Intranasal therapeutic strategies for management of Alzheimer's disease

Journal of Drug Targeting

Volumn 22, Issue 4, 2014, Pages 279-294

  Sood, Sumeet ^a   Jain, Kunal ^a   Gowthamarajan, K ^a  

^a JSS COLLEGE OF PHARMACY   (India)

Author keywords

Alzheimer's disease; Dementia; Intranasal; Nanoparticles; Neuroprotective

Indexed keywords

AMYLOID; ARECOLINE; BRAIN DERIVED NEUROTROPHIC FACTOR; CHITOSAN; CHOLINESTERASE INHIBITOR; CILIARY NEUROTROPHIC FACTOR; CURCUMIN; DEFEROXAMINE; DONEPEZIL; FIBROBLAST GROWTH FACTOR 2; GALANTAMINE; GROWTH FACTOR; HUPERIZIN A; INSULIN; LIPOSOME; MEMANTINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NANOCARRIER; NANOPARTICLE; NERVE GROWTH FACTOR; NEUROPROTECTIVE AGENT; PHYSOSTIGMINE; QUERCETIN; QUILOSTIGMINE; RIVASTIGMINE; SESQUITERPENE; SOMATOMEDIN C; TACRINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VACCINE;

ALZHEIMER DISEASE; AREA UNDER THE CURVE; BLOOD BRAIN BARRIER; BRAIN; CENTRAL NERVOUS SYSTEM; CHOLINERGIC ACTIVITY; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG FORMULATION; DRUG RELEASE; DRUG SAFETY; DRUG TARGETING; DRUG TRANSPORT; DRUG WITHDRAWAL; GENETIC ANALYSIS; HUMAN; HYDROGEL; INTRACELLULAR TRANSPORT; LIVER TOXICITY; MAXIMUM PLASMA CONCENTRATION; MICROEMULSION; MUCOADHESION; MUCOCILIARY CLEARANCE; NANOEMULSION; NAUSEA AND VOMITING; NEUROPROTECTION; NEUROTRANSMISSION; NONHUMAN; NOSE; NOSE CAVITY; PRIORITY JOURNAL; REVIEW; TIME TO MAXIMUM PLASMA CONCENTRATION; TRANSCYTOSIS; VACCINATION; DRUG EFFECTS; INTRANASAL DRUG ADMINISTRATION; METABOLISM; OLFACTORY EPITHELIUM; RESPIRATORY TRACT MUCOSA; TISSUE DISTRIBUTION;

ADMINISTRATION, INTRANASAL; ALZHEIMER DISEASE; BRAIN; DRUG DELIVERY SYSTEMS; HUMANS; NASAL ABSORPTION; NEUROPROTECTIVE AGENTS; OLFACTORY MUCOSA; RESPIRATORY MUCOSA; TISSUE DISTRIBUTION;

EID: 84898494198     PISSN: 1061186X     EISSN: 10292330     Source Type: Journal    
DOI: 10.3109/1061186X.2013.876644     Document Type: Review

References (189)

1. Brambilla D, Le Droumaguet B, Nicolas J, et al. Nanotechnologies for Alzheimer's disease: diagnosis, therapy, and safety issues. Nanomedicine 2011;7:521-40.
2. Batsch NL, Mittelman MS. World Alzheimer Report 2012. Overcoming the stigma of dementia. Available from: http://www.alz.org/documents-custom/world- report-2012-final.pdf [last accessed 31 Dec 2013].
3. Cummings JL, Cole G. Alzheimer disease. JAMA 2002;287: 2335-8.
4. Cole SL, Vassar R. Linking vascular disorders and Alzheimer's disease: potential involvement of BACE1. Neurobiol Aging 2009; 30:1535-44.
5. Roney C, Kulkarni P, Arora V, et al. Targeted nanoparticles for drug delivery through the blood-brain barrier for Alzheimer's disease. J Control Release 2005;108:193-214.
6. Liu G, Garrett MR, Men P, et al. Nanoparticle and other metal chelation therapeutics in Alzheimer disease. Biochim Biophys Acta 2005;1741:246-52.
7. Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease. Int J Biochem Cell Biol 2003;35:1505-35.
8. Price DL, Sisodia SS. Mutant genes in familial Alzheimer's disease and transgenic models. Annu Rev Neurosci 1998;21:479-505.
9. Arango D, Cruts M, Torres O, et al. Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet 2001;103:138-43.
10. Olson JM, Goddard KA, Dudek DM. The amyloid precursor protein locus and very-late-onset alzheimer disease. Am J Hum Genet 2001;69:895-9.
11. Olson JM, Goddard KAB, Dudek DM. A second locus for very-late-onset alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. Am J Hum Genet 2002;71:154-61.
12. McIlroy SP, Vahidassr MD, Savage DA, et al. Risk of Alzheimer's disease is associated with a very low-density lipoprotein receptor genotype in Northern Ireland. Am J Med Genet 1999;88:140-4.
13. Sanan DA, Weisgraber KH, Russell SJ, et al. Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 1994;94:860-9.
14. Ray B, Lahiri DK. Neuroinflammation in Alzheimer's disease: different molecular targets and potential therapeutic agents including curcumin. Curr Opin Pharmacol 2009;9:434-44.
15. Sambamurti K, Greig NH, Lahiri DK. Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer's disease. Neuromol Med 2002;1:1-31.
16. Kojro E, Gimpl G, Lammich S, et al. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci USA 2001;98:5815-20.
17. Gabuzda D, Busciglio J, Yankner BA. Inhibition of beta-amyloid production by activation of protein kinase C. J Neurochem 1993;61: 2326-9.
18. Golde TE, Younkin SG. Presenilins as therapeutic targets for the treatment of Alzheimer's disease. Trends Mol Med 2001;7:264-9.
19. Dingwall C. Spotlight on BACE: the secretases as targets for treatment in Alzheimer disease. J Clin Inves 2001;108:1243-6.
20. Howlett DR, Simmons DL, Dingwall C, et al. In search of an enzyme: the beta-secretase of Alzheimer's disease is an aspartic proteinase. Trends Neurosci 2000;23:565-70.
21. Vassar R. The beta-secretase, BACE: a prime drug target for Alzheimer's disease. J Mol Neurosci 2001;17:157-70.
22. Maiorini AF, Gaunt MJ, Jacobsen TM, et al. Potential novel targets for Alzheimer pharmacotherapy: I. Secretases. J Clin Pharm Ther 2002;27:169-83.
23. Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 1996;2:864-70.
24. Duff K, Eckman C, Zehr C, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 1996;383: 710-13.
25. Citron M, Westaway D, Xia W, et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Med 1997;3:67-72.
26. Schraen-Maschke S, Dhaenens C-M, Delacourte A, et al. Microtubule-associated protein tau gene: a risk factor in human neurodegenerative diseases. Neurobiol Dis 2004;15:449-60.
27. Hernández F, Avila J. The role of glycogen synthase kinase 3 in the early stages of Alzheimers' disease. FEBS Lett 2008;582: 3848-54.
28. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-59.
29. Bowen DM, Smith CB, White P, et al. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 1976;99:459-96.
30. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 1976;2:1403.
31. Auld DS, Kornecook TJ, Bastianetto S, et al. Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies. Progress Neurobiol 2002;68:209-45.
32. Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978; 272:827-9.
33. Sara VR, Hall K, Von Holtz H, et al. Evidence for the presence of specific receptors for insulin-like growth factors 1 (IGE-1) and 2 (IGF-2) and insulin throughout the adult human brain. Neurosci Lett 1982;34:39-44.
34. Schiöth HB, Craft S, Brooks SJ, et al. Brain insulin signaling and Alzheimer's disease: current evidence and future directions. Mol Neurobiol 2012;46:4-10.
35. Agrawal R, Mishra B, Tyagi E, et al. Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat. Pharmacol Res 2010;61:247-52.
36. Banks WA, Kastin AJ, Pan W. Uptake and degradation of blood-borne insulin by the olfactory bulb. Peptides 1999;20:373-8.
37. Woods SC, Seeley RJ, Baskin DG, et al. Insulin and the blood-brain barrier. Curr Pharm Des 2003;9:795-800.
38. Mosconi L, Mistur R, Switalski R, et al. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease. Eur J Nucl Med Mol Imaging 2009; 36:811-22.
39. Zhao W-Q, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta 2009;1792:482-96.
40. Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulinlike growth factor expression and signaling mechanisms in Alzheimer's disease-is this type 3 diabetes? J Alzheimer Dis 2005;7:63-80.
41. Messier C, Teutenberg K. The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer's disease. Neural Plast 2005;12:311-29.
42. Vagelatos NT, Eslick GD. Type 2 diabetes as a risk factor for Alzheimers disease: the confounders, interactions and neuropath-ology associated with this relationship. Epidemiol Rev 2013;35:152-60.
43. Dominguez RO, Pagano MA, Marschoff ER, et al. Alzheimer disease and cognitive impairment associated with diabetes mellitus type 2: associations and a hypothesis. Neurologia. doi:10.1016/j.nrl.2013.05.006.
44. Mehla J, Chauhan BC, Chauhan NB. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits. J Alzheimers Dis 2013. doi: 10.3233/JAD-131238.
45. Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA 1994;271:992-8.
46. Farlow M. A clinical overview of cholinesterase inhibitors in Alzheimer's disease. Int Psychogeriatr 2002;14:93-126.
47. Costantino HR, Leonard AK, Brandt G, et al. Intranasal administration of acetylcholinesterase inhibitors. BMC Neuroscience 2008; 9:S6.
48. Walter K, Müller M, Barkworth MF, et al. Pharmacokinetics of physostigmine in man following a single application of a transdermal system. Br J Clin Pharmacol 1995;39:59-63.
49. Gore AV, Liang AC, Chien YW. Comparative biomembrane permeation of tacrine using Yucatan minipigs and domestic pigs as the animal model. J Pharm Sci 1998;87:441-7.
50. Bleich S, Römer K, Wiltfang J, et al. Glutamate and the glutamate receptor system: a target for drug action. Int J Geriatr Psychiatry 2003;18:S33-40.
51. Koch HJ, Szecsey A, Haen E. NMDA-antagonism (memantine): an alternative pharmacological therapeutic principle in Alzheimer's and vascular dementia. Curr Pharm Des 2004;10:253-9.
52. Gilgun-Sherki Y, Melamed E, Offen D. Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 2001;40:959-75.
53. Kim HG, Oh MS. Herbal medicines for the prevention and treatment of Alzheimer's disease. Curr Pharm Des 2012;18:57-75.
54. Li F, Gong Q, Dong H, et al. Resveratrol, a neuroprotective supplement for Alzheimer's disease. Curr Pharm Des 2012;18: 27-33.
55. Magrone T, Marzulli G, Jirillo E. Immunopathogenesis of neurodegenerative diseases: current therapeutic models of neuro-protection with special reference to natural products. Curr Pharm Des 2012;18:34-42.
56. Barnham KJ, Bush AI. Metals in Alzheimer's and Parkinson's diseases. Curr Opin Chem Biol 2008;12:222-8.
57. Liu G, Men P, Kudo W, et al. Nanoparticle-chelator conjugates as inhibitors of amyloid-beta aggregation and neurotoxicity: a novel therapeutic approach for Alzheimer disease. Neurosci Lett 2009; 455:187-90.
58. Fawcett JR, Bordayo EZ, Jackson K, et al. Inactivation of the human brain muscarinic acetylcholine receptor by oxidative damage catalyzed by a low molecular weight endogenous inhibitor from Alzheimer's brain is prevented by pyrophosphate analogs, bioflavonoids and other antioxidants. Brain Res 2002; 950:10-20.
59. Atamna H, Frey WH, Ko N. Human and rodent amyloid-b peptides differentially bind heme: relevance to the human susceptibility to Alzheimers disease. Arch Biochem Biophys 2009;487:59-65.
60. Atamna H, Boyle K. Amyloid-b peptide binds with heme to form a peroxidase: relationship to the cytopathologies of Alzheimers disease. Proc Natl Acad Sci USA 2006;103:3381-6.
61. Atamna H, Frey II WH. A role of heme in Alzheimer's disease: heme binds amyloid b and has altered metabolism. Proc Natl Acad Sci USA 2004;101:11153-8.
62. Salloway S, Mintzer J, Weiner MF, et al. Disease-modifying therapies in Alzheimer's disease. Alzheimers Dement 2008;4: 65-79.
63. Sahni JK, Doggui S, Ali J, et al. Neurotherapeutic applications of nanoparticles in Alzheimers disease. J Control Release 2011;152: 208-31.
64. Pardridge WM. Targeting neurotherapeutic agents through the blood-brain barrier. Arch Neurol 2002;59:35-40.
65. Scherrmann J. Drug delivery to brain via the blood-brain barrier. Vasc Pharmacol 2002;38:349-54.
66. Jefferies WA, Brandon MR, Hunt SV, et al. Transferrin receptor on endothelium of brain capillaries. Nature 1984;312:162-3.
67. Dick AP, Harik SI, Klip A, et al. Identification and characterization of the glucose transporter of the blood-brain barrier by cytochalasin B binding and immunological reactivity. Proc Natl Acad Sci USA 1984;81:7233-7.
68. Miller DS. Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci 2010; 31:246-54.
69. Davis SS. Biomedical applications of nanotechnology-implications for drug targeting and gene therapy. Trends Biotechnol 1997; 15:217-24.
70. Illum L. Nasal drug delivery-possibilities, problems and solutions. J Control Release 2003;87:187-98.
71. Frey W, Liu J, Chen X. Delivery of 125I-NGF to the brain via the olfactory route. Drug Deliv 1997;4:87-92.
72. Reger MA, Watson GS, Frey WH, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 2006;27:451-8.
73. Deadwyler SA, Porrino L, Siegel JM, et al. Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 2007;27:14239-47.
74. Thorne RG, Hanson LR, Ross TM, et al. Delivery of interferon-beta to the monkey nervous system following intranasal administration. Neuroscience 2008;152:785-97.
75. Khan S, Patil K, Bobade N, et al. Formulation of intranasal mucoadhesive temperature-mediated in situ gel containing ropinirole and evaluation of brain targeting efficiency in rats. J Drug Target 2010;18:223-34.
76. Patel S, Chavhan S, Soni H, et al. Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route. J Drug Target 2011;19:468-74.
77. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 2000;11:1-18.
78. Florence AT. The oral absorption of micro-and nanoparticulates: neither exceptional nor unusual. Pharm Res 1997;14:259-66.
79. Lockman PR, Mumper RJ, Khan MA, et al. Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm 2002;28:1-13.
80. Ugwoke MI, Verbeke N, Kinget R. The biopharmaceutical aspects of nasal mucoadhesive drug delivery. J Pharm Pharmacol 2001;53: 3-21.
81. Kumar M, Misra A, Babbar K, et al. Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm 2008;358:285-91.
82. Kumar M, Misra A, Mishra AK, et al. Mucoadhesive nanoemul-sion-based intranasal drug delivery system of olanzapine for brain targeting. J Drug Target 2008;16:806-14.
83. Sood S, Jain K, Gowthamarajan K. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment. Colloids Surf B 2014;113:330-7.
84. El-Hameed MDA, Kellaway IW. Preparation and in vitro characterisation of mucoadhesive polymeric microspheres as intra-nasal delivery systems. Eur J Pharm Biopharm 1997;44:53-60.
85. Dalpiaz A, Scatturin A, Pavan B, et al. Poly(lactic acid) microspheres for the sustained release of antiischemic agents. Int J Pharm 2002;242:115-20.
86. Leo E, Contado C, Bortolotti F, et al. Nanoparticle formulation may affect the stabilization of an antiischemic prodrug. Int J Pharm 2006;307:103-13.
87. Jiang L, Gao L, Wang X, et al. The application of mucoadhesive polymers in nasal drug delivery. Drug Dev Ind Pharm 2010;36: 323-36.
88. Salamat-Miller N, Chittchang M, Johnston TP. The use of mucoadhesive polymers in buccal drug delivery. Adv Drug Deliv Rev 2005;57:1666-91.
89. Ahuja A, Khar RK, Ali J. Mucoadhesive drug delivery systems. Drug Dev Ind Pharm 1997;23:489-515.
90. Ugwoke MI, Agu RU, Verbeke N, et al. Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives. Adv Drug Deliv Rev 2005;57:1640-65.
91. Dhuria SV, Hanson LR, Frey II WH. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 2010;99:1654-73.
92. Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012;64:614-28.
93. Kristensson K, Olsson Y. Uptake of exogenous proteins in mouse olfactory cells. Acta Neuropathol 1971;19:145-54.
94. Hayashi M, Hirasawa T, Muraoka T, et al. Comparison of water influx and sieving coefficient in rat jejunal, rectal and nasal absorptions of antipyrine. Chem Pharm Bull 1985;33: 2149-52.
95. McMartin C, Hutchinson LE, Hyde R, et al. Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity. J Pharm Sci 1987;76:535-40.
96. Dalpiaz A, Contado C, Vighi E, et al. Preparation and characterization of particulate drug delivery systems for brain targeting. In: Ravikumar MNV, ed. Handbook of particulate drug delivery. California: American Scientific Publishers; 2008:95-119.
97. Chou K-J, Donovan MD. Lidocaine distribution into the CNS following nasal and arterial delivery: a comparison of local sampling and microdialysis techniques. Int J Pharm 1998;171: 53-61.
98. Sakane T, Akizuki M, Yamashita S, et al. The transport of a drug to the cerebrospinal fluid directly from the nasal cavity: the relation to the lipophilicity of the drug. Chem Pharm Bull 1991; 39:2456-8.
99. Sakane T, Akizuki M, Taki Y, et al. Direct drug transport from the rat nasal cavity to the cerebrospinal fluid: the relation to the molecular weight of drugs. J Pharm Pharmacol 1995;47:379-81.
100. Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm 2009;379:146-57.
101. Rothen-Rutishauser BM, Schürch S, Haenni B, et al. Interaction of fine particles and nanoparticles with red blood cells visualized with advanced microscopic techniques. Environ Sci Technol 2006; 40:4353-9.
102. Rejman J, Oberle V, Zuhorn IS, et al. Size-dependent internalization of particles via the pathways of clathrin-and caveolae-mediated endocytosis. Biochem J 2004;377:159-69.
103. Harush-Frenkel O, Rozentur E, Benita S, et al. Surface charge of nanoparticles determines their endocytic and transcytotic pathway in polarized MDCK cells. Biomacromolecules 2008;9:435-43.
104. Jones AT. Gateways and tools for drug delivery: endocytic pathways and the cellular dynamics of cell penetrating peptides. Int J Pharm 2008;354:34-8.
105. Aspden TJ, Mason JD, Jones NS, et al. Chitosan as a nasal delivery system: the effect of chitosan solutions on in vitro and in vivo mucociliary transport rates in human turbinates and volunteers. J Pharm Sci 1997;86:509-13.
106. Haffejee N, Du Plessis J, Müller DG, et al. Intranasal toxicity of selected absorption enhancers. Pharmazie 2001;56:882-8.
107. Callens C, Adriaens E, Dierckens K, et al. Toxicological evaluation of a bioadhesive nasal powder containing a starch and Carbopol 974 P on rabbit nasal mucosa and slug mucosa. J Control Release 2001;76:81-91.
108. Ingels KJ, Kortmann MJ, Nijziel MR, et al. Factors influencing ciliary beat measurements. Rhinology 1991;29:17-26.
109. Rusznak C, Devalia JL, Lozewicz S, et al. The assessment of nasal mucociliary clearance and the effect of drugs. Respir Med 1994; 88:89-101.
110. Romeo V, deMeireles J, Sileno A, et al. Effects of physicochem-ical properties and other factors on systemic nasal drug delivery. Adv Drug Deliv Rev 1998;29:89-116.
111. Pires A, Fortuna A, Alves G, et al. Intranasal drug delivery: how, why and what for? J Pharm Pharmaceut Sci 2009;12:288-311.
112. Frey WH, II. Method of administering neurologic agents to the brain. US Patent 5, 624, 898 filed 1989 and issued April 29, 1997.
113. Frey WH, II. Method for administering insulin to the brain. US Patent 6, 313, 093B1 filed 1999 and issued November 6, 2001.
114. Alcalá-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.
115. Benedict C, Frey WH, Schiöth HB, et al. Intranasal insulin as a therapeutic option in the treatment of cognitive impairments. Exp Gerontol 2011;46:112-15.
116. Hanson LR, Fine JM, Renner DB, et al. Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice. Drug Deliv Transl Res 2012;2:160-8.
117. Renner DB, Frey WH, Hanson LR. Intranasal delivery of siRNA to the olfactory bulbs of mice via the olfactory nerve pathway. Neurosci Lett 2012;513:193-7.
118. Freiherr J, Hallschmid M, Frey WH, et al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs 2013;27:505-14.
119. Zhao Y, Yue P, Tao T, et al. Drug brain distribution following intranasal administration of Huperzine A in situ gel in rats. Acta Pharmacol Sin 2007;28:273-8.
120. Illum L. Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems? J Pharm Sci 2007;96: 473-83.
121. Jogani VV, Shah PJ, Mishra P, et al. Nose-to-brain delivery of tacrine. J Pharm Pharmacol 2007;59:1199-205.
122. Jogani VV, Shah PJ, Mishra P, et al. Intranasal mucoadhesive microemulsion of tacrine to improve brain targeting. Alzheimer Dis Assoc Disord 2008;22:116-24.
123. Luppi B, Bigucci F, Corace G, et al. Albumin nanoparticles carrying cyclodextrins for nasal delivery of the anti-Alzheimer drug tacrine. Eur J Pharm Sci 2011;44:559-65.
124. Sramek JJ, Frackiewicz EJ, Cutler NR. Review of the acetyl-cholinesterase inhibitor galanthamine. Expert Opin Investig Drugs 2000;9:2393-402.
125. Leonard AK, Sileno AP, MacEvilly C, et al. Development of a novel high-concentration galantamine formulation suitable for intranasal delivery. J Pharm Sci 2005;94:1736-46.
126. Leonard AK, Sileno AP, Brandt GC, et al. In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo. Int J Pharm 2007;335:138-46.
127. Arumugam K, Subramanian GS, Mallayasamy SR, et al. A study of rivastigmine liposomes for delivery into the brain through intranasal route. Acta Pharm 2008;58:287-97.
128. Yang Z, Zhang Y, Wu K, et al. Tissue distribution and pharmacodynamics of rivastigmine after intranasal and intravenous administration in rats. Curr Alzheimer Res 2012;9:315-25.
129. Fazil M, Md S, Haque S, et al. Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting. Eur J Pharm Sci 2012;47:6-15.
130. Hussain MA, Mollica JA. Intranasal absorption of physostigmine and arecoline. J Pharm Sci 1991;80:750-1.
131. Dahlin M, Bjo E. Nasal administration of a physostigmine analogue (NXX-066) for Alzheimer's disease to rats. Int J Pharm 2001;212:267-74.
132. Hussain MA, Rakestraw D, Rowe S, et al. Nasal administration of a cognition enhancer provides improved bioavailability but not enhanced brain delivery. J Pharm Sci 1990;79:771-2.
133. Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med 2001;30:433-46.
134. Bastianetto S, Quirion R. Natural extracts as possible protective agents of brain aging. Neurobiol Aging 2002;23:891-97.
135. Manach C, Scalbert A, Morand C, et al. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79:727-47.
136. Tong-Un T, Muchimapura S, Phachonpai W, et al. Nasal administration of quercetin liposomes modulate cognitive impairment and inhibit acetylcholinesterase activity in hippocampus. Am J Neurosci 2010;1:21-7.
137. Phachonpai W, Wattanathorn J, Muchimapura S, et al. Neuroprotective effect of quercetin encapsulated liposomes: a novel therapeutic strategy against Alzheimer's disease. Am J Appl Sci 2010;7:480-5.
138. Gowthamarajan K, Jawahar N, Wake P, et al. Development of buccal tablets for curcumin using Anacardium occidentale gum. Carbohydr Polym 2012;88:1177-83.
139. Hamaguchi T, Ono K, Yamada M. REVIEW: curcumin and Alzheimer's disease. CNS Neurosci Ther 2010;16:285-97.
140. Ono K, Hasegawa K, Naiki H, et al. Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. J Neurosci Res 2004;75:742-50.
141. Giri RK, Rajagopal V, Kalra VK. Curcumin, the active constituent of turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth response-1 transcription factor. J Neurochem 2004;91:1199-210.
142. Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005;280:5892-901.
143. Lim GP, Chu T, Yang F, et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001;21:8370-7.
144. Ma Q-L, Yang F, Rosario ER, et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 2009;29:9078-89.
145. Piper JT, Singhal SS, Salameh MS, et al. Mechanisms of anticarcinogenic properties of curcumin: the effect of curcumin on glutathione linked detoxification enzymes in rat liver. Int J Biochem Cell Biol 1998;30:445-56.
146. Jain K, Sood S, Gowthamarajan J. Modulation of cerebral malaria by curcumin as an adjunctive therapy. Braz J Infect Dis 2013;17: 579-91.
147. Anand P, Kunnumakkara AB, Newman RA, et al. Bioavailability of curcumin: problems and promises. Mol Pharm 2007;4:807-18.
148. Chen X, Zhi F, Jia X, et al. Enhanced brain targeting of curcumin by intranasal administration of a thermosensitive poloxamer hydrogel. J Pharm Pharmacol 2013;65:807-16.
149. Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiol Aging 1996;17:123-30.
150. Francis G, Martinez J, Liu W, et al. Intranasal insulin ameliorates experimental diabetic neuropathy. Diabetes 2009;58:934-45.
151. Hallschmid M, Schultes B, Marshall L, et al. Transcortical direct current potential shift reflects immediate signaling of systemic insulin to the human brain. Diabetes 2004;53:2202-8.
152. Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 2004; 29:1326-34.
153. Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Archive Neurol 2012;69:29-38.
154. Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimer Dis 2008;13:323-31.
155. Francis GJ, Martinez JA, Liu WQ, et al. Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy. Brain 2008;131:3311-34.
156. Jauch-Chara K, Friedrich A, Rezmer A, et al. Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans. Diabetes 2012;61:2261-8.
157. Crapper McLachlan DR, Dalton AJ, Kruck TP, et al. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 1991;337:1304-8.
158. Hanson LR, Roeytenberg A, Martinez AM, et al. Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. J Pharmacol Exp Ther 2009;330: 679-86.
159. Fine JM, Baillargeon AM, Renner DB, et al. Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1a, and phosphorylates GSK3b in P301L tau transgenic mice. Exp Brain Res 2012;219:381-90.
160. Guo C, Wang T, Zheng W, et al. Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease. Neurobiol Aging 2013;34:562-75.
161. Danielyan L, Klein R, Hanson LR, et al. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res 2010;13:195-201.
162. Kurakhmaeva KB, Djindjikhashvili IA, Petrov VE, et al. Brain targeting of nerve growth factor using poly(butyl cyanoacrylate) nanoparticles. J Drug Target 2009;17:564-74.
163. Levi-Montalcini R. The nerve growth factor 35 years later. Science 1987;237:1154-62.
164. Fischer W, Wictorin K, Björklund A, et al. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 1987;329:65-8.
165. Hefti F, Dravid A, Hartikka J. Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltrans-ferase activity in adult rats with partial septo-hippocampal lesions. Brain Res 1984;293:305-11.
166. Tuszynski MH, Sang H, Yoshida K, et al. Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brain. Ann Neurol 1991;30:625-36.
167. Ruberti F, Capsoni S, Comparini A, et al. Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J Neurosci 2000;20:2589-601.
168. Capsoni S, Ugolini G, Comparini A, et al. Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci USA 2000;97:6826-31.
169. Capsoni S, Giannotta S, Cattaneo A. Early events of Alzheimerlike neurodegeneration in anti-nerve growth factor transgenic mice. Brain Aging 2002;2:39-40.
170. Capsoni S, Giannotta S, Cattaneo A. Beta-amyloid plaques in a model for sporadic Alzheimer's disease based on transgenic anti-nerve growth factor antibodies. Mol Cell Neurosci 2002;21:15-28.
171. Eriksdotter Jönhagen M, Nordberg A, Amberla K, et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement Geriatr Cogn Disord 1998;9:246-57.
172. Tuszynski MH, Blesch A. Nerve growth factor: from animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer's disease. Prog Brain Res 2004;146:441-9.
173. Chen X-Q, Fawcett JR, Rahman Y-E, et al. Delivery of nerve growth factor to the brain via the olfactory pathway. J Alzheimer Dis 1998;1:35-44.
174. Capsoni S, Giannotta S, Cattaneo A. Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice. Proc Natl Acad Sci USA 2002;99: 12432-7.
175. Capsoni S, Marinelli S, Ceci M, et al. Intranasal "'painless"' human nerve growth factors slows amyloid neurodegeneration and prevents memory deficits in App X PS1 Mice. PLoS ONE 2012;7: 1-16.
176. Thorns V, Masliah E. Evidence for neuroprotective effects of acidic fibroblast growth factor in Alzheimer disease. J Neuropathol Exp Neurol 1999;58:296-306.
177. Reuss B, von Bohlen und Halbach O. Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res 2003;313:139-57.
178. 14-154 attenuates disease progression in mouse model of Alzheimer's disease. Neuroscience 2012;223:225-37.
179. Gozes I, Schächter P, Shani Y, et al. Vasoactive intestinal peptide gene expression from embryos to aging rats. Neuroendocrinology 1988;47:27-31.
180. Gozes I, Glowa J, Brenneman DE, et al. Learning and sexual deficiencies in transgenic mice carrying a chimeric vasoactive intestinal peptide gene. J Mol Neurosci 1993;4:185-93.
181. Glowa JR, Panlilio LV, Brenneman DE, et al. Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist. Brain Res 1992;570: 49-53.
182. Gozes I, Bardea A, Reshef A, et al. Neuroprotective strategy for Alzheimer disease: intranasal administration of a fatty neuropep-tide. Proc Natl Acad Sci USA 1996;93:427-32.
183. 25-35-treated rats following intranasal administration. Eur J Pharm Biopharm 2012;80:368-78.
184. Pappolla MA, Sos M, Omar RA, et al. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neurosci 1997;17:1683-90.
185. Pappolla M, Bozner P, Soto C, et al. Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem 1998;273:7185-8.
186. Jayachandra Babu R, Dayal PP, Pawar K, et al. Nose-to-brain transport of melatonin from polymer gel suspensions: a micro-dialysis study in rats. J Drug Target 2011;19:731-40.
187. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173-7.
188. Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:916-19.
189. Cattepoel S, Hanenberg M, Kulic L, et al. Chronic intranasal treatment with an anti-Ab(30-42) scFv antibody ameliorates amyloid pathology in a transgenic mouse model of Alzheimer's disease. PLoS ONE 2011;6:e18296.