Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration
Abstract
We investigated the CNS delivery of insulin-like growth factor-I (IGF-I), a 7.65 kDa protein neurotrophic factor, following intranasal administration and the possible pathways and mechanisms underlying transport from the nasal passages to the CNS. Anesthetized adult male Sprague-Dawley rats were given [125I]-IGF-I intranasally or intravenously and then killed by perfusion-fixation within 30 min. Other animals were killed following cisternal puncture and withdrawal of cerebrospinal fluid (CSF) or intranasal administration of unlabeled IGF-I or vehicle. Both gamma counting of microdissected tissue and high resolution phosphor imaging of tissue sections showed that the tissue concentrations and distribution following intranasal administration were consistent with two routes of rapid entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages with the olfactory bulbs and rostral brain regions (e.g. anterior olfactory nucleus and frontal cortex) and the other associated with the peripheral trigeminal system connecting the nasal passages with brainstem and spinal cord regions. Intranasal administration of [125I]-IGF-I also targeted the deep cervical lymph nodes, consistent with their possible role in lymphatic drainage of both the nasal passages and the CNS. Cisternal CSF did not contain [125I]-IGF-I following intranasal administration. Intravenous [125I]-IGF-I resulted in blood and peripheral tissue exposure similar to that seen following intranasal administration but CNS concentrations were significantly lower. Finally, delivery of IGF-I into the CNS activated IGF-I signaling pathways, confirming some portion of the IGF-I that reached CNS target sites was functionally intact. The results suggest intranasally delivered IGF-I can bypass the blood-brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.
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Frey II et al. confirmed that IGF1 reached central nervous system target sites in rats after administration of [125I]-labeled IGF1.
“Frey II et al. investigated the delivery of IGF1 to CNS, confirming they reached CNS target sites of rats by administering a mixture of [125I]-labeled IGF1.179”
From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [179]
Through the nasal route, a drug can access the brain directly along the trigeminal and olfactory nerves located in the upper part of the nasal cavity.
“Through the nasal route, the drug can access the brain directly along the trigeminal and olfactory nerves, which are located in the upper part of the nasal cavity.”
From Nanoemulsions for “Nose-to-Brain” Drug Delivery (2019) · cites this paper as [8]
Olfactory and trigeminal pathways are the only routes by which the brain is connected to the outside environment.
“Olfactory and trigeminal pathways are the only routes by which the brain is connected to the outside environment [8,9].”
From Nanoemulsions for “Nose-to-Brain” Drug Delivery (2019) · cites this paper as [8]
In Sprague-Dawley rats, intranasally administered insulin-like growth factor-1 rapidly acts on multiple sites within the brain and spinal cord.
“Experiments in Sprague-Dawley rats relying on gamma counting and high-resolution phosphor imaging of tissue sections show that IN administered insulin-like growth factor-1 rapidly acts on multiple sites within the brain and spinal cord.”
From Intranasal insulin (2021) · cites this paper as [31]
Cites
The rat brain in stereotaxic coordinates
Palkovits, M. (1983) · Neuropeptides · doi:10.1016/0143-4179(83)90049-5 · Cited by 28,988 · see citing works
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
Handbook of Sensory Physiology
Sanders, M. D. (1975) · British Journal of Ophthalmology · doi:10.1136/bjo.59.2.111-c · Cited by 7,166 · see citing works
Rinderknecht, E., & HUMBEL, R. E. (1978) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)40889-1 · Cited by 1,548 · see citing works
Sniffing neuropeptides: A transnasal approach to the human brain
Born, J., Lange, T., Kern, W., McGregor, G. P., Bickel, U., & Fehm, H. L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-849 · Cited by 1,356 · see citing works
Transport of drugs from the nasal cavity to the central nervous system
Illum, L. (2000) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(00)00087-7 · Cited by 907 · see citing works
Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view
Cserr, H. F., & Knopf, P. M. (1992) · Immunology Today · doi:10.1016/0167-5699(92)90027-5 · Cited by 648 · see citing works
Carro, E., Trejo, J. L., Busiguina, S., & Torres-Aleman, I. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-15-05678.2001 · Cited by 601 · see citing works
Physiology of the CSF and Blood-Brain Barriers
Davson, H., & Segal, M. B. (1996) · Medical Entomology and Zoology · Cited by 576 · see citing works
Maps and guide to microdissection of the rat brain
Palkovits, M., & Brownstein, M. (1988) · Medical Entomology and Zoology · Cited by 550 · see citing works
Insulin and Insulin-like Growth Factor-1 Regulate Tau Phosphorylation in Cultured Human Neurons*
Hong, M., & Lee, V. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.31.19547 · Cited by 533 · see citing works
Kida, S., Pantazis, A., & Weller, R. O. (1993) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1993.tb00476.x · Cited by 520 · see citing works
Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain
Balin, B. J., Gérard, H. C., Arking, E. J., Appelt, D. M., Branigan, P. J., Abrams, J. T., Whittum-Hudson, J. A., & Hudson, A. P. (1998) · Medical Microbiology and Immunology · doi:10.1007/s004300050071 · Cited by 506 · see citing works
A crucial role for B cells in neuroinvasive scrapie
Klein, M. A., Frigg, R., Flechsig, E., Raeber, A. J., Kalinke, U., Bluethmann, H., Bootz, F., Suter, M., Zinkernagel, R. M., & Aguzzi, A. (1997) · Nature · doi:10.1038/37789 · Cited by 490 · see citing works
Delivery of Neurotrophic Factors to the Central Nervous System: Pharmacokinetic Considerations
Thorne, R. G., & Frey, W. H. (2001) · Clinical Pharmacokinetics · doi:10.2165/00003088-200140120-00003 · Cited by 487 · see citing works
Self-citationDrug and Gene Delivery to the Brain
Pardridge, W. M. (2002) · Neuron · doi:10.1016/s0896-6273(02)01054-1 · Cited by 405 · see citing works
Patterns of lymphatic drainage in the adult laboratory rat.
Tilney, N. L. (1971) · PubMed · Cited by 404 · see citing works
Neurobiology of Taste and Smell
Finger, T. E., & Silver, W. L. (1991) · Cited by 400 · see citing works
Insulin-like growth factors cross the blood-brain barrier.
Reinhardt, R., & Bondy, C. A. (1994) · Endocrinology · doi:10.1210/endo.135.5.7525251 · Cited by 384 · see citing works
Maps and guide to microdissection of the rat brain
Bruyn, G. W. (1988) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(88)90044-5 · Cited by 370 · see citing works
O'Kusky, J. R., Ye, P., & D'Ercole, A. J. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-22-08435.2000 · Cited by 358 · see citing works
Balin, B. J., Broadwell, R. D., Salcman, M., & El‐Kalliny, M. (1986) · Journal of Comparative Neurology · doi:10.1002/cne.902510209 · Cited by 358 · see citing works
Quantitative analysis of the olfactory pathway for drug delivery to the brain
Thorne, R. G., Emory, C. R., Ala, T. A., & Frey, W. H. (1995) · Brain Research · doi:10.1016/0006-8993(95)00637-6 · Cited by 352 · see citing works
Self-citationThoenen, H., & Sendtner, M. (2002) · Nature Neuroscience · doi:10.1038/nn938 · Cited by 336 · see citing works
Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit
Bradbury, M. W., Cserr, H. F., & Westrop, R. J. (1981) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.1981.240.4.f329 · Cited by 335 · see citing works
Doré, S., Kar, S., & Quirion, R. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4772 · Cited by 325 · see citing works
Free insulin‐like growth factors (IGF‐I and IGF‐II) in human serum
Frystyk, J., Skjærbæk, C. B., Dinesen, B., & Ørskov, H. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00602-4 · Cited by 306 · see citing works
Taste and Smell in Vertebrates.
(1971) · Annals of Internal Medicine · doi:10.7326/0003-4819-75-5-825_2 · Cited by 282 · see citing works
Butler, A. A., Yakar, S., Gewolb, I. H., Karas, M., Okubo, Y., & LeRoith, D. (1998) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/s0305-0491(98)10106-2 · Cited by 254 · see citing works
Lesniak, M. A., Hill, J. M., Kieß, W., Rojeski, M., Pert, C. B., & Roth, J. (1988) · Endocrinology · doi:10.1210/endo-123-4-2089 · Cited by 252 · see citing works
Liu, X., Fawcett, J. R., Thorne, R. G., DeFor, T. A., & Frey, W. H. (2001) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(01)00532-9 · Cited by 250 · see citing works
Self-citationDelivery of Nerve Growth Factor to the Brain via the Olfactory Pathway
Chen, X., Fawcett, J. R., Rahman, Y., Ala, T. A., & Frey, W. H. (1998) · Journal of Alzheimer s Disease · doi:10.3233/jad-1998-1102 · Cited by 247 · see citing works
Self-citationChlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice
Little, C. S., Hammond, C. J., MacIntyre, A., Balin, B. J., & Appelt, D. M. (2004) · Neurobiology of Aging · doi:10.1016/s0197-4580(03)00127-1 · Cited by 243 · see citing works
Schaefer, M. L., Böttger, B., Silver, W. L., & Finger, T. E. (2002) · The Journal of Comparative Neurology · doi:10.1002/cne.10143 · Cited by 239 · see citing works
Russell and Rubinstein's pathology of tumors of the nervous system
Bigner, D. D., McLendon, R. E., Bruner, J. M., et al. (1998) · Hodder Arnold eBooks · Cited by 232 · see citing works
Weller, R. O. (1998) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199810000-00001 · Cited by 224 · see citing works
Distribution of extracellular tracers in perivascular spaces of the rat brain
Ichimura, T., Fraser, P. A., & Cserr, H. F. (1991) · Brain Research · doi:10.1016/0006-8993(91)91275-6 · Cited by 215 · see citing works
Capsoni, S., Giannotta, S., & Cattaneo, A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192442999 · Cited by 214 · see citing works
Weller, R. O., Engelhardt, B., & Phillips, M. J. (1996) · Brain Pathology · doi:10.1111/j.1750-3639.1996.tb00855.x · Cited by 213 · see citing works
Bradbury, M. W. B., & Westrop, R. J. (1983) · The Journal of Physiology · doi:10.1113/jphysiol.1983.sp014731 · Cited by 211 · see citing works
Delivery of 125 I-NGF to the Brain via the Olfactory Route
Frey, W. H., Liu, J., Chen, X., Thorne, R. G., Fawcett, J. R., Ala, T. A., & Rahman, Y. (1997) · Drug Delivery · doi:10.3109/10717549709051878 · Cited by 210 · see citing works
Self-citationShipley, M. T. (1985) · Brain Research Bulletin · doi:10.1016/0361-9230(85)90129-7 · Cited by 208 · see citing works
Central nervous system effects of intranasally administered insulin during euglycemia in men.
Kern, W., Jan Born, A., Schreiber, H., & Fehm, H. (1999) · Diabetes · doi:10.2337/diabetes.48.3.557 · Cited by 192 · see citing works
What is the role of circulating IGF-I?
Roith, D. L., Scavo, L. M., & Butler, A. A. (2001) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(00)00349-0 · Cited by 188 · see citing works
Neuroprotective strategy for Alzheimer disease: intranasal administration of a fatty neuropeptide.
Gozes, I., Bardea, A., Reshef, A., Zamostiano, R., Zhukovsky, S., Rubinraut, S., Fridkin, M., & Brenneman, D. E. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.1.427 · Cited by 181 · see citing works
Broadwell, R. D., & Balin, B. J. (1985) · The Journal of Comparative Neurology · doi:10.1002/cne.902420410 · Cited by 180 · see citing works
Lindholm, D., Carroll, P., Tzimagiorgis, G., & Thoenen, H. (1996) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1996.tb01607.x · Cited by 180 · see citing works
Bohannon, N. J. V., Wilcox, B. J., Figlewicz, D. P., Dorsa, D. M., & Baskin, D. G. (1988) · Brain Research · doi:10.1016/0006-8993(88)90931-6 · Cited by 177 · see citing works
Nonolfactory Responses from the Nasal Cavity: Jacobson’s Organ and the Trigeminal System
Tucker, D. M. (1971) · Handbook of sensory physiology · doi:10.1007/978-3-642-65126-7_7 · Cited by 176 · see citing works
Gozes, I., Giladi, E., Pinhasov, A., Bardea, A., & Brenneman, D. E. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)39336-x · Cited by 157 · see citing works
Experimental biology of the lymphatic circulation
Johnston, M. G. (1985) · Elsevier eBooks · Cited by 156 · see citing works
Circulating IGF-I: New Perspectives for a New Century
Rosen, C. J., & Pollak, M. (1999) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(98)00126-x · Cited by 154 · see citing works
The Olfactory Neuron and the Blood-Brain Barrier
de Lorenzo, A. J. D. (2008) · Novartis Foundation symposium · doi:10.1002/9780470715369.ch9 · Cited by 150 · see citing works
Liu, X., Fawcett, J. R., Thorne, R. G., & Frey, W. H. (2001) · Neuroscience Letters · doi:10.1016/s0304-3940(01)01982-6 · Cited by 150 · see citing works
Self-citationBaker, H. A., & Spencer, R. F. (1986) · Experimental Brain Research · doi:10.1007/bf00237470 · Cited by 147 · see citing works
Demonstration of terminalis, olfactory, trigeminal and perivascular nerves in the rat nasal septum
Bojsen-møller, F. (1975) · The Journal of comparative neurology · doi:10.1002/cne.901590206 · Cited by 145 · see citing works
Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity
Sakane, T., Akizuki, M., Yoshida, M., Yamashita, S., NADAI, T., Hashida, M., & Sezaki, H. (1991) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1991.tb03510.x · Cited by 144 · see citing works
Werther, G. A., Abate, M., Hogg, A., Cheesman, H., Oldfield, B. J., Hards, D. K., Hudson, P. M., Power, B. E., Freed, K. A., & Herington, A. C. (1990) · Molecular Endocrinology · doi:10.1210/mend-4-5-773 · Cited by 141 · see citing works
Alzheimer's disease may begin in the nose and may be caused by aluminosilicates
Roberts, E. (1986) · Neurobiology of Aging · doi:10.1016/0197-4580(86)90119-3 · Cited by 134 · see citing works
Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats
Dufès, C., Olivier, J., Gaillard, F. P., Gaillard, A., Couet, W. R., & Jm, M. (2003) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(03)00039-5 · Cited by 134 · see citing works
Anton, F., & Peppel, P. (1991) · Neuroscience · doi:10.1016/0306-4522(91)90354-q · Cited by 133 · see citing works
Ocrant, I., Fay, C. T., & Parmelee, J. T. (1990) · Endocrinology · doi:10.1210/endo-127-3-1260 · Cited by 119 · see citing works
Baldauf, E., Diringer, H., & Beekes, M. (1997) · Journal of General Virology · doi:10.1099/0022-1317-78-5-1187 · Cited by 116 · see citing works
Insulin-Like Growth Factors as Mediators of Functional Plasticity in the Adult Brain
Torres‐Alemán, I. (1999) · Hormone and Metabolic Research · doi:10.1055/s-2007-978707 · Cited by 115 · see citing works
Insulin-like growth factors cross the blood-brain barrier
Reinhardt, R. (1994) · Endocrinology · doi:10.1210/en.135.5.1753 · Cited by 108 · see citing works
Werther, G. A., Hogg, A., Oldfield, B. J., McKinley, M. J., Figdor, R., & Mendelsohn, F. A. O. (1989) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.1989.tb00131.x · Cited by 104 · see citing works
Cerebral neurogenesis is induced by intranasal administration of growth factors
Jin, K., Xie, L., Childs, J., Sun, Y., Mao, X. O., Logvinova, A. V., & Greenberg, D. A. (2003) · Annals of Neurology · doi:10.1002/ana.10506 · Cited by 104 · see citing works
Serial cerebrospinal fluid sampling in a rat model to study drug uptake from the nasal cavity
van den Berg, M. P., Romeijn, S. G., Verhoef, J. C., & Merkus, F. W. H. M. (2002) · Journal of Neuroscience Methods · doi:10.1016/s0165-0270(02)00033-x · Cited by 104 · see citing works
Mattson, M. P., & Cheng, B. (1993) · PubMed · Cited by 103 · see citing works
Casamassima, A., & Rozengurt, E. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.40.26149 · Cited by 100 · see citing works
Loddick, S. A., Liu, X.-J., Lu, Z.-X., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1894 · Cited by 91 · see citing works
Dynamic properties of lymphatic pathways for the absorption of cerebrospinal fluid
Brinker, T., Lüdemann, W. O., von Rautenfeld, D. B., & Samii, M. (1997) · Acta Neuropathologica · doi:10.1007/s004010050738 · Cited by 86 · see citing works
Neuroprotective peptide drug delivery and development: potential new therapeutics
Gozes, I. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01931-7 · Cited by 82 · see citing works
The Olfactory System and Alzheimer's Disease
Moyano, H. F., & Barragán, E. I. (1989) · International Journal of Neuroscience · doi:10.3109/00207458909084824 · Cited by 82 · see citing works
Direct access of drugs to the human brain after intranasal drug administration?
Merkus, P., Guchelaar, H.-J., Bosch, D. A., & Merkus, F. W. H. M. (2003) · Neurology · doi:10.1212/01.wnl.0000067993.60735.77 · Cited by 81 · see citing works
Extraneural metastases of paediatric brain tumours
Rickert, C. H. (2003) · Acta Neuropathologica · doi:10.1007/s00401-002-0666-x · Cited by 76 · see citing works
Recombinant proteins for neurodegenerative diseases: the delivery issue
Aebischer, P., & Ridet, J. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01899-3 · Cited by 72 · see citing works
Lymph node metastases from glioblastoma multiforme.
Wallace, C. J., Forsyth, P. A., & Edwards, D. R. (1997) · PubMed · Cited by 71 · see citing works
Human herpes virus infections and Alzheimer's disease
Deatly, A. M., Haase, A. T., Fewster, P. H., LEWIS, E., & Ball, M. J. (1990) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1990.tb01158.x · Cited by 71 · see citing works
Pulford, B. E., & Ishii, D. N. (2001) · Endocrinology · doi:10.1210/endo.142.1.7894 · Cited by 71 · see citing works
Insulin‐like Growth Factor Receptors: Implications for Nervous System Function
LeRoith, D., Werner, H., Faria, T. N., Kato, H., Adamo, M. L., & Roberts, C. T. (1993) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1993.tb26202.x · Cited by 70 · see citing works
Ballard, F. J., Knowles, S. E., WALTON, P. E., et al. (1991) · Journal of Endocrinology · doi:10.1677/joe.0.1280197 · Cited by 68 · see citing works
Anatomical pathways for lymphatic drainage of the brain and their pathological significance
Kida, S., Weller, R. O., Zhang, E. T., Phillips, M., & Iannotti, F. (1995) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1995.tb01048.x · Cited by 68 · see citing works
Jin, Y., Dons, L. E., Kristensson, K., et al. (2001) · Infection and Immunity · doi:10.1128/iai.69.2.1093-1100.2001 · Cited by 62 · see citing works
Chou, R. C., & Levy, G. (1981) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)32758-8 · Cited by 61 · see citing works
Tagami, M., Yamagata, K., Nara, Y., et al. (1997) · PubMed · Cited by 57 · see citing works
Insulinlike growth factor binding proteins
Spagnoli, A., & Rosenfeld, R. G. (1997) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/00060793-199702000-00001 · Cited by 54 · see citing works
LECOMTE, J. (1963) · PubMed · Cited by 53 · see citing works
González Cámpora, R., Otal Salaverrí, C., Ramírez, F. J. V., Villadiego, M. S., & Davidson, H. G. (1993) · PubMed · Cited by 48 · see citing works
Moss, A., Unger, J. W., Moxley, R. T., & Livingston, J. N. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.12.4453 · Cited by 47 · see citing works
Firth, S. M., McDougall, F. K., McLachlan, A. J., et al. (2002) · Endocrinology · doi:10.1210/endo.143.5.8764 · Cited by 46 · see citing works
Outflow of cerebrospinal fluid
Tans, J. T. J. (1990) · Clinical Neurology and Neurosurgery · doi:10.1016/0303-8467(90)90050-f · Cited by 46 · see citing works
Upton, Z., Yandell, C. A., Degger, B. G., et al. (1998) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/s0305-0491(98)10111-6 · Cited by 42 · see citing works
Transport and absorption of drugs via the lymphatic system
Porter, C. J. H., & Charman, W. N. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00146-6 · Cited by 36 · see citing works
The brain and the lymphatic system (I).
Földi, M. (1996) · PubMed · Cited by 33 · see citing works
Olfactory Absorption of Insulin to the Brain
Sigurdsson, P., Thorvaldsson, T., Gizurarson, S. S., & Gunnarsson, E. (1997) · Drug Delivery · doi:10.3109/10717549709051892 · Cited by 33 · see citing works
Pulford, B. E. (2001) · Endocrinology · doi:10.1210/en.142.1.213 · Cited by 28 · see citing works
Cervical Metastatic Glioblastoma Multiforme
Zappia, J. J., & Wolf, G. T. (1992) · Archives of Otolaryngology - Head and Neck Surgery · doi:10.1001/archotol.1992.01880070085016 · Cited by 22 · see citing works
A case of cervical lymph node metastasis resulting from glioblastoma multiforme.
Datta, C. K., Weinstein, J., Bland, J., et al. (1998) · PubMed · Cited by 21 · see citing works
Skjærbæk, C. B., Frystyk, J., Grøfte, T., et al. (1999) · Growth Hormone & IGF Research · doi:10.1054/ghir.1999.0090 · Cited by 20 · see citing works
Shinya, K., SILVANO, F. D., MORITA, T., Shimada, A., Nakajima, M., Ito, T., Otsuki, K., & Umemura, T. (1998) · Journal of Veterinary Medical Science · doi:10.1292/jvms.60.627 · Cited by 19 · see citing works
Iwanow, G., & Romodanowsky, K. (1928) · Research in Experimental Medicine · doi:10.1007/bf02630424 · Cited by 17 · see citing works
Cervical lymph nodes play the role of regional lymph nodes in brain tumour immunity in rats
Okamoto, Yamashita, Hasegawa, Fujisawa, Yamashima, Hashimoto, Nonomura, Matsumoto, & Kida (1999) · Neuropathology and Applied Neurobiology · doi:10.1046/j.1365-2990.1999.00165.x · Cited by 17 · see citing works
Firth, S. M. (2002) · Endocrinology · doi:10.1210/en.143.5.1669 · Cited by 15 · see citing works
Kidney as an important metabolic organ for recombinant human insulin-like growth factor-I.
Tanaka, Y., Kitao, K., Hata, T., et al. (1997) · PubMed · Cited by 4 · see citing works
Activity‐Dependent Neurotrophic Factor
Gozes, I., & Brenneman, D. E. (2002) · Wiley Encyclopedia of Molecular Medicine · doi:10.1002/0471203076.emm0428 · Cited by 1 · see citing works
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The blood–brain barrier: Structure, regulation and drug delivery
Wu, D., Chen, Q., Chen, X., Han, F., Chen, Z., & Wang, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01481-w · Cited by 1,906 · see citing works
“179 The results from high-resolution phosphor imaging autoradiography established the speci fi c binding of IGF1 and binding sites.”
BackgroundIntranasal delivery to the central nervous system: Mechanisms and experimental considerations
Dhuria, S. V., Hanson, L. R., & Frey, W. H. (2010) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.21924 · Cited by 1,239 · see citing works
Self-citationIntranasal insulin improves cognition and modulates β-amyloid in early AD
Reger, M. A., Watson, G. S., Green, P. S., Wilkinson, C. W., Baker, L. D., Cholerton, B., Fishel, M. A., Plymate, S. R., Breitner, J. C. S., DeGroodt, W., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000265401.62434.36 · Cited by 830 · see citing works
Nanoparticles for direct nose-to-brain delivery of drugs
Mistry, A., Stolnik, S., & Illum, L. (2009) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2009.06.019 · Cited by 734 · see citing works
Mechanism of intranasal drug delivery directly to the brain
Crowe, T. P., Greenlee, M. H. W., Kanthasamy, A. G., & Hsu, W. H. (2018) · Life Sciences · doi:10.1016/j.lfs.2017.12.025 · Cited by 721 · see citing works
Intranasal Drug Delivery: How, Why and What For?
Pires, A., Fortuna, A., Alves, G., & Falcão, A. (2009) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j3nc79 · Cited by 641 · see citing works
The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?
Abbott, N. J., Pizzo, M. E., Preston, J. E., Janigro, D., & Thorne, R. G. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1812-4 · Cited by 593 · see citing works
Self-citationAlzheimer's disease as homeostatic responses to age-related myelin breakdown
Bartzokis, G. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.08.007 · Cited by 546 · see citing works
Pardeshi, C. V., & Belgamwar, V. S. (2013) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.2013.790887 · Cited by 482 · see citing works
Striepens, N., Kendrick, K. M., Hanking, V., Landgraf, R., Wüllner, U., Maier, W., & Hurlemann, R. (2013) · Scientific Reports · doi:10.1038/srep03440 · Cited by 452 · see citing works
Progress in brain targeting drug delivery system by nasal route
Khan, A. R., Liu, M., Khan, M. W., & Zhai, G. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.09.001 · Cited by 402 · see citing works
Craft, S., Raman, R., Chow, T. W., Rafii, M. S., Sun, C.-K., Rissman, R. A., Donohue, M. C., Brewer, J. B., Jenkins, C., Harless, K., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.1840 · Cited by 389 · see citing works
Guastella, A. J., Hickie, I. B., McGuinness, M. M., Otis, M., Woods, E. A., Disinger, H. M., Chan, H.-K., Chen, T. F., & Banati, R. B. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.11.019 · Cited by 357 · see citing works
Diabetes mellitus and Alzheimer's disease: shared pathology and treatment?
Akter, K., Lanza, E. A., Martin, S. A., Myronyuk, N., Rua, M., & Raffa, R. B. (2011) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2010.03830.x · Cited by 352 · see citing works
Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics
Bourganis, V., Kammona, O., Alexopoulos, A., & Kiparissides, C. (2018) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2018.05.009 · Cited by 357 · see citing works
Intranasal Treatment of Central Nervous System Dysfunction in Humans
Chapman, C. D., Frey, W. H., Craft, S., Danielyan, L., Hallschmid, M., Schiöth, H. B., & Benedict, C. (2013) · Pharmaceutical Research · doi:10.1007/s11095-012-0915-1 · Cited by 310 · see citing works
Self-citationSurface-Modified Nanocarriers for Nose-To-Brain Delivery: From Bioadhesion to Targeting
Sonvico, F., Clementino, A. R., Buttini, F., Colombo, G., Pescina, S., Stanisçuaski Guterres, S., Raffin Pohlmann, A., & Nicoli, S. (2018) · doi:10.20944/preprints201802.0077.v1 · Cited by 306 · see citing works
Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart
Benedict, C., Hallschmid, M., Schmitz, K., Schultes, B., Ratter, F., Fehm, H. L., Born, J., & Kern, W. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301193 · Cited by 302 · see citing works
Benedict, C., Kern, W., Schultes, B., Born, J., & Hallschmid, M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2606 · Cited by 296 · see citing works
Nanoemulsions for “Nose-to-Brain” Drug Delivery
Bonferoni, M. C., Rossi, S., Sandri, G., Ferrari, F., Gavini, E., Rassu, G., & Giunchedi, P. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11020084 · Cited by 269 · see citing works
Butovsky, O. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26836 · Cited by 261 · see citing works
Lee, M. R., Scheidweiler, K. B., Diao, X. X., Akhlaghi, F., Cummins, A., Huestis, M. A., Leggio, L., & Averbeck, B. B. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.27 · Cited by 235 · see citing works
Marks, D. R., Tucker, K., Cavallin, M. A., Mast, T. G., & Fadool, D. A. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1350-09.2009 · Cited by 242 · see citing works
Current Strategies to Enhance Delivery of Drugs across the Blood–Brain Barrier
Teleanu, R. I., Preda, M. D., Niculescu, A.-G., Vladâcenco, O., Radu, C. I., Grumezescu, A. M., & Teleanu, D. M. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14050987 · Cited by 200 · see citing works
Evidence of nose-to-brain delivery of nanoemulsions: Cargoes but not vehicles
Ahmad, E., Feng, Y., Qi, J., Fan, W., Ma, Y., He, H., Xia, F., Dong, X., Zhao, W., Lu, Y., et al. (2017) · Nanoscale · doi:10.1039/c6nr07581a · Cited by 194 · see citing works
CSF and blood oxytocin concentration changes following intranasal delivery in macaque
Dal Monte, O., Noble, P. L., Turchi, J., Cummins, A., & Averbeck, B. B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103677 · Cited by 177 · see citing works
MacDonald, K., & Feifel, D. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00035 · Cited by 181 · see citing works
Zhang, H., Hao, Y., Manor, B., Novak, P., Milberg, W., Zhang, J., Fang, J., & Novak, V. (2015) · Diabetes · doi:10.2337/db14-1000 · Cited by 176 · see citing works
Intranasal administration of oxytocin: behavioral and clinical effects, a review
Veening, J. G., & Olivier, B. (2013) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.04.012 · Cited by 169 · see citing works
Oxytocin enhances observational fear in mice
Pisansky, M. T., Hanson, L. R., Gottesman, I. I., & Gewirtz, J. C. (2017) · Nature Communications · doi:10.1038/s41467-017-02279-5 · Cited by 167 · see citing works
Kanazawa, T., Taki, H., Tanaka, K., Takashima, Y., & Okada, H. (2011) · Pharmaceutical Research · doi:10.1007/s11095-011-0440-7 · Cited by 166 · see citing works
Obese men respond to cognitive but not to catabolic brain insulin signaling
Hallschmid, M., Benedict, C., Schultes, B., Born, J., & Kern, W. (2008) · International Journal of Obesity · doi:10.1038/sj.ijo.0803722 · Cited by 165 · see citing works
Effect of Intranasal Insulin on Cognitive Function: A Systematic Review
Shemesh, E., Rudich, A., Harman-Boehm, I., & Cukierman-Yaffe, T. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1802 · Cited by 162 · see citing works
Quintana, D. S., Alvares, G. A., Hickie, I. B., & Guastella, A. J. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.12.011 · Cited by 149 · see citing works
Chen, J.-H., Ke, K.-F., Lu, J.-H., Qiu, Y.-H., & Peng, Y.-P. (2015) · PLOS ONE · doi:10.1371/journal.pone.0116549 · Cited by 151 · see citing works
Distribution of insulin in trigeminal nerve and brain after intranasal administration
Lochhead, J. J., Kellohen, K. L., Ronaldson, P. T., & Davis, T. P. (2019) · Scientific Reports · doi:10.1038/s41598-019-39191-5 · Cited by 146 · see citing works
Ott, V., Benedict, C., Schultes, B., Born, J., & Hallschmid, M. (2012) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01490.x · Cited by 139 · see citing works
Nose-To-Brain Delivery of PLGA-Diazepam Nanoparticles
Sharma, D., Sharma, R. K., Sharma, N., Gabrani, R., Sharma, S. K., Ali, J., & Dang, S. (2015) · AAPS PharmSciTech · doi:10.1208/s12249-015-0294-0 · Cited by 127 · see citing works
Intranasal delivery of insulin via the olfactory nerve pathway
Renner, D. B., Svitak, A. L., Gallus, N. J., Ericson, M. E., Frey, W. H., & Hanson, L. R. (2012) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.2012.01555.x · Cited by 116 · see citing works
Self-citationPathak, R., Prasad Dash, R., Misra, M., & Nivsarkar, M. (2014) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2014.02.002 · Cited by 113 · see citing works
Quintana, D. S., Guastella, A. J., Westlye, L. T., & Andreassen, O. A. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.166 · Cited by 107 · see citing works
Hallschmid, M. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12934 · Cited by 113 · see citing works
Quintana, D. S., Westlye, L. T., Alnæs, D., Rustan, Ø. G., Kaufmann, T., Smerud, K. T., Mahmoud, R. A., Djupesland, P. G., & Andreassen, O. A. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.04.010 · Cited by 102 · see citing works
Intranasal oxytocin effects on social cognition: A critique
Evans, S. L., Dal Monte, O., Noble, P., & Averbeck, B. B. (2014) · Brain Research · doi:10.1016/j.brainres.2013.11.008 · Cited by 97 · see citing works
Wu, H., Zhou, Y., Wang, Y., Tong, L., Wang, F., Song, S., Xu, L., Liu, B., Yan, H., & Sun, Z. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.717192 · Cited by 90 · see citing works
Ionescu, I. A., Dine, J., Yen, Y.-C., Buell, D. R., Herrmann, L., Holsboer, F., Eder, M., Landgraf, R., & Schmidt, U. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.317 · Cited by 87 · see citing works
Pusic, K. M., Pusic, A. D., Kemme, J., & Kraig, R. P. (2014) · Glia · doi:10.1002/glia.22672 · Cited by 85 · see citing works
A randomized dose-ranging study of neuropeptide Y in patients with posttraumatic stress disorder
Sayed, S., Van Dam, N. T., Horn, S. R., Kautz, M. M., Parides, M., Costi, S., Collins, K. A., Iacoviello, B., Iosifescu, D. V., Mathé, A. A., et al. (2018) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx109 · Cited by 79 · see citing works
Yadav, S., Gattacceca, F., Panicucci, R., & Amiji, M. M. (2015) · Molecular Pharmaceutics · doi:10.1021/mp5008376 · Cited by 76 · see citing works
Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review
Salahudeen, M. S., Wright, C. M., & Peterson, G. M. (2020) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098620937899 · Cited by 72 · see citing works
Nageeb El-Helaly, S., Abd Elbary, A., Kassem, M. A., & El-Nabarawi, M. A. (2017) · Drug Delivery · doi:10.1080/10717544.2017.1309476 · Cited by 69 · see citing works
Belur, L. R., Temme, A., Podetz-Pedersen, K. M., Riedl, M., Vulchanova, L., Robinson, N., Hanson, L. R., Kozarsky, K. F., Orchard, P. J., Frey, W. H., et al. (2017) · Human Gene Therapy · doi:10.1089/hum.2017.187 · Cited by 67 · see citing works
Self-citationIntranasal delivery of siRNA to the olfactory bulbs of mice via the olfactory nerve pathway
Renner, D. B., Frey, W. H., & Hanson, L. R. (2012) · Neuroscience Letters · doi:10.1016/j.neulet.2012.02.037 · Cited by 62 · see citing works
Self-citationFerreira, S. T. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12959 · Cited by 59 · see citing works
Ludwig, M., Tobin, V. A., Callahan, M. F., Papadaki, E., Becker, A., Engelmann, M., & Leng, G. (2013) · Journal of Neuroendocrinology · doi:10.1111/jne.12046 · Cited by 37 · see citing works
Yu, C., Meng, J., Chen, J., & Tang, X. (2009) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2009.03.006 · Cited by 28 · see citing works
Fitzgerald, G. S., Chuchta, T. G., & McNay, E. C. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14160 · Cited by 22 · see citing works
Improving Research Standards to Restore Trust in Intranasal Oxytocin
Carson, D. S., Yuan, H., & Labuschagne, I. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.08.031 · Cited by 15 · see citing works
- Authors
- Thorne, R. G., Pronk, G. J., Padmanabhan, V., & Frey, W. H.
- Affiliations
- Regions Hospital (US)
- Corresponding author
- Frey, W.H.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2004-01
- Volume
- 127
- Issue
- 2
- Pages
- 481-496
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2077756131
- Cited by
- 958
- References
- 106
- Citations by year
- 2026: 33 · 2025: 47 · 2024: 55 · 2023: 52 · 2022: 50 · 2021: 64 · 2020: 54 · 2019: 46 · 2018: 47 · 2017: 58 · 2016: 44 · 2015: 40 · 2014: 51 · 2013: 46 · 2012: 52
- FWCI
- 14.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- insulin-like growth factor I, intranasal drug delivery, olfactory pathway, trigeminal pathway, blood-brain barrier bypass, spinal cord, olfactory bulb, anterior olfactory nucleus, deep cervical lymph nodes, cerebrospinal fluid, IGF-1 signaling, neurotrophic factor delivery
- MeSH terms
- Administration, Intranasal, Animals, Blood-Brain Barrier, Brain, Cerebrospinal Fluid, Dose-Response Relationship, Drug, Insulin-Like Growth Factor I, Iodine Radioisotopes, Lymph Nodes, Male, Olfactory Nerve, Olfactory Pathways, Reaction Time, Spinal Cord, Trigeminal Nerve, Signal Transduction, Rats, Sprague-Dawley, Rats
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