Issues Related to Intranasal Delivery of Neuropeptides to Temporal Lobe Targets

  • Michael J. Kubek
  • Israel Ringel
  • Abraham J. Domb


The nasal cavity is the first line of defense from airborne pathogens yet it has been known since antiquity that the nose and its mucosal lining serves as a locus for drug delivery to the systemic circulation and brain. The intranasal application of tobacco snuff, cocaine, and various hallucinogens and psychotropic agents are well known examples (Doty, 1995). Intranasal delivery of peptides to blood is a more recent accomplishment (Pontiroli, 1998). Delivery of neuropeptides directly to specific CNS loci is just beginning to emerge and timely reviews on this approach have appeared. Advantages of this means of crossing the blood brain barrier include: ease of use, long-term compliance, uninterrupted delivery, ease of dosing and treatment schedules (Baker, 1995; Mathison et al.,1998; Agarwal and Mishra, 1999; Thome et al.,1995; Ilium, 2000). However, several transolfactory barriers exist. Solutes entering the nasal cavity are destined for three regions: 1) vestibular; 2) respiratory and 3) olfactory. The olfactory region is the most functionally important site for direct access to the brain. Three major barriers to neuropeptide bioavailability exist in this region: 1) presence of tight junctions between sensory and supporting cells, preventing epithelial transport to the submucous space; 2) a mucous layer containing protective proteolytic/hydrolytic enzymes that impart an enzymatic barrier to nasally administered drugs and peptides and; 3) mucous layer clearance that influences time-dependent neuropeptide absorptive (uptake) availability. Following olfactory neuronal uptake, neuropeptides are susceptible to further degradation as they are carried by axonal transport and following synapses of the olfactory tract to primary CNS targets; namely amygdala, hippocampus, piriform, and entorhinal cortices. Sufficient sustained neuropeptide release at these targets is necessary for a pharmacological effect. We reported previously that site-specific delivery of the neuropeptide Thyrotropin-releasing hormone fabricated as polyanhydride microdisks can attenuate kindled epileptogenesis indicating that it is likely carried to sites in the brain where it affects local excitability (Kubek et al.,1998). We suggest that intranasal application of surfaceeroding TRH-polyanhydride microstructures would enhance: 1) olfactory nerve uptake; 2) transneuronal transport and transfer; and 3) site-specific release of TRH in temporal lobe targets for the treatment of certain neurodegenerative disorders. In addition to its clinical importance, TRH is the smallest neuropeptide to date, and would serve as a prototype peptide in further understanding this delivery pathway.


Olfactory Bulb Temporal Lobe Epilepsy Entorhinal Cortex Olfactory Epithelium Piriform Cortex 
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  1. Agarwal, V., and Mishra, B. 1999, Recent trends in drug delivery systems: intranasal drug delivery. Indian J. Exp. Biol. 37: 6–16.PubMedGoogle Scholar
  2. Baker, H. 1995, Transport Phenomena within the Olfactory System. In R. Doty (Ed.), Handbook of Olfaction and Gustation. Marcel Dekker, New York, pp. 173–190.Google Scholar
  3. Borkenstein, M.H. 1983, The effects of intranasally sprayed synthetic TRH on TSH and on PRL secretion in children. European J. Ped. 140: 17–18.CrossRefGoogle Scholar
  4. Brannon-Peppas, L. 1997, Polymers in controlled drug delivery. Medical Plastics and Biomaterials 97: 1–16.Google Scholar
  5. Brown, R.E. 1985, The rodents I: effects of odours on reproductive physiology (primer effects). In R.E. Brown and D.W. MacDonald (Eds.). Social odours in mammals. Clarendon Press, Oxford pp. 245–344.Google Scholar
  6. Calza, L., Giardino, L., Ceccatelli, S., Zanni, M., Elde, R., and Hokfelt, T. 1992, Distribution of Thyrotropin-Releasing Hormone Receptor Messenger RNA in the Rat Brain: An In Situ Hybridization Study. Neuroscience 51: 891–909.PubMedCrossRefGoogle Scholar
  7. Cao, J., O’Donnell, D., Vu, H., Payza, K., Pou, C., Godbout, C., Jakob, A., Pelletier, M., Lembo, P., Ahmad, S., and Walker, P. 1998, Cloning and characterization of a cDNA encoding a novel subtype of rat thyrotropin-releasing hormone receptor. J. Biol. Chem. 273: 32281–32287.PubMedCrossRefGoogle Scholar
  8. Chen, X., Fawcett, J.R., Rahman, Y.E., Ala, T.A., and Frey II, W.H. 1998, Delivery of nerve growth factor to the brain via the olfactory pathway. J. Alzheimer’s Disease 1: 35–44.Google Scholar
  9. Chepournova, N.E., Kossova, G.V., Abbasova, K., Prahlad Chandra Kumar, C., Chepournov, S.A., and Ashmarin, I.P. 1994, Thyrotropin-Releasing hormone (TRH) in ultra low doses decreases severity of seizures in rats. Neuropeptides 26: 52(abstract).CrossRefGoogle Scholar
  10. Cross, R., and Scholey, J. 1999, Kinesin: the tail unfolds. Nat. Cell Biol., 1, E119–121.PubMedCrossRefGoogle Scholar
  11. Distal, H., Ayabe-Kanamura, S., Martinez-Gomez, M., Schicker, I., Kobayakawa, T., Saito, S., and Hudson, R. 1999, Perception of everyday odors—Correlation between intensity, familiarity and strength of hedonic judgement. Chem. Senses 24: 191–199.CrossRefGoogle Scholar
  12. Domb, A.J. 1994, Implantable Biodegradable Polymers for Site-Specific Drug Delivery. In A.J. Domb (Ed.), Polymeric Site-Specific Pharmacotherapy. John Wiley and Sons Ltd., England pp. 1–26.Google Scholar
  13. Domb, A.J., and Nudelman, R. 1995, In vivo and in vitro elimination of aliphatic polyanhydrides. Biomaterials 16: 319–323.PubMedCrossRefGoogle Scholar
  14. Doty, R.L. (1995). Introduction and Historical Perspective. In R. Doty (Ed.), Handbook of Olfaction and Gustation. Marcel Dekker, New York, pp. 1–32.Google Scholar
  15. Duntas, L., Keck, F.S., Loos, U., and Pfeiffer, E.F. 1988, Pharmacokinetics and pharmacodynamics of protirelin (TRH) in man. Dtsch Med Wochenschr 113: 1354–1357.PubMedCrossRefGoogle Scholar
  16. Eymin, C., Champier, J., Duvernoy, H.M., Martin, D., Kopp, N., and Jordan, D. 1993, Distribution of thyrotropin-releasing hormone binding sites: autoradiographic study in infant and adult human hippocampal formation. Brain Res. 605: 139–146.PubMedCrossRefGoogle Scholar
  17. Faden, A.I., Fox, G., Fan, L., Knoblach, S., Araldi, G.L., and Kozikowski, A.P. 1999, Neuroprotective and cognitive enhancing effects of novel small peptides. Ann. N Y Acad. Sci., 890: 120–125.PubMedCrossRefGoogle Scholar
  18. Faden, A.I., Fox, G.B., Fan, L., Araldi, G.L., Qiao, L., Wang, S., and Kozikowski, A.P. 1999, Novel TRH analog improves motor and cognitive recovery after traumatic brain injury in rodents. Am. J Physiol. 277: (Pt 2), R1196–1204.PubMedGoogle Scholar
  19. Ferrari, E., Cucinotta, D., Albizatti, M.G., Bartorelli, L., Colombo, N., Ferretti, G., Galetti, G., Galliano, U., Grezzana, L.G., Pedone, V., Sard, G., Scali, G., Zamboni, M., Girardello, R., Poli, A., and Ambrosoli, L. 1998, Effectiveness and Safety of Posatirelin in the Treatment of Senile Dementia: A Multicenter, Double Blind, Placebo-Controlled Study. Arch. Gerontol. Geriatr. suppl. 6: 163–174.CrossRefGoogle Scholar
  20. Fisher, R.S. 1989, Animal models of the epilepsies. Brain Research Reviews 14: 245–278.PubMedCrossRefGoogle Scholar
  21. Frey II, W.H., Liu, J., Chen, X., Thome, R.G., Fawcett, J.R., Ala, T.A., and Rahman, Y.E. 1997, Delivery of 125I-NGF to the brain via the olfactory route. Drug Del. 4: 87–92.CrossRefGoogle Scholar
  22. Grafstein, B. 1971, Transneuronal transfer of radioactivity in the central nervous system. Science 172: 11–19.CrossRefGoogle Scholar
  23. Griffiths, E.C., Kelly, J.A., Ashcroft, A., Ward, D.J., and Robson, B. 1989, Part V. TRH metabolism. Comparative metabolism and conformation of TRH and its analogues. Ann. N Y Acad. Sci. 553: 217–231.PubMedCrossRefGoogle Scholar
  24. Hashimoto, T., Wada, T., Fukuda, N., and Nagaoka, A. 1993, Effect of thyrotropin-releasing hormone on pentobarbitone-induced sleep in rats: continuous treatment with a sustained release injectable formulation. J. Pharm. Pharmacol. 45: 94–97.PubMedCrossRefGoogle Scholar
  25. Heuer, H., Schafer, M.K.-H., and Bauer, K. 1998, The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme: The Third Element of the Thyrotropin-Releasing Hormone-Signaling System. Thyroid 8: 915–920.PubMedCrossRefGoogle Scholar
  26. Hussain, M.A., and Aungst, B.J. 1992, Nasal absorption of leucine enkephalin in rats and the effects of aminopeptidase inhibition, as determined from the percentage of the dose unabsorbed. Pharmaceutical Res. 9: 1362–1364.CrossRefGoogle Scholar
  27. Ilium, L. 2000, Transport of drugs from the nasal cavity to the central nervous system. Eur. J. Pharm. Sci. 11: 1–18.CrossRefGoogle Scholar
  28. Itadani, H., Nakamura, T., Itoh, J., Iwaasa, H., Kanatani, A., Borkowski, J., Ihara, M., and Ohta, M. 1998, Cloning and characterization of a new subtype of thyrotropin-releasing hormone receptors. Biochem. Biophys. Res. Comm. 250: 68–71.PubMedCrossRefGoogle Scholar
  29. Jaworska-Feil, L., Budziszewska, B., and Lason, W. 1995, The effects of repeated amphetamine administration on the thyrotropin-releasing hormone level: Its release and receptors in the rat brain. Neuropeptides 29: 171–176.PubMedCrossRefGoogle Scholar
  30. Jaworska-Feil, L., Turchan, J., Przewlocka, B., Budziszewska, B., Leskiewicz, M., and Lason, W. 1999, Effects of Pilocarpine-and kainate-induced seizures on thyrotropinreleasing hormone biosynthesis and receptors in the rat brain. J Neural. Transm. 106: 395–407.PubMedCrossRefGoogle Scholar
  31. Kagatani, S., Inaba, N., Fukui, M., and Sonobe, T. 1998, Nasal absorption kinetic behavior of azetirelin and its enhancement by acylcarnitines in rats. Pharm. Res. 15: 77–81.PubMedCrossRefGoogle Scholar
  32. Knoblach, S.M., and Kubek, M.J. 1994, Thyrotropin-releasing hormone release is enhanced in hippocampal slices after electroconvulsive shock. J. Neurochem. 62: 119–125.PubMedCrossRefGoogle Scholar
  33. Kratskin, I.L. (1995). Functional Anatomy, Central Connections, and Neurochemistry of the Mammalian Olfactory Bulb. In R. Doty (Ed.), Handbook of Olfaction and Gustation. Marcel Dekker, New York, pp. 103–126.Google Scholar
  34. Kristensson, K., and Olsson, Y. 1971, Uptake of exogenous proteins in mouse olfactory cells. Acta Neuropathol. 19: 145–154.PubMedCrossRefGoogle Scholar
  35. Kubek, M.J. (1986). Thyrotropin-releasing hormone: Localization of specific hypothalamic and extrahypothalamic sites of CNS modulation. In R.C.A. Frederickson, H. Hendrie, J.N. Hingtgen, and M.H. Aprison (Eds.), Neuroregulation of Autonomic, Endocrine and Immune Systems. Martinus-Nijhoff, Boston, pp. 265–301.CrossRefGoogle Scholar
  36. Kubek, M.J., Knoblach, S.M., Sharif, N.A., Burt, D.R., Buterbaugh, G.G., and Fuson, K.S. 1993, Thyrotropin-releasing hormone gene expression and receptors are differentially modified in limbic foci by seizures. Ann. Neurology 33: 70–76.CrossRefGoogle Scholar
  37. Kubek, M.J., Liang, D., Byrd, K.E., and Domb, A.J. 1998, Prolonged seizure suppression by a single implantable polymeric-TRH microdisk preparation. Brain Res. 809: 189–197.PubMedCrossRefGoogle Scholar
  38. Kubek, M.J., Low, W.C., Sattin, A., Morzorati, S.L., Meyerhoff, J.L., and Larsen, S.H. 1989, Role of TRH in Seizure Modulation. Ann. NY Acad. Sci. 553: 286–303.PubMedCrossRefGoogle Scholar
  39. Lanza, D.C., and Clerico, D.M. (1995). Anatomy of the Human Nasal Passages. In R. Doty (Ed.), Handbook of Olfaction and Gustation. Marcel Dekker, New York, pp. 53–73.Google Scholar
  40. Lewis, J., and Dahl, A.R. (1995). Olfactory Mucosa: Composition, Enzymatic Localization, and Metabolism. In R. Doty (Ed.), Handbook of Olfaction and Gustation.. Marcel Dekker, New York, pp. 33–52.Google Scholar
  41. Loscher, W. 1997, Animal models of intractable epilepsy. Prog Neurobiol. 53: 239–258.PubMedCrossRefGoogle Scholar
  42. Manaker, S., Eichen, A., Winokur, A., Rhodes, C.H., and Rainbow, T.C. 1986, Autoradiographic localization of thyrotropin releasing hormone receptors in human brain. Neurol. 36: 641–646.CrossRefGoogle Scholar
  43. Mantyh, P.W., and Hunt, S.P. 1985, Localization by light microscopic autoradiography in rat brain using (3H)(3-Me-His2)TRH as the radioligand. J. Neurosci. 5: 551–561.PubMedGoogle Scholar
  44. Marangell, L.B., George, M.S., Bissette, G., Pazzaglia, P., Huggins, T., and Post, R.M. 1994, Carbamazepine increases cerebrospinal fluid thyrotropin-releasing hormone levels in affectively ill patients. Arch. Gen. Psychiatry 51: 625–628.PubMedCrossRefGoogle Scholar
  45. Marangell, L.B., George, M.S., Callahan, A.M., Ketter, T.A., Pazzaglia, P.J., L’Herrou, T.A., Leverich, G.S., and Post, R.M. 1997, Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients. Arch. Gen. Psychiatry 54: 214–222.PubMedCrossRefGoogle Scholar
  46. Mathison, S., Nagilla, R., and Kompella, U.B. 1998, Nasal route for direct delivery of solutes to the central nervous system: fact or fiction? J. Drug Target. 5: 415–441.PubMedCrossRefGoogle Scholar
  47. Matsui, K., Itoh, K., Mizumachi, M., Kubo, H., Goto, T., Sato, S., and Wada, K. 1996, Effect of intranasal administration of thyrotropin-releasing hormone on ataxic gait in staggerer mice. Neurosci. Lett. 212: 115–118.PubMedCrossRefGoogle Scholar
  48. McNamara, J.O. 1994, Cellular and molecular basis of epilepsy. J. Neurosci. 74: 3417–3425.Google Scholar
  49. McNamara, J.O. (1996). Drugs effective in the therapy of the epilepsies. In J.G. Hardman, A. Goodman Gilman, and L.E. Limbird (Eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics. McGraw Hill, New York, pp. 461–486.Google Scholar
  50. McNamara, J.O., Bonhaus, D.W., and Shin, C. (1993). The kindling model of epilepsy. In P.A. Schwartzkroin (Ed.), Epilepsy: Models, Mechanisms, and Concepts. Cambridge University Press, Cambridge, pp. 27–47.CrossRefGoogle Scholar
  51. Middleton, J.C., and Tipton, A.J. 1998. Synthetic biodegradable polymers as medical devices. Medical Plastics and Biomaterials 98: 1–17.Google Scholar
  52. Mitsuma, T., and Nogimori, T. 1984, Changes in plasma thyrotrophin-releasing hormone, thyrotrophin, prolactin and thyroid hormone levels after intravenous, intranasal or rectal administration of synthetic thyrotrophin-releasing hormone in man. Acta. Endocrinol. (Copenh), 107: 207–212.Google Scholar
  53. Mori, N., and Fukatsu, T. 1992, Anticonvulsant effect of DN-1417, a derivative of Thyrotropin-Releasing hormone, and liposome-entrapped DN-1417, on amygdaloidkindled rats. Epilepsia 33: 994–1000.PubMedCrossRefGoogle Scholar
  54. Morrison, E.E., and Moran, D.T. (1995). Anatomy and Ultrastructure of the Human Olfactory Neuroepithelium. In R. Doty (Ed.), Handbook of Olfaction and Gustation. Marcel Dekker,6New York, pp. 75–101.Google Scholar
  55. Nilini, E.A., and Sevarino, K.A. 1999, The biology of pro-Thyrotropin-Releasing Hormone-derived peptides. Endocrine Reviews 20: 599–648.CrossRefGoogle Scholar
  56. O’Cuinn, G., O’Connor, B., and Elmore, M. 1990, Degradation of thyrotropin-releasing hormone and luteinising hormone-releasing hormone by enzymes of brain tissue. J. Neurochem. 54: 1–13.PubMedCrossRefGoogle Scholar
  57. O’Dowd, B.F., Lee, D.K., Huang, W., Nguyen, T., Cheng, R., Liu, Y., Wang, B., Gershengorn, M.C., and George, S.R. 2000, TRH-R2 exhibits similar binding and acute signaling but distinct regulation and anatomic distribution compared with TRH-R1. Mol. Endocrinol. 14: 183–193.PubMedCrossRefGoogle Scholar
  58. Ochs, S., and Brimijoin, W.S. (1993). Axonal transport. In P.J. Dyck, P.K. Thomas, J.W. Griffin, P.A. Low, and J.F. Poduslo (Eds.), Peripheral Neuropathy. Saunders, Philidelphia, pp. 331–360.Google Scholar
  59. Okamoto, M., Sato, M., Moriwake, T., Morimoto, K., Ogawa, T., Morita, K., Nakatsu, T., and Ogawa, N. 1985, The prophylactic and anticonvulsant effects of a TRH analog (DN-1417) on amygdaloid kindling model of epilepsy. Folia Psychiatrica Neurologica Japonica 39: 313–316.Google Scholar
  60. Perras, B., Marshall, L., Kohler, G., Born, J., and Fehm, H.L. 1999, Sleep and endocrine changes after intranasal administration of growth hormone-releasing hormone in young and aged humans. Psychoneuroendocrinology 24: 743–757.PubMedCrossRefGoogle Scholar
  61. Peters, F., Schulze-Tollert, J., and Schuth, W. 1991, Thyrotrophin-releasing hormone—a lactation-promoting agent? Br J Obstet Gynaecol 98, 880–88PubMedCrossRefGoogle Scholar
  62. Pontiroli, A.E. 1998, Peptide hormones: Review of current and emerging uses by nasal delivery. Adv Drug Deliv. Rev. 29: 81–87.PubMedCrossRefGoogle Scholar
  63. Racine, R. 1978, Kindling: The First Decade. Neurosurg. 3: 234–252.CrossRefGoogle Scholar
  64. Racine, R.J. 1972, Modification of seizure activity by electrical stimulation: II. Motor seizure. Electroencephalography Clin. Neurophysiol. 32: 281–294.CrossRefGoogle Scholar
  65. Racine, R.J., Ivy, G.O., and Milgram, N.W. 1989, Kindling: clinical relevance and anatomical substrate. In T.G. Bolwig and M.R. Trimble (Eds.), The Clinical Relevance of Kindling, (pp. 15–34). New York: John Wiley and Sons.Google Scholar
  66. Renming, X., Ishihara, K., Sasa, M., Ujihara, H., Momiyama, T., Fujita, Y., Todo, N., Serikawa, T., Yamada, J., and Takaori, S. 1992, Antiepileptic effect of CNK-602A, a novel thyrotropin-releasing hormone analog, on absence-like and tonic seizures of spontaneously epileptic rats. European J. Pharm. 223: 185–192.CrossRefGoogle Scholar
  67. Rosen, J.B., Weiss, S.R.B., and Post, R.M. 1994, Contingent tolerance to carbamazepine: alterations in TRH mRNA and TRH receptor binding in limbic structures. Brain Res. 651: 252–260.PubMedCrossRefGoogle Scholar
  68. Sakai, S., Baba, H., Sato, M., and Wada, J.A. 1991, Effect of DN-1417 on Photosensitivity and Cortically Kindled Seizure in Senegalese Baboons, Papio papio. Epilepsia 32: 16–21.PubMedCrossRefGoogle Scholar
  69. Sarkar, M.A. 1992, Drug metabolism in the nasal mucosa. Pharm. Res. 9: 1–9.PubMedCrossRefGoogle Scholar
  70. Sato, M., and Morimoto, K. 1983, Anti-epileptic effects of TRH-T and DN-1417. Kurume Med. J. 30: 57–64.CrossRefGoogle Scholar
  71. Sato, M., Morimoto, K., and Wada, J.A. 1984, Antiepileptic effects of thyrotropin-releasing hormone and its new derivative, DN-1417, examined in feline amygdaloid kindling preparation. Epilepsia 25: 537–544.PubMedCrossRefGoogle Scholar
  72. Schipper, N.G., Verhoef, J.C., DeLannoy, L.M., Romeijn, S.G., Brakkee, J.H., Wiegant, V.M., Gispen, W.H., and Merkus, F.W. 1993, Nasal administration of an ACTH(4-9) peptide analogue with dimethyl-beta-cyclodextrin as an absorption enhancer: pharmacokinetics and dynamics. British Journal of Pharmacology, 110, 1335–1340.PubMedCrossRefGoogle Scholar
  73. Schurr, W., Knoll, B., Ziegler, R., Anders, R., and Merkle, H.P. 1985, Comparative study of intravenous, nasal, oral and buccal TRH administration among healthy subjects. J. Endocrinol. Inves. 8: 41–44.Google Scholar
  74. Sharif, N.A. 1989, Quantitative autoradiography of TRH receptors in discrete brain regions of different mammalian species. Ann. N Y Acad. Sci. 553: 147–175.PubMedCrossRefGoogle Scholar
  75. Shipley, M.T. 1985, 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. 15: 129–142.PubMedCrossRefGoogle Scholar
  76. Smolnik, R., Molle, M., Fehm, H.L., and Born, J. 1999, Brain potentials and attention after acute and subchronic intranasal administration of ACTH 4-10 and desacetyl-alpha-MSH in humans. Neuroendocrinol. 70: 63–72.CrossRefGoogle Scholar
  77. Staub, J.J., Ryff-Deleche, A.S., Paul, S., Girard, J., Polc, B., and von der Ohe, M. 1985, Intranasal thyrotrophin releasing hormone is a potent stimulus for TSH release in man (comparison with intravenous and oral TRH). Clin Endocrinol. (Oxf) 22: 567–572.CrossRefGoogle Scholar
  78. Szabolcs, I., Ploenes, C., Bernard, W., and Herrmann, J. 1989, Thyrotropin-releasing hormone in geriatric patients: intravenous versus intranasal application. Acta Endocrinol. (Copenh) 120: 149–154.Google Scholar
  79. Tabata, Y., Domb, A., and Langer, R. 1994, Injectable polyanhydride granules provide controlled release of water-soluble drugs with a reduced initial burst. J. Pharm. Sci. 83: 5–11.PubMedCrossRefGoogle Scholar
  80. Takeuchi, Y. 1996, Thyrotropin-releasing hormone (Protirelin): Role in the treatment of epilepsy. CNS Drugs 6: 341–350.CrossRefGoogle Scholar
  81. Thome, R.G., Emory, CR., Ala, T.A., and Frey, W.H., 2nd. 1995, Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res. 692: 278–282.CrossRefGoogle Scholar
  82. Ujihara, H., Renming, X., Sasa, M., Ishihara, K., Fujita, Y., Yoshimura, M., Kishimoto, T., Serikawa, T., Yamada, J., and Takaori, S. 1991, Inhibition by thyrotropin-releasing hormone of epileptic seizures in spontaneously epileptic rats. European J. Pharm. 196: 15–19.CrossRefGoogle Scholar
  83. Uribe, R.M., Joseph-Bravo, P., Ponce, G., Cisneros, M., Aceves, C., and Charli, J.L. 1994, Influence of thyroid status on TRH metabolism in rat olfactory bulb. Peptides 15: 435–439.PubMedCrossRefGoogle Scholar
  84. Wan, R.Q., Noguera, E.C., and Weiss, S.R. 1998, Anticonvulsant effects of intrahippocampal injection of TRH in amygdala kindled rats. Neuroreport 9: 677–682.PubMedCrossRefGoogle Scholar
  85. Yamashita, K., Mori, A., and Otsuki, S. 1990, Changes in brain thyrotropin-releasing hormone (TRH) of seizure-prone El mice. Exptl. Neurol. 108: 71–75.CrossRefGoogle Scholar
  86. Yatsugi, S., and Yamamoto, M. 1991, Anticonvulsive properties of YM-14673, a new TRH analogue, in amygdaloid-kindled rats. Pharmacol. Biochem. Behav. 38: 669–672.PubMedCrossRefGoogle Scholar
  87. Zarate, A., Villalobos, H., Canales, E.S., Soria, J., Arcovedo, F., and MacGregor, C. 1976, The effect of oral administration of thyrotropin-releasing hormone on lactation. J. Clin. Endocrinol. Metab. 43: 301–305.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Michael J. Kubek
    • 1
  • Israel Ringel
    • 2
  • Abraham J. Domb
    • 3
  1. 1.Departments of Anatomy and Cell Biology, and PsychiatryIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of PharmacologyThe Hebrew University of JerusalemJerusalemIsrael
  3. 3.Department of Pharmaceutical Chemistry and Natural Products School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael

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