Nutrition
Volume 26, Issue 6 , Pages 624-633 , June 2010

Intranasal insulin: From nose to brain

  • R.I. Henkin, M.D., Ph.D.

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +202-364-4180; fax: +202-364-9727.

Received 17 April 2009 ,Accepted 3 August 2009.

References 

  1. Patton JS, Bukar J, Nagarajan S. Inhaled insulin. Adv Drug Deliv Rev. 1999;35:235–247
  2. Pfützner A, Mann AE, Steiner SS. Technosphere/insulin—a new approach for effective delivery of human insulin via the pulmonary route. Diabetes Technol Ther. 2002;4:589–594
  3. Agu RU, Ugwoke MI, Armand M, Kinget R, Verbeke N. The lung as a route for systemic delivery of therapeutic proteins and peptides. Respir Res. 2001;2:198–209
  4. Garcia-Contreras L, Smyth H. Liquid-spray or dry powder systems for inhaled delivery of peptide and proteins?. Am J Drug Deliv. 2005;3:29–45
  5. Onoue S, Hashimoto N, Yamada S. Dry powder inhalation systems for pulmonary delivery of therapeutic peptides and proteins. Expert Opin Ther Pat. 2008;18:429–442
  6. DeCamp MM. Inhaled cyclosporine—a breath of fresh air?. N Engl J Med. 2006;354:191–193
  7. Kern W, Born J, Schreiber H, Fehm HL. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes. 1999;48:557–563
  8. Pontiroli AE, Alberetto M, Secchi A, Dossi G, Bosi I, Pozza G. Insulin given intranasally induces hypoglycaemia in normal and diabetic subjects. Br Med J (Clin Res Ed). 1982;284:303–306
  9. Moses AC, Gordon GS, Carey MC, Flier JS. Insulin administered intranasally as an insulin-bile salt aerosol: effectiveness and reproducibility in normal and diabetic subjects. Diabetes. 1983;32:1040–1047
  10. Salzman R, Manson JE, Griffing GT, Kimmerle R, Ruderman N, McCall A, et al. Intranasal aerosolized insulin. Mixed-meal studies and long-term use in type I diabetes. N Engl J Med. 1985;312:1078–1084
  11. Saffran M, Kumar G, Savariar C, Burnham J, Williams F, Neckers D. A new approach to the oral administration of insulin and other peptide drugs. Science. 1986;233:1081–1084
  12. Lassmann-Vaque V, Thiers D, Vialettes B, Vaque P. Preprandial intranasal insulin. Lancet. 1988;1:367–368
  13. Lalej-Bennis D, Boillot J, Bardin C, Zirinis P, Coste A, Escudier E, et al. Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance. Diabetes Metab. 2001;27:372–377
  14. Dreyer K, Vaag A, Bech K, Hansen P, Sørensen AR, Mygind N. Intranasal administration of insulin with phospholipids as absorption enhancer: pharmacokinetics in normal subjects. Diabet Med. 1992;9:335–340
  15. Frauman AG, Cooper ME, Parsons BJ, Jerums G, Louis WJ. Long term use of intranasal insulin in insulin-dependent diabetic patients. Diabetes Care. 1987;10:573–578
  16. Frauman AG, Jerums G, Louis WJ. Effects of intranasal insulin in non-obese type 2 diabetes. Diabetes Res Clin. 1987;3:197–202
  17. Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med. 2003;20:886–898
  18. Heinemann L, Pfutzner A, Heise T. Alternative routes of administration as an approach to improve insulin therapy: update on dermal, oral, nasal and pulmonary insulin delivery. Curr Pharm Des. 2001;7:1327–1351
  19. Barnett AH. Exubera inhaled insulin: a review. Int J Clin Pract. 2004;58:394–401
  20. Hirsch IB. Arguments against the use of inhaled insulin. Diabetes Technol Ther. 2007;9:S111–S114
  21. Waknine Y. Exubera gets lung cancer warning. Available at Medscape Medical News. April 9, 2008;http://www.medscape.comAccessed April 15, 2009
  22. Ferrari LR. New insulin analogues and insulin delivery devices for the perioperative management of diabetic patients. Curr Opin Anaesthesiol. 2008;21:401–405
  23. Davis SN. Postprandial physiology and the pathogenesis of type 2 diabetes mellitus. Insulin. 2008;3(suppl 2):132–140
  24. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29:1326–1334
  25. Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006;27:451–458
  26. Hallschmid M, Benedict C, Schultes B, Perras B, Fehm HL, Kern W, et al. Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders. Regul Pept. 2008;149:79–83
  27. Liu XF, Fawcett JR, Thorne RG, DeFor TA, Frey WH. Intranasal administration of insulin-like growth factor-I bypasses the blood–brain barrier and protects against focal cerebral ischemic damage. J Neurol Sci. 2001;187:91–97
  28. Liu XF, Fawcett JR, Thorne RG, Frey WH. Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neurosci Lett. 2001;308:91–94
  29. Sigurdsson P, Thorvaldsson T, Gizurarson S, Gunnarsson E. Olfactory absorption of insulin to the brain. Drug Deliv. 1997;4:195–200
  30. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience. 2004;127:481–496
  31. Frey WH, Liu J, Chen X, Thorne RG, Fawcett JR, Ala TA, et al. Delivery of 125I-NGF to the brain via the olfactory route. Drug Deliv. 1997;4:87–92
  32. Anderson MF, Aberg MAI, Nilsson M, Eriksson PS. Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Dev Brain Res. 2002;134:115–122
  33. Henkin RI, Martin BM. Nasal seroproteins, their physiology and pathology. Am J Rhinol. 2000;14:A–82
  34. Henkin RI, Doherty AE, Martin BM. Nasal seroproteins: a new frontier in the exploration of physiology and pathology of nasal and sinus disease. In:  Veldman JE,  Passàli D,  Lim DJ editor. New frontiers in immunobiology in otolaryngology. The Hague: Kugler; 2000;p. 127–152
  35. Velicu I, Henkin RI. Insulin is present in human saliva and nasal mucus. J Invest Med. 2006;54(suppl 2):S385
  36. Henkin RI, Velicu I. Insulin receptors as well as insulin are present in saliva and nasal mucus. J Invest Med. 2006;54(suppl 2):S378
  37. Henkin RI, Lippoldt RE, Bilstad J, Edelhoch H. A zinc protein isolated from human parotid saliva. Proc Natl Acad Sci U S A. 1975;72:488–492
  38. Henkin RI, Velicu I. cAMP and cGMP in nasal mucus: relationships to taste and smell dysfunction, gender and age. Clin Invest Med. 2008;31:E71–E77
  39. Henkin RI, Velicu I. cAMP and cGMP in nasal mucus related to severity of smell loss in patients with smell dysfunction. Clin Invest Med. 2008;31:E78–E84
  40. Lake JK, Power C, Cole TJ. Child to adult body mass index in the 1958 British birth cohort: associations with parental obesity. Arch Dis Child. 1997;77:376–381
  41. Murakami K, Taniguchi H, Baba S. Presence of insulin-like immunoreactivity and its biosynthesis in rat and human parotid gland. Diabetologia. 1982;22:358–361
  42. Kerr M, Lee A, Wang PL, Purushotham KR, Chegini N, Yamamoto H, et al. Detection of insulin and insulin-like growth factors I and II in saliva and potential synthesis in the salivary glands of mice. Effects of type 1 diabetes mellitus. Biochem Pharmacol. 1995;49:1521–1531
  43. Fekete Z, Korec R, Feketeova E, Murty VL, Piotrowski J, Slomiany A, et al. Salivary and plasma insulin levels in man. Biochem Mol Biol Int. 1993;30:623–629
  44. Carter DA, Wobken JD, Dixit PK, Bauer GE. Immunoreactive insulin in rat salivary glands and its dependence on age and serum insulin levels. Proc Soc Exp Biol Med. 1995;209:245–250
  45. Marchetti P, Grossi C, Giannarelli R, Masoni A, Cristofani R, Giannecchini M, et al. Salivary immunoreactive insulin: a new entry in clinical chemistry?. Clin Chem. 1988;34:1478–1480
  46. Vallego G, Mead PM, Gaynor DH, Devlin JT, Robbins DC. Characterization of immunoreactive insulin in human saliva: evidence against production in situ. Diebetologia. 1984;27:437–440
  47. Marchetti P, Benzi L, Masoni A, Cecchetti P, Giannarelli R, Di Cianni G, et al. Salivary insulin concentrations in type 2 (non–insulin-dependent) diabetic patients and obese non-diabetic subjects: relationship to changes in plasma insulin levels after an oral glucose load. Diabetologia. 1986;29:695–698
  48. Sweeney EA, Juan CS, AvRuskin TW. Turner's syndrome and carbohydrate metabolism. II. Parotid salivary insulin concentration in normal subjects and in patients with gonadal dysgenesis. Am J Med Sci. 1979;227:153–162
  49. Ruan KH, Ke DR, Huang XW, Ni DR, Pan SZ, Yao RH, et al. Determination of insulin in human saliva using a more sensitive sandwich enzyme immunoassay. Anal Lett. 1988;21:381–394
  50. Sweeney EA, Antoniades HN. The presence of immunologically reactive insulin in parotid saliva and its relation to changes in serum insulin concentration. Vox Sang. 1967;13:54–56
  51. Marchetti P, Giannarelli R, Masoni A, Cecchetti P, Di Carlo A, Navalesi R. Salivary immunoreactive insulin concentrations are related to plasma free-insulin levels in insulin-treated diabetic patients. Diabetes Metab. 1990;16:16–20
  52. Costigan DC, Guyda HJ, Posner BI. Free insulin-like growth factor I (IGF-I) and IGF-II in human saliva. J Clin Endocrinol Metab. 1988;66:1014–1018
  53. Ryan J, Mantle T, Costigan DC. A normal population study of human salivary insulin-like growth factor 1 (IGF 1) concentrations from birth through puberty. J Clin Endocrinol Metab. 1992;74:774–778
  54. Ryan J, Mantle T, McQuaid S, Costigan DC. Salivary insulin-like growth factor-I originates from local synthesis. J Endocrinol. 1992;135:85–90
  55. Lawrence AM, Tan S, Hojvat S, Kirsteins L. Salivary gland hyperglycemic factor: an extrapancreatic source of glucagon-like material. Science. 1977;195:70–72
  56. Gröschl M, Topf HG, Bohlender J, Zenk J, Klussmann S, Dötsch J, et al. Identification of ghrelin in human saliva: production by the salivary glands and potential role in proliferation of oral keratinocytes. Clin Chem. 2005;51:997–1006
  57. Oxford GE, Tayari L, Barfoot MD, Peck AB, Tanaka Y, Humphreys-Beher MG. Salivary EGF levels reduced in diabetic patients. J Diabetes Complications. 2000;14:140–145
  58. Astaneie F, Afshari M, Mojtahedi A, Mostafalou S, Zamani MJ, Larijani B, et al. Total antioxidant capacity and levels of epidermal growth factor and nitric oxide in blood and saliva of insulin-dependent diabetic patients. Arch Med Res. 2005;36:376–381
  59. Law JS, Henkin RI. Low parotid saliva calmodulin in patients with taste and smell dysfunction. Biochem Med Metab Biol. 1986;36:118–124
  60. Henkin RI. Calmodulin in saliva (letter to the editor). J Dent Res. 1997;76:1430
  61. Henkin RI, Lippoldt RE, Bilstad J, Wolf RO, Lum CKL, Edelhoch H. Fractionation of human parotid saliva. J Biol Chem. 1978;253:7556–7565
  62. Henkin RI, Velicu I, Papathanasiu A. cAMP and cGMP in human parotid saliva: relationships to taste and smell dysfunction, gender and age. Am J Med Sci. 2007;334:431–440
  63. Rosenzweig JL, Havrankova J, Lesniak MA, Brownstein M, Roth J. Insulin is ubiquitous in extrapancreatic tissues of rats and humans. Proc Natl Acad Sci U S A. 1980;77:572–576
  64. Kojima H, Fujimiya M, Matsumura K, Nakahara T, Hara M, Chan L. Extrapancreatic insulin-producing cells in multiple organs in diabetes. Proc Natl Acad Sci U S A. 2004;101:2458–2463
  65. Goldfine ID, German MS, Tseng HC, Wang J, Bolaffi JL, Chen JW, et al. The endocrine secretion of human insulin and growth hormone by exocrine glands of the gastrointestinal tract. Nat Biotechnol. 1997;15:1378–1382
  66. Rocha EM, Cunha DA, Carneiro EM, Boschero AC, Saad MJA, Velloso LA. Identification of insulin in the tear film and insulin receptor and IGF-1 receptor on the human ocular surface. Invest Ophthalmol Vis Sci. 2002;43:963–967
  67. Schwander JC, Hauri C, Zapf J, Froesch ER. Synthesis and secretion of insulin-like growth factor and its binding protein by the perfused rat liver: dependence on growth hormone status. Endocrinology. 1983;113:297–305
  68. Valera A, Fillat C, Costa C, Sabater J, Visa J, Pujol A, et al. Regulated expression of human insulin in the liver of transgenic mice corrects diabetic alterations. FASEB J. 1994;8:440–447
  69. Casado B, Pannell LK, Iadarola P, Baraniuk JN. Identification of human nasal mucous proteins using proteomics. Proteomics. 2005;5:2949–2959
  70. Monte JC, Nagle MA, Eraly SA, Nigam SK. Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa. Biochem Biophys Res Commun. 2004;323:429–436
  71. Scaloni A, Paolini S, Brandazza A, Fantacci M, Bottiglieri C, Marchese S, et al. Purification, cloning and characterisation of odorant- and pheromone-binding proteins from pig nasal epithelium. Cell Mol Life Sci. 2001;58:823–834
  72. Federico G, Maremmani C, Cinquanta L, Baroncelli GI, Fattori B, Saggese G. Mucus of the human olfactory epithelium contains the insulin-like growth factor-I system which is altered in some neurodegenerative diseases. Brain Res. 1999;835:306–314
  73. Petruson B, Hansson HA, Petruson K. Insulin-like growth factor I is a possible pathogenic mechanism in nasal polyps. Acta Otolaryngol. 1988;106:156–160
  74. Hankiss J, Hadhazy C. Resorption of insulin and asthmolysin by the nasal mucous membrane. Acta Med Acad Sci Hung. 1958;12:107–114
  75. Werther GA, Hogg A, Oldfield BJ, McKinley MJ, Figdor R, Allen AM, et al. Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology. 1987;121:1562–1570
  76. Raizada MK. Localization of insulin-like immunoreactivity in the neurons from primary cultures of rat brain. Exp Cell Res. 1983;143:351–357
  77. Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad U S A. 1978;75:5737–5741
  78. Havrankova J, Brownstein M, Roth J. Insulin and insulin receptors in rodent brain. Diabetologia. 1981;20:268–273
  79. Baskin DG, Figlewicz DP, Woods SC, Porte D, Dorsa DM. Insulin in the brain. Annu Rev Physiol. 1987;49:335–347
  80. Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature. 1978;272:827–829
  81. Hill JM, Lesniak MA, Pert CB, Roth J. Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience. 1986;17:1127–1138
  82. Marks JL, Porte D, Stahl WL, Baskin DG. Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology. 1990;127:3234–3236
  83. Kar S, Chabot JG, Quirion R. Quantitative autoradiographic localization of [125I]insulin-like growth factor I, [125I]insulin-like growth factor II, and [125I]insulin receptor binding sites in developing and adult rat brain. J Comp Neurol. 1993;333:375–397
  84. Lesniak MA, Hill JM, Kiess W, Rojeski M, Pert CB, Roth J. Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin. Endocrinology. 1988;123:2089–2099
  85. Schulingkamp RJ, Pagano TC, Hung D, Raffa RB. Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev. 2000;24:855–872
  86. Baskin DG, Porte D, Guest K, Dorsa DM. Regional concentrations of insulin in the rat brain. Endocrinology. 1983;112:898–903
  87. Havrankova J, Roth J, Brownstein MJ. Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents. J Clin Invest. 1979;64:636–642
  88. Heidenreich KA, Zahniser NR, Berhanu P, Brandenburg D, Olefsky JM. Structural differences between insulin receptors in the brain and peripheral target tissues. J Bio Chem. 1983;258:8527–8530
  89. Hendricks SA, Agardh CD, Taylor SI, Roth J. Unique features of the insulin receptor in rat brain. J Neurochem. 1984;43:1302–1309
  90. Leloup C, Arluison M, Kassis N, Lepetit N, Cartier N, Ferré P, et al. Discrete brain areas express the insulin-responsive glucose transporter GLUT4. Mol Brain Res. 1996;38:45–53
  91. Kobayashi M, Nikami H, Morimatsu M, Saito M. Expression and localization of insulin-regulatable glucose transporter (GLUT4) in rat brain. Neurosci Lett. 1996;213:103–106
  92. Vannucci SJ, Maher F, Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia. 1997;21:2–21
  93. Muntzel MS, Morgan DA, Mark AL, Johnson AK. Intracerebroventricular insulin produces nonuniform regional increases in sympathetic nerve activity. Am J Physiol Regul Integr Comp Physiol. 1994;267:R1350–R1355
  94. Brussee V, Cunningham FA, Zochodne DW. Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes. 2004;53:1824–1830
  95. Recio-Pinto E, Lang FF, Ishii DN. Insulin and insulin-like growth factor II permit nerve growth factor binding and the neurite formation response in cultured human neuroblastoma cells. Proc Natl Acad Sci U S A. 1984;81:2562–2566
  96. Recio-Pinto E, Rechler MM, Ishii DN. Effects of insulin, insulin-like growth factor-II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J Neurosci. 1986;6:1211–1219
  97. Wanant S, Quon MJ. Insulin receptor binding kinetics: modeling and simulation studies. J Theor Biol. 2000;205:355–364
  98. Kovacs P, Morales JC, Karkanias GB. Central insulin administration maintains reproductive behavior in diabetic female rats. Neuroendocrinology. 2003;78:90–95
  99. Marty N, Dallaporta M, Thorens B. Brain glucose sensing, counterregulation, and energy homeostasis. Physiology (Bethesda). 2007;22:241–251
  100. Gerozissis K. Brain insulin: regulation, mechanisms of action and functions. Cell Mol Neurobiol. 2003;23:873–874
  101. Voll CL, Auer RN. Insulin attenuates ischemic brain damage independent of its hypoglycemic effect. J Cereb Blood Flow Metab. 1991;11:1006–1014
  102. Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm. 1998;105:423–438
  103. Izumi Y, Pinard E, Roussel S, Seylaz J. Insulin protects brain tissue against focal ischemia in rats. Neurosci Lett. 1992;144:121–123
  104. Bondy CA, Cheng CM. Signaling by insulin-like growth factor 1 in brain. Eur J Pharmacol. 2004;490:25–31
  105. Rees-Jones RW, Hendricks SA, Quarum M, Roth J. The insulin receptor of rat brain is coupled to tyrosine kinase activity. J Biol Chem. 1984;259:3470–3474
  106. Zhang WJ, Tan YF, Yue JTY, Vranic M, Wojtowicz JM. Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurol Scand. 2008;117:205–210
  107. Biessels GJ, Cristino NA, Rutten GJ, Hamers FPT, Erkelens DW, Gispen WH. Neurophysiological changes in the central and peripheral nervous system of streptozotocin-diabetic rats. Brain. 1999;122:757–768
  108. Di Luca M, Ruts L, Gardoni F, Catabeni F, Biessels GJ, Gispen WH. NMDA receptor subunits are modified transcriptionally and post-translationally in the brain of streptozotocin-diabetic rats. Diabetologia. 1999;42:693–701
  109. Grünblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S. Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem. 2007;101:757–770
  110. Sima AAF, Sugimoto K. Experimental diabetic neuropathy: an update. Diabetologia. 1999;42:773–788
  111. Cameron NE, Cotter MA, Low PA. Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol Endocrinol Metab. 1991;261:E1–E8
  112. Martin PM, Roon P, Van Ells TK, Ganapathy V, Smith SB. Death of retinal neurons in streptozotocin-induced diabetic mice. Invest Ophthalmol Vis Sci. 2004;45:3330–3336
  113. Gizurarson S, Thorvaldsson T, Sigurdsson P, Gunnarsson E. Selective delivery of insulin into the brain: intraolfactory absorption. Int J Pharm. 1996;140:77–83
  114. Stockhorst U, de Fries D, Steingrueber HJ, Scherbaum WA. Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans. Physiol Behav. 2004;83:47–54
  115. Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289:2122–2125
  116. Mercola J. Insulin receptors in brain tied to appetite and weight gain. Available at Health Newsletter. October 2000;http://www.mercola.comAccessed April 15, 2009
  117. Dahlin M, Bergman U, Jansson B, Björk E, Brittebo E. Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res. 2000;17:737–742
  118. Chemuturi NV, Haraldsson JE, Prisinzano T, Donovan M. Role of dopamine transporter (DAT) in dopamine transport across the nasal mucosa. Life Sci. 2006;79:1391–1398
  119. Frey WH, Liu J, Chen X, Thorne RG, Fawcett JR, Ala TA, et al. Delivery of 125I-NGF to the brain via the olfactory route. Int J Pharm Drug Del. 1997;4:87–92
  120. Westin UE, Boström E, Grasjö J, Hammarlund-Udenaes M, Björk E. Direct nose-to-brain transfer of morphine after nasal administration to rats. Pharm Res. 2006;23:565–572
  121. Charlton ST, Whetstone J, Fayinka ST, Read KD, Illum L, Davis SS. Evaluation of direct transport pathways of glycine receptor antagonists and an angiotensin antagonist from the nasal cavity to the central nervous system in the rat model. Pharm Res. 2008;25:1531–1543
  122. Ma YP, Ma MM, Ge S, Guo RB, Zhang HJ, Frey WH, et al. Intranasally delivered TGF-β1 enters brain and regulates gene expressions of its receptors in rats. Brain Res Bull. 2007;74:271–277
  123. Kandimalla KK, Donovan MD. Transport of hydroxyzine and triprolidine across bovine olfactory mucosa: role of passive diffusion in the direct nose-to-brain uptake of small molecules. Int J Pharm. 2005;302:133–144
  124. Vyas TK, Shahiwala A, Marathe S, Misra A. Intranasal drug delivery for brain targeting. Curr Drug Deliv. 2005;2:165–175
  125. Han IK, Kim MY, Byun HM, Hwang TS, Kim JM, Hwang KW, et al. Enhanced brain targeting efficiency of intranasally administered plasmid DNA: an alternative route for brain gene therapy. J Mol Med. 2007;85:75–83
  126. Graff CL, Zhao R, Pollack GM. Pharmacokinetics of substrate uptake and distribution in murine brain after nasal instillation. Pharm Res. 2005;22:235–244
  127. Shipley MT. Transport of molecules from nose to brain: transneuronal anterograde and retrograde labeling in the rat olfactory system by wheat germ agglutinin-horseradish peroxidase applied to the nasal epithelium. Brain Res Bull. 1983;15:129–142
  128. Wu H, Hu K, Jiang X. From nose to brain: understanding transport capacity and transport rate of drugs. Expert Opin Drug Deliv. 2008;5:1159–1168
  129. Tanaka SI, Yamakawa T, Kimura M, Aoki I, Kamei J, Okuda K, et al. Daily nasal inoculation with the insulin gene ameliorates diabetes in mice. Diabetes Res Clin Pract. 2004;63:1–9
  130. Dahlin M, Jansson B, Björk E. Levels of dopamine in blood and brain following nasal administration to rats. Eur J Pharm Sci. 2001;14:75–80
  131. Thorne RG, Emory CR, Ala TA, Frey WH. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res. 1995;692:278–282
  132. Putcha L, Tietze KJ, Bourne DW, Parise CM, Hunter RP, Cintrón NM. Bioavailability of intranasal scopolamine in normal subjects. J Pharm Sci. 1996;85:899–902
  133. Kubek MJ, Ringel I, Domb AJ. Issues in intranasal neuropeptide uptake. In:  Kobiler D,  Lustig S,  Shapiro S editor. Blood–brain barrier: drug delivery and brain pathology. New York: Springer; 2001;p. 331
  134. Illum L. Is nose-to-brain transport of drugs in man a reality?. J Pharm Pharmacol. 2004;56:3–17
  135. Rao DB, Wong BA, McManus BE, McElveen AM, James AR, Dorman DC. Inhaled iron, unlike manganese, is not transported to the rat brain via the olfactory pathway. Toxicol Appl Pharmacol. 2003;193:116–126
  136. Thompson K, Molina RM, Donaghey T, Schwob JE, Brain JD, Wessling-Resnick M. Olfactory uptake of manganese requires DMT1 and is enhanced by anemia. FASEB J. 2007;21:223–230
  137. Evans J, Hastings L. Accumulation of Cd(II) in the CNS depending on the route of administration: intraperitoneal, intratracheal, or intranasal. Toxicol Sci. 1992;19:275–278
  138. Chow HS, Chen Z, Matsuura GT. Direct transport of cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats. J Pharm Sci. 1995;88:754–758
  139. Dorman DC, Brenneman KA, McElveen AM, Lynch SE, Roberts KC, Wong BA. Olfactory transport: a direct route of delivery of inhaled manganese phosphate to the rat brain. J Toxicol Environ Health A. 2002;65:1493–1511
  140. Dorman DC, Struve MF, Wong BA, Dye JA, Robertson ID. Correlation of brain magnetic resonance imaging changes with pallidal manganese concentrations in rhesus monkeys following subchronic manganese inhalation. Toxicol Sci. 2006;92:219–227
  141. Keverne EB, de la Riva C. Pheromones in mice: reciprocal interaction between the nose and brain. Nature. 1982;296:148–150
  142. Majde JA, Bohnet SG, Ellis GA, Churchill L, Leyva-Grado V, Wu M, et al. Detection of mouse-adapted human influenza virus in the olfactory bulbs of mice within hours after intranasal infection. J Neurovirol. 2007;13:399–409
  143. Sunderman FW. Nasal toxicity, carcinogenicity, and olfactory uptake of metals. Ann Clin Lab Sci. 2001;31:3–24
  144. Lewis J, Bench G, Myers O, Tinner B, Staines W, Barr E, et al. Trigeminal uptake and clearance of inhaled manganese chloride in rats and mice. Neurotoxicology. 2005;26:113–123
  145. Stockhorst U, Pietrowsky R. Olfactory perception, communication, and the nose-to-brain pathway. Physiol Behav. 2004;83:3–11
  146. Reinhardt RR, Bondy CA. Insulin-like growth factors cross the blood–brain barrier. Endocrinology. 1994;135:1753–1761
  147. Kastin AJ, Pan W. Intranasal leptin: blood–brain barrier bypass (BBBB) for obesity?. Endocrinology. 2006;147:2086–2087
  148. Dahlin M, Björk E. Nasal absorption of (S)-UH-301 and its transport into the cerebrospinal fluid in rats. Int J Pharm. 2000;195:197–205
  149. Banks WA. The source of cerebral insulin. Eur J Pharm. 2004;490:5–12
  150. Pardridge WM, Eisenberg J, Yang J. Human blood–brain barrier insulin receptor. J Neurochem. 1985;44:1771–1778
  151. Pereswetoff-Morath L. Microspheres as nasal drug delivery systems. Adv Drug Deliv Rev. 1998;29:185–194
  152. Pereswetoff-Morath L, Edman P. Dextran microspheres as a potential nasal drug delivery system for insulin–in vitro and in vivo properties. Int J Pharm. 1995;124:37–44
  153. Abd El-Hameed MD, Kellaway LW. Preparation and in vitro characterization of mucoadhesive polymeric microspheres as intra-nasal delivery systems. Eur J Pharm Biopharm. 1997;44:53–60
  154. Shao Z, Krishnamoorthy R, Mitra AK. Cyclodextrins as nasal absorption promoters of insulin: mechanistic evaluations. Pharm Res. 1992;9:1157–1163
  155. Illum L, Farraj NF, Davis SS. Chitosan as a novel delivery system for peptide drugs. Pharm Res. 1994;11:1186–1189
  156. Hermens WA, Hooymans PM, Verhoef JC, Merkus FW. Effects of absorption enhancers on human nasal tissue ciliary movement in vitro. Pharm Res. 1990;7:144–146
  157. Cheng YH, Dyer AM, Jabbal-Gill I, Hinchcliffe M, Nankervis R, Smith A, et al. Intranasal delivery of recombinant human growth hormone (somatropin) in sheep using chitosan-based powder formulations. Eur J Pharm Sci. 2005;26:9–15
  158. Charlton S, Jones NS, Davis SS, Illum L. Distribution and clearance of bioadhesive formulations from the olfactory region in man: effect of polymer type and nasal delivery device. Eur J Pharm Sci. 2007;30:295–302
  159. Zhang Q, Jiang X, Jiang W, Lu W, Su L, Shi Z. Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain. Int J Pharm. 2004;275:85–96
  160. Widner H, Jönsson BA, Hallstadius L, Wingårdh K, Strand SE, Johansson BB. Scintigraphic method to quantify the passage from brain parenchyma to the deep cervical lymph nodes in rats. Eur J Nucl Med. 1987;13:456–461
  161. Yamada S, DePasquale M, Patlak CS, Cserr HF. Albumin outflow into deep cervical lymph from different regions of rabbit brain. Am Physiol Heart Circ Physiol. 1991;261:H1197–H1204
  162. Wyatt TD. Pheromones and animal behaviour: communication by smell and taste. New York: Cambridge University Press; 2003;
  163. McClintock MK. Menstrual synchorony and suppression. Nature. 1971;329:244–245
  164. In:  Houck LD,  Drickamer LC editor. Foundations of animal behavior: classic papers with commentaries. Chicago: University of Chicago Press; 1996;
  165. Karlson P, Butenandt A. Pheromones (ectohormones) in insects. Annu Rev Entomol. 1959;4:39–58
  166. Michael RP, Keverne EB. Primate sex pheromones of vaginal origin. Nature. 1970;225:84–85
  167. Pietrowsky R, Strüben C, Mölle M, Fehm HL, Born J. Brain potential changes after intranasal vs. intravenous administration of vasopressin: evidence for a direct nose–brain pathway for peptide in humans. Biol Psychiatry. 1996;39:332–340
  168. Jadhav KR, Gambhire MN, Shaikh IM, Kadam VJ, Pisal SS. Nasal drug delivery system–factors affecting and applications. Curr Drug Deliv. 2007;2:27–38

PII: S0899-9007(09)00333-5

doi: 10.1016/j.nut.2009.08.003

Nutrition
Volume 26, Issue 6 , Pages 624-633 , June 2010