jung, K. H., Jeon, D., Lim, J. Y., ... & Roh, J. K. (2012). Erythropoietin improves memory function with reducing endothelial dysfunction and amyloid‐beta burden in Alzheimer’s disease models. Journal of neurochemistry, 120(1), 115-124. [43] Ehrenreich, H., Hinze-Selch, D., Stawicki, S., Aust, C., Knolle-Veentjer, S., Wilms, S., ... & Ritzen, M. (2007). Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Molecular psychiatry, 12(2), 206-220. [44] Ehrenreich, H., Fischer, B., Norra, C., Schellenberger, F., Stender, N., Stiefel, M., ... & Bartels, C. (2007). Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain, 130(10), 2577-2588. [45] Haiden, N., Klebermass, K., Cardona, F., Schwindt, J., Berger, A., Kohlhauser-Vollmuth, C., ... & Pollak, A. (2006). A randomized, controlled trial of the effects of adding vitamin B12 and folate to erythropoietin for the treatment of anemia of prematurity. Pediatrics, 118(1), 180-188. [46] Sargin, D., El-Kordi, A., Agarwal, A., Müller, M., Wojcik, S. M., Hassouna, I., ... & Ehrenreich, H. (2011). Expression of constitutively active erythropoietin receptor in pyramidal neurons of cortex and hippocampus boosts higher cognitive functions in mice. BMC biology, 9(1), 27. [47] Adamcio, B., Sargin, D., Stradomska, A., Medrihan, L., Gertler, C., Theis, F., ... & Sperling, S. (2008). Erythropoietin enhances hippocampal long-term potentiation and memory. BMC biology, 6(1), 37. [48] Bagha, N., & Edalatmanesh, M. A. (2018). Effectiveness of erythropoietin on working memory, passive avoidance learning and anxiety-like behaviors in prenatal food restriction model. Report of Health Care, 4(1), 36-43. [49] Miskowiak, K. W., Vinberg, M., Harmer, C. J., Ehrenreich, H., & Kessing, L. V. (2012). Erythropoietin: a candidate treatment for mood symptoms and memory dysfunction in depression. Psychopharmacology, 219(3), 687-698.
