• Leo Rex

Erythropoietin for Cognitive Enhancement

To watch the companion video to this series, click here.

To read the previous article in this series, click here.


THE VALUE OF EPO


As the reader will recall, even short-term EPO treatment is remarkably trophic for both neurons and oligodendrocytes. Neuronal loss is a hallmark of the aging and damaged brain – it is characteristic of all human dementia. Moreover, brain mass correlates strongly with intelligence, and adult neurogenesis is the driving factor behind brain plasticity, the trait that allows us to adapt our thinking to changing environments over time. As the astute reader will recall from the article series on finasteride, oligodendrogenesis is crucial to the maintenance of myelination of axons, and as the viewer of my YouTube channel will recall, genes involved in myelination are tied to human intelligence. EPO treatment also provides an antidepressant effect through at least two mechanisms: through neurogenesis, and through the reduction of pro-inflammatory cytokines which have been shown to play a causal role in the development of depression.


When delivered prior to injury, the neuroprotective effect of EPO is profound. It is tempting to speculate that pre-treatment with EPO could protect people from glutamate or dopamine-induced excitotoxicity that can result from recreational drug use (e.g. MDMA or ketamine), some performance-enhancing drug use (e.g. high-dosed anabolic steroids), and traumatic injury (e.g. for fighters).


While the angiogenic effect of EPO is concerning for the progression of pre-existing brain tumors, in a healthy brain, it is likely to produce better brain function. Vascular endothelial growth factor (VEGF) is downregulated as we age, and endothelial function is critical to overall cognitive function.


Before discussing hypothetical and speculative use of these molecules, we should briefly review the value of intranasal administration. Note that this article is speculative and not medical advice.


INTRANASAL ADMINISTRATION


Intranasal administration of drugs circumvents the blood-brain barrier. Above the respiratory area of the nasal cavity, the olfactory area contains exposed neurons, through which particles can directly enter the olfactory bulb of the brain. Though EPO and the variants of EPO covered in this review pass the blood brain barrier, intranasal administration offers the benefit of concentrating the molecule in the brain.


Studies on intranasal administration of insulin have indicated that blood insulin levels do not rise[1], confirming the localization of molecules delivered through intranasal systems. For a drug to be effectively administered intranasally, its liquid volume must not exceed 100-250 ml[2][3][4], or if it is a powder, it must not exceed 20-50 mg[5][6]. Moreover, it must be protected from degradation by nasal cavity enzymes. Delivery in aqueous solutions is inefficient, unless penetration enhancers (e.g. tetradecyl-b-D-maltoside[7] or the Cell Penetrating Peptide CPP[8], containing arginine). Viscosity-increasing molecules such as carboxymethylcellulose have been added to increase residence time in the nasal cavity[9].


Nonetheless, it appears that distribution of the particle past the olfactory bulb is dependent on particle size, as 100 nm particles diffuse through the brain whereas 900 nm particles do not[10], and there is evidence of nanoparticle formulations (either lipid-based or polymer-based) providing superior delivery to solutions[11][12][13]. Drugs can be delivered by either propeller-activated or breath-activated nasal delivery devices, of which three (Optinose, Precision Olfactory Delivery, and Vianase) have already been used in human studies.


THE ATTRACTIVE MOLECULES

From the author’s analysis, it appears that carbamylated EPO (CEBO) is unique. It is not angiogenic, and therefore has less of an oncogenic potential for those prone to cancers, and it provides neuroprotective and neurotrophic effects not fully mediated by the EPOR. CEBO could be delivered either systemically or by intranasal administration, most conveniently in an aqueous solution of tetradecyl-b-D-maltoside, as progesterone was in the previous series on finasteride. In fact, as both progesterone and CEBO have independent effects on oligodendrogenesis and myelination of axons, a combined product of nanoparticles would be particularly attractive.


In addition to the safer molecule CEBO, it is tempting to speculate that results could be maximized with the addition of a second molecule that works primarily through the EPOR and produces angiogenesis. This molecule would have to be delivered only intranasally, as systemic angiogenesis is dangerous, and should likely be used sparingly for its angiogenic effect on the brain. The molecule could be one of the molecules designed by the first two research teams in the previous article, such as Epobis.


CONCLUSION


The derivatives of EPO discussed in this series provide neuroprotective, neurotrophic, and cognitive enhancing benefits as powerful as any we have yet seen in the literature. Unfortunately, the commercial world is mostly unaware of these powerful molecules, and instead, they produce racetams in abundance. To help get these products to market, please tell others about this article series, and if not that, then tell people what you learned from it. Spread the word.


To return to the introduction to this series, click here.

[1] Hamidovic, A., Khafaja, M., Brandon, V., Anderson, J., Ray, G., Allan, A. M., & Burge, M. R. (2017). Reduction of smoking urges with intranasal insulin: a randomized, crossover, placebo-controlled clinical trial. Molecular psychiatry, 22(10), 1413-1421. [2] Santos-Morales, O., Díaz-Machado, A., Jiménez-Rodríguez, D., Pomares-Iturralde, Y., Festary-Casanovas, T., González-Delgado, C. A., ... & Garcia-Garcia, I. (2017). Nasal administration of the neuroprotective candidate NeuroEPO to healthy volunteers: a randomized, parallel, open-label safety study. BMC neurology, 17(1), 129. [3] Davis, S. S. (1999). Delivery of peptide and non-peptide drugs through the respiratory tract. Pharmaceutical science & technology today, 2(11), 450-456. [4] Djupesland, P. G., Messina, J. C., & Mahmoud, R. A. (2014). The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview. Therapeutic delivery, 5(6), 709-733. [5] Tepper, S. J., & Johnstone, M. R. (2018). Breath-powered sumatriptan dry nasal powder: an intranasal medication delivery system for acute treatment of migraine. Medical devices (Auckland, NZ), 11, 147. [6] Shrewsbury, S. B., Swardstrom, M., Satterly, K. H., Campbell, J., Tugiono, N., Gillies, J. D., & Hoekman, J. (2019). Placebo/Active Controlled, Safety, Pharmaco-Kinetic/Dynamic Study of INP105 (POD® olanzapine) in Healthy Adults. Western Journal of Emergency Medicine: Integrating Emergency Care with Population Health, 20(2). [7] Buchthal, B., Weiss, U., & Bading, H. (2018). Post-injury nose-to-brain delivery of activin a and serpinb2 reduces brain damage in a mouse stroke model. Molecular Therapy, 26(10), 2357-2365. [8] Kamei, N., Okada, N., Ikeda, T., Choi, H., Fujiwara, Y., Okumura, H., & Takeda-Morishita, M. (2018). Effective nose-to-brain delivery of exendin-4 via coadministration with cell-penetrating peptides for improving progressive cognitive dysfunction. Scientific reports, 8(1), 1-14. [9] Shingaki, T., Inoue, D., Furubayashi, T., Sakane, T., Katsumi, H., Yamamoto, A., & Yamashita, S. (2010). Transnasal delivery of methotrexate to brain tumors in rats: a new strategy for brain tumor chemotherapy. Molecular pharmaceutics, 7(5), 1561-1568. [10] Ahmad, E., Feng, Y., Qi, J., Fan, W., Ma, Y., He, H., ... & Wu, W. (2017). Evidence of nose-to-brain delivery of nanoemulsions: cargoes but not vehicles. Nanoscale, 9(3), 1174-1183. [11] Godfrey, L., Iannitelli, A., Garrett, N. L., Moger, J., Imbert, I., King, T., ... & Uchegbu, I. F. (2018). Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia. Journal of Controlled Release, 270, 135-144. [12] Shah B, Khunt D, Misra M, and Padh H (2016) Application of Box-Behnken design for optimization and development of quetiapine fumarate loaded chitosan nanoparticles for brain delivery via intranasal route [13] Shah B, Khunt D, Misra M, and Padh H (2018) Formulation and in-vivo pharmacokinetic consideration of intranasal microemulsion and mucoadhesive microemulsion of rivastigmine for brain targeting

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