Intranasal erythropoietin therapy in nervous system disorders

Expert Opinion on Drug Delivery

Volumn 8, Issue 1, 2011, Pages 19-32

  Genc, Sermin ^a   Zadeoglulari, Zeynep ^a   Oner, Meryem Gulfem ^a   Genc, Kursad ^a   Digicaylioglu, Murat ^b  

^a DOKUZ EYLUL UNIVERSITY   (Turkey)

^b UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

Author keywords

Bloodbrain barrier; Erythropoietin; Nasal drug delivery; Nervous system; Neuroprotection; Stroke

Indexed keywords

ALTEPLASE; ERYTHROPOIETIN; GELATINASE B; METHYLPREDNISOLONE; NEUROTROPHIC FACTOR; PEPTIDE FRAGMENT; PLACEBO; PYROGLUTAMIC ACID; RECOMBINANT ERYTHROPOIETIN; SOMATOMEDIN C;

ABSENCE OF SIDE EFFECTS; ALZHEIMER DISEASE; AMNESIA; BLOOD BRAIN BARRIER; BRAIN DISEASE; BRAIN EDEMA; BRAIN HEMORRHAGE; BRAIN ISCHEMIA; CEREBRAL PALSY; DIABETIC NEUROPATHY; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG MEGADOSE; DRUG TOXICITY; ENCEPHALOMALACIA; ENZYME LINKED IMMUNOSORBENT ASSAY; EPILEPSY; FRIEDREICH ATAXIA; HUMAN; HYPERTENSION; LUNG DYSPLASIA; MULTIPLE SCLEROSIS; NECROTIZING ENTEROCOLITIS; NERVE DEGENERATION; NERVE INJURY; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE; PARKINSONISM; RETROLENTAL FIBROPLASIA; REVIEW; SCHIZOPHRENIA; SEIZURE; SEPTICEMIA; SPINAL CORD INJURY; STROKE; SUBARACHNOID HEMORRHAGE; THROMBOEMBOLISM; TRAUMATIC BRAIN INJURY; TUMOR GROWTH;

ADMINISTRATION, INTRANASAL; ANIMALS; BRAIN; CENTRAL NERVOUS SYSTEM DISEASES; DISEASE MODELS, ANIMAL; DRUG DELIVERY SYSTEMS; ERYTHROPOIETIN; HUMANS; NEUROPROTECTIVE AGENTS;

EID: 78650534309     PISSN: 17425247     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425247.2011.540236     Document Type: Review

References (89)

1. Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem 1977;252:5558-64 (Pubitemid 8167007)
2. Jacobs K, Shoemaker C, Rudersdorf R, et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 1985;313:806-10 (Pubitemid 15130833)
3. Lin FK, Suggs S, Lin CH, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 1985;82:7580-4 (Pubitemid 16204391)
4. Jelkmann W. Erythropoietin after a century of research: Younger than ever. Eur J Haematol 2007;78:183-205 (Pubitemid 46246531)
5. Winearls CG, Oliver DO, Pippard MJ, et al. Effect of human erythropoietin derived from recombinant DNA on the anemia of patients maintained by chronic haemodialysis. Lancet 1986;2:1175-8
6. Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 2005;6:484-94 (Pubitemid 40769173)
7. Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA 2004;101:14907-12 (Pubitemid 39410773)
8. Sanchez PE, Fares RP, Risso JJ, et al. Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons. Proc Natl Acad Sci USA 2009;106:9848-53
9. Chen ZY, Warin R, Noguchi CT. Erythropoietin and normal brain development: Receptor expression determines multi-tissue response. Neurodegener Dis 2006;3:68-75 (Pubitemid 43760371)
10. Ehrenreich H, Degner D, Meller J, et al. Erythropoietin: A candidate compound for neuroprotection in schizophrenia. Mol Psychiatry 2004;9:42-54 (Pubitemid 38175081)
11. Siren AL, Fasshauer T, Bartels C, Ehrenreich H. Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics 2009;6:108-27
12. Digicaylioglu M. Erythropoietin in stroke: Quo vadis. Expert Opin Biol Ther 2010;10:937-49 . A comprehensive review of alternative strategies for administration of erythropoietin to the CNS.
13. Jerndal M, Forsberg K, Sena ES, et al. A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab 2010;30:961-8
14. McPherson RJ, Juul SE. Erythropoietin for infants with hypoxic-ischemic encephalopathy. Curr Opin Pediatr 2010;22:139-45
15. Minnerup J, Heidrich J, Rogalewski A, et al. The efficacy of erythropoietin and its analogues in animal stroke models: A meta-analysis. Stroke 2009;40:3113-20
16. Boesch S, Sturm B, Hering S, et al. Friedreich's ataxia: Clinical pilot trial with recombinant human erythropoietin. Ann Neurol 2007;62:521-4 (Pubitemid 350308777)
17. Boesch S, Sturm B, Hering S, et al. Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: A clinical pilot trial. Mov Disord 2008;23:1940-4
18. Ehrenreich H, Hinze-Selch D, Stawicki S, et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 2007;12:206-20 (Pubitemid 46160985)
19. Ehrenreich H, Fischer B, Norra C, et al. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 2007;130:2577-88 (Pubitemid 46160985)
20. Fauchere JC, Dame C, Vonthein R, et al. An approach to using recombinant erythropoietin for neuroprotection in very preterm infants. Pediatrics 2008;122:375-82
21. Juul SE, McPherson RJ, Bauer LA, et al. A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: Pharmacokinetics and safety. Pediatrics 2008;122:383-91
22. Springborg JB, Moller C, Gideon P, et al. Erythropoietin in patients with aneurysmal subarachnoid haemorrhage: A double blind randomised clinical trial. Acta Neurochir 2007;149:1089-101 (Pubitemid 350132087)
23. Tseng MY, Hutchinson PJ, Richards HK, et al. Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: A phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg 2009;111:171-80
24. Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics 2009;124:218-26
25. Bernaudin M, Marti HH, Roussel S, et al. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 1999;19:643-51 (Pubitemid 30161216)
26. Genc S, Kuralay F, Genc K, et al. Erythropoietin exerts neuroprotection in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated C57/BL mice via increasing nitric oxide production. Neurosci Lett 2001;298:139-41 (Pubitemid 32037074)
27. Sakanaka M, Wen TC, Matsuda S, et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 1998;95:4635-40 (Pubitemid 28207965)
28. Banks WA, Jumbe NL, Farrell CL, et al. Passage of erythropoietic agents across the blood-brain barrier: A comparison of human and murine erythropoietin and the analog darbepoetin alfa. Eur J Pharmacol 2004;505:93-101
29. Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000;97:10526-31
30. Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 2002;8:495-505 (Pubitemid 36337492)
31. Xenocostas A, Cheung WK, Farrell F, et al. The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin. Eur J Clin Pharmacol 2005;61:189-95 (Pubitemid 40768551)
32. Chang ZY, Chiang CH, Lu DW, Yeh MK. Erythropoiesis-stimulating protein delivery in providing erythropoiesis and neuroprotection. Expert Opin Drug Deliv 2008;5:1313-21
33. Costantino HR, Illum L, Brandt G, et al. Intranasal delivery: Physicochemical and therapeutic aspects. Int J Pharm 2007;337:1-24 (Pubitemid 46756063)
34. Dhuria SV, Hanson LR, Frey WH II. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J Pharm Sci 2010;99:1654-73 . A comprehensive and updated review of nose-to-CNS drug delivery.
35. Hanson LR, Frey WH II. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 2008;9(Suppl 3):S5
36. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 2000;11:1-18 A comprehensive review of nose-to-CNS drug delivery. (Pubitemid 30410839)
37. Mathison S, Nagilla R, Kompella UB. Nasal route for direct delivery of solutes to the central nervous system: Fact or fiction? J Drug Target 1998;5:415-41 (Pubitemid 28499678)
38. Wu H, Hu K, Jiang X. From nose to brain: Understanding transport capacity and transport rate of drugs. Expert Opin Drug Deliv 2008;5:1159-68 A comprehensive review of nose-to-CNS drug delivery.
39. Thorne RG, Frey WH II. Delivery of neurotrophic factors to the central nervous system: Pharmacokinetic considerations. Clin Pharmacokinet 2001;40:907-46
40. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH II. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004;127:481-96 (Pubitemid 38950662)
41. Thorne RG, Hanson LR, Ross TM, et al. Delivery of interferon-b to the monkey nervous system following intranasal administration. Neuroscience 2008;152:785-97
42. Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm 2009;379:146-57
43. Li Y, Field PM, Raisman G. Olfactory ensheathing cells and olfactory nerve fibroblasts maintain continuous open channels for regrowth of olfactory nerve fibres. Glia 2005;52:245-51 (Pubitemid 43076155)
44. Hadaczek P, Yamashita Y, Mirek H, et al. The 'perivascular pump' driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain. Mol Ther 2006;14:69-78 (Pubitemid 43922142)
45. Weller RO, Djuanda E, Yow HY, Carare RO. Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 2009;117:1-14
46. Born J, Lange T, Kern W, et al. Sniffing neuropeptides: A transnasal approach to the human brain. Nat Neurosci 2002;5:514-16 (Pubitemid 34568991)
47. Yu YP, Xu QQ, Zhang Q, et al. Intranasal recombinant human erythropoietin protects rats against focal cerebral ischemia. Neurosci Lett 2005;387:5-10 (Pubitemid 41138199)
48. Gross EA, Swenberg JA, Fields S, Popp JA. Comparative morphometry of the nasal cavity in rats and mice. J Anat 1982;135:83-8 (Pubitemid 12041734)
49. Hallschmid M, Benedict C, Schultes B, et al. Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders. Regul Pept 2008;149:79-83
50. Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008;70:440-8
51. Graff CL, Pollack GM. Nasal drug administration: Potential for targeted central nervous system delivery. J Pharm Sci 2005;94:1187-95
52. Reger MA, Watson GS, Frey WH II, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype. Neurobiol Aging 2006;27:451-8
53. Garcia-Rodriguez JC, Sosa-Teste I. The nasal route as a potential pathway for delivery of erythropoietin in the treatment of acute ischemic stroke in humans. Sci World J 2009;9:970-81 A comprehensive review of intranasal Neuro-EPO delivery.
54. Fletcher L, Kohli S, Sprague SM, et al. Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation. J Neurosurg 2009;111:164-70
55. Guan J, Beilharz EJ, Skinner SJ, et al. Intracerebral transportation and cellular localisation of insulin-like growth factor-1 following central administration to rats with hypoxic-ischemic brain injury. Brain Res 2000;853:163-73 (Pubitemid 30035216)
56. Lin S, Fan LW, Rhodes PG, Cai Z. Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Exp Neurol 2009;217:361-70
57. Balin BJ, Broadwell RD, Salcman M, el-Kalliny M. Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J Comp Neurol 1986;251:260-80 (Pubitemid 16027854)
58. Matsuoka Y, Gray AJ, Hirata-Fukae C, et al. Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage. J Mol Neurosci 2007;31:165-70 (Pubitemid 46742300)
59. Macdonald K, Macdonald TM. The peptide that binds: A systematic review of oxytocin and its prosocial effects in humans. Harv Rev Psychiatry 2010;18:1-21
60. Ehrenreich H, Weissenborn K, Prange H, et al. EPO Stroke Trial Group. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 2009;40:647-56 The first large clinical trial of EPO therapy in human stroke with negative results.
61. Rasmussen P, Foged EM, Krogh-Madsen R, et al. Effects of erythropoietin administration on cerebral metabolism and exercise capacity in men. J Appl Physiol 2010;109(2):476-83
62. Banks WA, Erickson MA. The blood-brain barrier and immune function and dysfunction. Neurobiol Dis 2010;37:26-32
63. Fisher M, Feuerstein G, Howells DW, et al. STAIR Group. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 2009;40:2244-50
64. Philip M, Benatar M, Fisher M, Savitz SI. Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke 2009;40:577-81
65. Minnerup J, Wersching H, Schabitz WR. EPO for stroke therapy -Is there a future for further clinical development? Exp Transl Stroke Med 2010;2:10
66. Zechariah A, Elali A, Hermann DM. Combination of tissue-plasminogen activator with erythropoietin induces blood-brain barrier permeability, extracellular matrix disaggregation, and DNA fragmentation after focal cerebral ischemia in mice. Stroke 2010;41:1008-12
67. Jia L, Chopp M, Zhang L, et al. Erythropoietin in combination of tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke. Stroke 2010; PMID: 20671252. DOI: 10.1161/ STROKEAHA.110.586198
68. Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-stimulating agents-time for a reevaluation. N Engl J Med 2010;362:189-92
69. Pfeffer MA, Burdmann EA, Chen CY, et al. TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-32
70. Sauerborn M, Brinks V, Jiskoot W, Schellekens H. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci 2010;31(2):53-9
71. Esmon CT, Glass JD. The APCs of neuroprotection. J Clin Invest 2009;119:3205-7
72. Erbayraktar S, Grasso G, Sfacteria A, et al. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci USA 2003;100:6741-6 (Pubitemid 36666650)
73. Masuda S, Okano M, Yamagishi K, et al. A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 1994;269:19488-93 (Pubitemid 24978761)
74. Leist M, Ghezzi P, Grasso G, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 2004;305:239-42 (Pubitemid 38886736)
75. Wang Y, Zhang ZG, Rhodes K, et al. Post-ischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia. Br J Pharmacol 2007;151:1377-84 (Pubitemid 47255890)
76. Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci USA 2008;105:10925-30
77. Pankratova S, Kiryushko D, Sonn K, et al. Neuroprotective properties of a novel, non-haematopoietic agonist of the erythropoietin receptor. Brain 2010;133:2281-94
78. Shimoda N, Maitani Y, Machida Y, Nagai T. Effects of dose, pH and osmolarity on intranasal absorption of recombinant human erythropoietin in rats. Biol Pharm Bull 1995;18:734-9
79. Alcala-Barraza SR, Lee MS, Hanson LR, et al. Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS. J Drug Target 2010;18:179-90
80. Hermann DM. Enhancing the delivery of erythropoietin and its variants into the ischemic brain. Sci World J 2009;9:967-9
81. Sosa I, Garcia Rodriguez JC, Santana J, et al. Intranasal administration of recombinant human erythropoietin exerts neuroprotective effects on post-ischemic brain injury in Mongolian gerbils. Pharmacologyonline 2006;1:100-12
82. Miskowiak KW, Favaron E, Hafizi S, et al. Effects of erythropoietin on emotional processing biases in patients with major depression: An exploratory fMRI study. Psychopharmacology 2009;207:133-42
83. Miskowiak KW, Favaron E, Hafizi S, et al. Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients. Psychopharmacology 2010;210:419-28
84. Garcia-Garcia F, Krueger JM. Intracerebroventricular injection of erythropoietin enhances sleep in the rat. Brain Res Bull 2003;61:541-6 (Pubitemid 37117202)
85. Lagarto A, Bueno V, Guerra I, et al. Absence of hematological side effects in acute and subacute nasal dosing of erythropoietin with a low content of sialic acid. Exp Toxicol Pathol 2010; PMID: 20488687. DOI: 10.1016/ j.etp.2010.04.008
86. Cao Y, Lathia JD, Eyler CE, et al. Erythropoietin receptor signaling through STAT3 is required for glioma stem cell maintenance. Genes Cancer 2010;1:50-61
87. Nico B, Annese T, Guidolin D, et al. Epo is involved in angiogenesis in human glioma. J Neurooncol 2010; PMID: 20614229. DOI: 10.1007/ s11060-010-0294-6
88. Cramer SC, Fitzpatrick C, Warren M, et al. The beta-hCG+erythropoietin in acute stroke (BETAS) study: A 3-center, single-dose, open-label, noncontrolled, phase IIa safety trial. Stroke 2010;41(5):927-31
89. Kang YJ, Digicaylioglu M, Russo R, et al. Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders. Ann Neurol 2010;68(3):342-52