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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Review Article

Nose-to-brain Delivery of Natural Compounds for the Treatment of Central Nervous System Disorders

Author(s): Joana Bicker, Ana Fortuna, Gilberto Alves and Amílcar Falcão*

Volume 26, Issue 5, 2020

Page: [594 - 619] Pages: 26

DOI: 10.2174/1381612826666200115101544

Price: $65

TIMBC 2025
Abstract

Background: Several natural compounds have demonstrated potential for the treatment of central nervous system disorders such as ischemic cerebrovascular disease, glioblastoma, neuropathic pain, neurodegenerative diseases, multiple sclerosis and migraine. This is due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. Nevertheless, many of these molecules have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations. Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration, by enabling a direct transport into the brain through the olfactory and trigeminal nerves. With this approach, the blood-brain barrier is circumvented and peripheral exposure is reduced, thereby minimizing possible adverse effects.

Objective: Herein, brain-targeting strategies for nose-to-brain delivery of natural compounds, including flavonoids, cannabinoids, essential oils and terpenes, will be reviewed and discussed. Brain and plasma pharmacokinetics of these molecules will be analyzed and related to their physicochemical characteristics and formulation properties.

Conclusion: Natural compounds constitute relevant alternatives for the treatment of brain diseases but often require loading into nanocarrier systems to reach the central nervous system in sufficient concentrations. Future challenges lie in a deeper characterization of their therapeutic mechanisms and in the development of effective, safe and brain-targeted delivery systems for their intranasal administration.

Keywords: Brain distribution, Central nervous system, intranasal, natural compounds, nose-to-brain, pharmacokinetics, phytochemicals.

« Previous
[1]
Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7(1): 41-53.
[http://dx.doi.org/10.1038/nrn1824] [PMID: 16371949 ]
[2]
Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis 2013; 36(3): 437-49.
[http://dx.doi.org/10.1007/s10545-013-9608-0] [PMID: 23609350 ]
[3]
Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG. The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Acta Neuropathol 2018; 135(3): 387-407.
[http://dx.doi.org/10.1007/s00401-018-1812-4] [PMID: 29428972 ]
[4]
Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis 2010; 37(1): 13-25.
[http://dx.doi.org/10.1016/j.nbd.2009.07.030] [PMID: 19664713 ]
[5]
Patel MM, Patel BM. Crossing the blood-brain barrier: recent advances in drug delivery to the brain. CNS Drugs 2017; 31(2): 109-33.
[http://dx.doi.org/10.1007/s40263-016-0405-9] [PMID: 28101766 ]
[6]
Bellavance MA, Blanchette M, Fortin D. Recent advances in blood-brain barrier disruption as a CNS delivery strategy. AAPS J 2008; 10(1): 166-77.
[http://dx.doi.org/10.1208/s12248-008-9018-7] [PMID: 18446517 ]
[7]
Hersh DS, Wadajkar AS, Roberts N, et al. Evolving drug delivery strategies to overcome the blood brain barrier. Curr Pharm Des 2016; 22(9): 1177-93.
[http://dx.doi.org/10.2174/1381612822666151221150733] [PMID: 26685681 ]
[8]
Wu SK, Chu PC, Chai WY, et al. Characterization of different microbubbles in assisting focused ultrasound-induced blood-brain barrier opening. Sci Rep 2017; 7: 46689.
[http://dx.doi.org/10.1038/srep46689] [PMID: 28425493 ]
[9]
Ha SW, Hwang K, Jin J, et al. Ultrasound-sensitizing nanoparticle complex for overcoming the blood-brain barrier: an effective drug delivery system. Int J Nanomedicine 2019; 14: 3743-52.
[http://dx.doi.org/10.2147/IJN.S193258] [PMID: 31213800 ]
[10]
Peng C, Sun T, Vykhodtseva N, et al. Intracranial nonthermal ablation mediated by transcranial focused ultrasound and phase-shift nanoemulsions. Ultrasound Med Biol 2019; 45(8): 2104-17.
[http://dx.doi.org/10.1016/j.ultrasmedbio.2019.04.010] [PMID: 31101446 ]
[11]
Moura RP, Martins C, Pinto S, Sousa F, Sarmento B. Blood-brain barrier receptors and transporters: an insight on their function and how to exploit them through nanotechnology. Expert Opin Drug Deliv 2019; 16(3): 271-85.
[http://dx.doi.org/10.1080/17425247.2019.1583205] [PMID: 30767695 ]
[12]
Shahjin F, Chand S, Yelamanchili SV. Extracellular vesicles as drug delivery vehicles to the central nervous system. J Neuroimmune Pharmacol 2019. In Press
[http://dx.doi.org/10.1007/s11481-019-09875-w] [PMID: 31485884 ]
[13]
Rufino-Ramos D, Albuquerque PR, Carmona V, Perfeito R, Nobre RJ, Pereira de Almeida L. Extracellular vesicles: novel promising delivery systems for therapy of brain diseases. J Control Release 2017; 262: 247-58.
[http://dx.doi.org/10.1016/j.jconrel.2017.07.001] [PMID: 28687495]
[14]
Pardridge WM. CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv 2016; 13(7): 963-75.
[http://dx.doi.org/10.1517/17425247.2016.1171315] [PMID: 27020469 ]
[15]
Hammarlund-Udenaes M, Fridén M, Syvänen S, Gupta A. On the rate and extent of drug delivery to the brain. Pharm Res 2008; 25(8): 1737-50.
[http://dx.doi.org/10.1007/s11095-007-9502-2] [PMID: 18058202 ]
[16]
Pizzo ME, Wolak DJ, Kumar NN, et al. Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery. J Physiol 2018; 596(3): 445-75.
[http://dx.doi.org/10.1113/JP275105] [PMID: 29023798 ]
[17]
Serralheiro A, Alves G, Sousa J, Fortuna A, Falcão A. Nose as a route for drug delivery. Nasal Physiol Pathophysiol Nasal Disord 2013; pp. 191-215.
[18]
Fan Y, Chen M, Zhang J, Maincent P, Xia X, Wu W. Updated progress of nanocarrier-based intranasal drug delivery systems for treatment of brain diseases. Crit Rev Ther Drug Carrier Syst 2018; 35(5): 433-67.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.2018024697] [PMID: 30317945]
[19]
Fortuna A, Alves G, Serralheiro A, Sousa J, Falcão A. Intranasal delivery of systemic-acting drugs: small-molecules and biomacromolecules. Eur J Pharm Biopharm 2014; 88(1): 8-27.
[http://dx.doi.org/10.1016/j.ejpb.2014.03.004] [PMID: 24681294 ]
[20]
Guo J, Duan JA, Shang EX, Tang Y, Qian D. Determination of ligustilide in rat brain after nasal administration of essential oil from Rhizoma Chuanxiong. Fitoterapia 2009; 80(3): 168-72.
[http://dx.doi.org/10.1016/j.fitote.2009.01.003] [PMID: 19535021 ]
[21]
Ahirrao M, Shrotriya S. In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting. Drug Dev Ind Pharm 2017; 43(10): 1686-93.
[http://dx.doi.org/10.1080/03639045.2017.1338721] [PMID: 28574732 ]
[22]
Rankovic Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J Med Chem 2015; 58(6): 2584-608.
[http://dx.doi.org/10.1021/jm501535r] [PMID: 25494650 ]
[23]
Di L, Rong H, Feng B. Demystifying brain penetration in central nervous system drug discovery. Miniperspective. J Med Chem 2013; 56(1): 2-12.
[http://dx.doi.org/10.1021/jm301297f] [PMID: 23075026 ]
[24]
Hitchcock SA, Pennington LD. Structure-brain exposure relationships. J Med Chem 2006; 49(26): 7559-83.
[http://dx.doi.org/10.1021/jm060642i] [PMID: 17181137 ]
[25]
van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky OA. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J Drug Target 1998; 6(2): 151-65.
[http://dx.doi.org/10.3109/10611869808997889] [PMID: 9886238 ]
[26]
Wager TT, Chandrasekaran RY, Hou X, et al. Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes. ACS Chem Neurosci 2010; 1(6): 420-34.
[http://dx.doi.org/10.1021/cn100007x] [PMID: 22778836 ]
[27]
Yao Y, Chen T, Huang J, Zhang H, Tian M. Effect of chinese herbal medicine on molecular imaging of neurological disorders Int Rev Neurobiol. 1st ed. Elsevier Inc 2017.
[28]
Sowndhararajan K, Deepa P, Kim M, Park SJ, Kim S. Neuroprotective and cognitive enhancement potentials of baicalin: a review. Brain Sci 2018; 8(6): 1-24.
[http://dx.doi.org/10.3390/brainsci8060104] [PMID: 29891783 ]
[29]
Li N, Je YJ, Yang M, Jiang XH, Ma JH. Pharmacokinetics of baicalin-phospholipid complex in rat plasma and brain tissues after intranasal and intravenous administration. Pharmazie 2011; 66(5): 374-7.
[PMID: 21699072 ]
[30]
Liu S, Ho PC. Intranasal administration of brain-targeted HP-β-CD/chitosan nanoparticles for delivery of scutellarin, a compound with protective effect in cerebral ischaemia. J Pharm Pharmacol 2017; 69(11): 1495-501.
[http://dx.doi.org/10.1111/jphp.12797] [PMID: 28809432 ]
[31]
Waring MJ. Defining optimum lipophilicity and molecular weight ranges for drug candidates-molecular weight dependent lower logD limits based on permeability. Bioorg Med Chem Lett 2009; 19(10): 2844-51.
[http://dx.doi.org/10.1016/j.bmcl.2009.03.109] [PMID: 19361989 ]
[32]
Sasaki K, Yonebayashi S, Yoshida M, Shimizu K, Aotsuka T, Takayama K. Improvement in the bioavailability of poorly absorbed glycyrrhizin via various non-vascular administration routes in rats. Int J Pharm 2003; 265(1-2): 95-102.
[http://dx.doi.org/10.1016/S0378-5173(03)00407-1] [PMID: 14522122 ]
[33]
Ahmad N, Al-Subaiec AM, Ahmad R, et al. Brain-targeted glycyrrhizic-acid-loaded surface decorated nanoparticles for treatment of cerebral ischaemia and its toxicity assessment. Artif Cells Nanomed Biotechnol 2019; 47(1): 475-90.
[http://dx.doi.org/10.1080/21691401.2018.1561458] [PMID: 30739499 ]
[34]
Bobade V, Bodhankar SL, Aswar U, Vishwaraman M, Thakurdesai P. Prophylactic effects of asiaticoside-based standardized extract of Centella asiatica (L.) Urban leaves on experimental migraine: involvement of 5HT1A/1B receptors. Chin J Nat Med 2015; 13(4): 274-82.
[http://dx.doi.org/10.1016/S1875-5364(15)30014-5] [PMID: 25908624 ]
[35]
Guo Q, Li P, Wang Z, et al. Brain distribution pharmacokinetics and integrated pharmacokinetics of panax notoginsenoside R1, Ginsenosides Rg1, Rb1, Re and Rd in rats after intranasal administration of panax notoginseng saponins assessed by UPLC/MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 969: 264-71.
[http://dx.doi.org/10.1016/j.jchromb.2014.08.034] [PMID: 25203723 ]
[36]
Pajouhesh H, Lenz GR. Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2005; 2(4): 541-53.
[http://dx.doi.org/10.1602/neurorx.2.4.541] [PMID: 16489364 ]
[37]
Rege SD, Geetha T, Griffin GD, Broderick TL, Babu JR. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci 2014; 6: 218.
[http://dx.doi.org/10.3389/fnagi.2014.00218] [PMID: 25309423 ]
[38]
Andrade S, Ramalho MJ, Pereira MDC, Loureiro JA. Resveratrol brain delivery for neurological disorders prevention and treatment. Front Pharmacol 2018; 9: 1261.
[http://dx.doi.org/10.3389/fphar.2018.01261] [PMID: 30524273 ]
[39]
Carlsson SK, Brothers SP, Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med 2014; 6(11): 1359-70.
[http://dx.doi.org/10.15252/emmm.201302627] [PMID: 25312641 ]
[40]
Basso J, Miranda A, Sousa J, Pais A, Vitorino C. Repurposing drugs for glioblastoma: From bench to bedside. Cancer Lett 2018; 428: 173-83.
[http://dx.doi.org/10.1016/j.canlet.2018.04.039] [PMID: 29729291 ]
[41]
Desai V, Bhushan A. Natural bioactive compounds: alternative approach to the treatment of glioblastoma multiforme. BioMed Res Int 2017; 20179363040
[http://dx.doi.org/10.1155/2017/9363040]
[42]
Erices JI, Torres Á, Niechi I, Bernales I, Quezada C. Current natural therapies in the treatment against glioblastoma. Phytother Res 2018; 32(11): 2191-201.
[http://dx.doi.org/10.1002/ptr.6170] [PMID: 30109743 ]
[43]
Park MN, Song HS, Kim M, et al. Review of natural product-derived compounds as potent antiglioblastoma drugs. BioMed Res Int 2017; 20178139848
[http://dx.doi.org/10.1155/2017/8139848]
[44]
Vengoji R, Macha MA, Batra SK, Shonka NA. Natural products: a hope for glioblastoma patients. Oncotarget 2018; 9(31): 22194-219.
[http://dx.doi.org/10.18632/oncotarget.25175] [PMID: 29774132 ]
[45]
Fan HC, Chi CS, Chang YK, Tung MC, Lin SZ, Harn HJ. The molecular mechanisms of plant-derived compounds targeting brain cancer. Int J Mol Sci 2018; 19(2): 1-15.
[http://dx.doi.org/10.3390/ijms19020395] [PMID: 29385679 ]
[46]
Sabir F, Ismail R, Csoka I. Nose-to-brain delivery of antiglioblastoma drugs embedded into lipid nanocarrier systems: status quo and outlook. Drug Discov Today 2019; 6446(19): 30388-5.
[http://dx.doi.org/10.1016/j.drudis.2019.10.005] [PMID: 31629966 ]
[47]
Bruinsmann FA, Richter Vaz G, de Cristo Soares Alves A, et al. Nasal drug delivery of anticancer drugs for the treatment of glioblastoma: preclinical and clinical trials. Molecules 2019; 24(23): 1-32.
[http://dx.doi.org/10.3390/molecules24234312] [PMID: 31779126 ]
[48]
Zheng Y, Liu H, Liang Y. Genistein exerts potent antitumour effects alongside anaesthetic, propofol, by suppressing cell proliferation and nuclear factor-κB-mediated signalling and through upregulating microRNA-218 expression in an intracranial rat brain tumour model. J Pharm Pharmacol 2017; 69(11): 1565-77.
[http://dx.doi.org/10.1111/jphp.12781] [PMID: 28776680 ]
[49]
da Silva AB, Cerqueira Coelho PL. das Neves Oliveira M, et al. The flavonoid rutin and its aglycone quercetin modulate the microglia inflammatory profile improving antiglioma activity. Brain Behav Immun 2019; 1591(19): 30042.
[http://dx.doi.org/10.1016/j.bbi.2019.05.003] [PMID: 31059805 ]
[50]
Yang SH, Wang SM, Syu JP, et al. Andrographolide induces apoptosis of C6 glioma cells via the ERK-p53-caspase 7-PARP pathway. BioMed Res Int 2014; 2014312847
[51]
Yang SL, Kuo FH, Chen PN, et al. Andrographolide suppresses the migratory ability of human glioblastoma multiforme cells by targeting ERK1/2-mediated matrix metalloproteinase-2 expression. Oncotarget 2017; 8(62): 105860-72.
[http://dx.doi.org/10.18632/oncotarget.22407] [PMID: 29285298 ]
[52]
Li Y, Zhang P, Qiu F, et al. Inactivation of PI3K/Akt signaling mediates proliferation inhibition and G2/M phase arrest induced by andrographolide in human glioblastoma cells. Life Sci 2012; 90(25-26): 962-7.
[http://dx.doi.org/10.1016/j.lfs.2012.04.044] [PMID: 22634579 ]
[53]
Hou J, Kim S, Sung C, Choi C. Ginsenoside Rg3 prevents oxidative stress-induced astrocytic senescence and ameliorates senescence paracrine effects on glioblastoma. Molecules 2017; 22(9): 1-14.
[http://dx.doi.org/10.3390/molecules22091516] [PMID: 28891967 ]
[54]
Mukherjee S, Baidoo J, Fried A, et al. Curcumin changes the polarity of tumor-associated microglia and eliminates glioblastoma. Int J Cancer 2016; 139(12): 2838-49.
[http://dx.doi.org/10.1002/ijc.30398] [PMID: 27543754 ]
[55]
Lim KJ, Bisht S, Bar EE, Maitra A, Eberhart CG. A polymeric nanoparticle formulation of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain tumors. Cancer Biol Ther 2011; 11(5): 464-73.
[http://dx.doi.org/10.4161/cbt.11.5.14410] [PMID: 21193839 ]
[56]
Mukherjee S, Baidoo JNE, Sampat S, et al. Liposomal tricurin, a synergistic combination of curcumin, epicatechin gallate and resveratrol, repolarizes tumor-associated microglia/macrophages, and eliminates glioblastoma (GBM) and GBM Stem Cells. Molecules 2018; 23(1): 1-21.
[http://dx.doi.org/10.3390/molecules23010201] [PMID: 29346317 ]
[57]
Jhaveri A, Luther E, Torchilin V. The effect of transferrin-targeted, resveratrol-loaded liposomes on neurosphere cultures of glioblastoma: implications for targeting tumour-initiating cells. J Drug Target 2019; 27(5-6): 601-13.
[http://dx.doi.org/10.1080/1061186X.2018.1550647] [PMID: 30475084 ]
[58]
Li H, Liu Y, Jiao Y, et al. Resveratrol sensitizes glioblastoma-initiating cells to temozolomide by inducing cell apoptosis and promoting differentiation. Oncol Rep 2016; 35(1): 343-51.
[http://dx.doi.org/10.3892/or.2015.4346] [PMID: 26498391 ]
[59]
Öztürk Y, Günaydın C, Yalçın F, Nazıroğlu M, Braidy N. Resveratrol enhances apoptotic and oxidant effects of paclitaxel through TRPM2 channel activation in DBTRG glioblastoma cells. Oxid Med Cell Longev 2019; 2019 4619865
[60]
Önay Uçar E, Şengelen A. Resveratrol and siRNA in combination reduces Hsp27 expression and induces caspase-3 activity in human glioblastoma cells. Cell Stress Chaperones 2019; 24(4): 763-75.
[http://dx.doi.org/10.1007/s12192-019-01004-z] [PMID: 31073903 ]
[61]
Sang DP, Li RJ, Lan Q. Quercetin sensitizes human glioblastoma cells to temozolomide in vitro via inhibition of Hsp27. Acta Pharmacol Sin 2014; 35(6): 832-8.
[http://dx.doi.org/10.1038/aps.2014.22] [PMID: 24902789 ]
[62]
Liu Y, Tang ZG, Lin Y, et al. Effects of quercetin on proliferation and migration of human glioblastoma U251 cells. Biomed Pharmacother 2017; 92: 33-8.
[http://dx.doi.org/10.1016/j.biopha.2017.05.044] [PMID: 28528183 ]
[63]
da Fonseca CO, Simão M, Lins IR, Caetano RO, Futuro D, Quirico-Santos T. Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma. J Cancer Res Clin Oncol 2011; 137(2): 287-93.
[http://dx.doi.org/10.1007/s00432-010-0873-0] [PMID: 20401670 ]
[64]
Chen TC, Fonseca CO, Schönthal AH. Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy. Am J Cancer Res 2015; 5(5): 1580-93.
[PMID: 26175929 ]
[65]
Chen TC, da Fonseca CO, Schönthal AH. Intranasal perillyl alcohol for glioma therapy: molecular mechanisms and clinical development. Int J Mol Sci 2018; 19(12): 1-21.
[http://dx.doi.org/10.3390/ijms19123905] [PMID: 30563210 ]
[66]
Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology 2008; 55(3): 310-8.
[http://dx.doi.org/10.1016/j.neuropharm.2008.01.005] [PMID: 18308346 ]
[67]
Woodruff TM, Thundyil J, Tang SC, Sobey CG, Taylor SM, Arumugam TV. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener 2011; 6(1): 11.
[http://dx.doi.org/10.1186/1750-1326-6-11] [PMID: 21266064 ]
[68]
Ahmad N, Ahmad R, Naqvi AA, et al. Rutin-encapsulated chitosan nanoparticles targeted to the brain in the treatment of cerebral ischemia. Int J Biol Macromol 2016; 91: 640-55.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.06.001] [PMID: 27264648 ]
[69]
Li H, Wang H, Chen JH, Wang LH, Zhang HS, Fan Y. Determination of amino acid neurotransmitters in cerebral cortex of rats administered with baicalin prior to cerebral ischemia by capillary electrophoresis-laser-induced fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 788(1): 93-101.
[http://dx.doi.org/10.1016/S1570-0232(02)01032-2] [PMID: 12668075 ]
[70]
Zhou ZQ, Li YL, Ao ZB, et al. Baicalin protects neonatal rat brains against hypoxicischemic injury by upregulating glutamate transporter 1 via the phosphoinositide 3-kinase/protein kinase B. Neural Regen Res 2017; 12: 1625-31.
[http://dx.doi.org/10.4103/1673-5374.217335] [PMID: 29171427 ]
[71]
Liu Z, Zhang L, He Q, et al. Effect of Baicalin-loaded PEGylated cationic solid lipid nanoparticles modified by OX26 antibody on regulating the levels of baicalin and amino acids during cerebral ischemia-reperfusion in rats. Int J Pharm 2015; 489(1-2): 131-8.
[http://dx.doi.org/10.1016/j.ijpharm.2015.04.049] [PMID: 25895718 ]
[72]
Chen H, Guan B, Chen X, et al. Baicalin attenuates blood-brain barrier disruption and hemorrhagic transformation and improves neurological outcome in ischemic stroke rats with delayed t-PA treatment: involvement of ONOO-MMP-9 pathway. Transl Stroke Res 2018; 9(5): 515-29.
[http://dx.doi.org/10.1007/s12975-017-0598-3] [PMID: 29275501 ]
[73]
Wang PQ, Liu Q, Xu WJ, et al. Pure mechanistic analysis of additive neuroprotective effects between baicalin and jasminoidin in ischemic stroke mice. Acta Pharmacol Sin 2018; 39(6): 961-74.
[http://dx.doi.org/10.1038/aps.2017.145] [PMID: 29345255 ]
[74]
Wu J, Wang B, Li M, Shi YH, Wang C, Kang YG. Network pharmacology identification of mechanisms of cerebral ischemia injury amelioration by baicalin and geniposide. Eur J Pharmacol 2019; 859172484
[http://dx.doi.org/10.1016/j.ejphar.2019.172484] [PMID: 31229537 ]
[75]
Cheng F, Ma C, Sun L, et al. Synergistic neuroprotective effects of Geniposide and ursodeoxycholic acid in hypoxia-reoxygenation injury in SH-SY5Y cells. Exp Ther Med 2018; 15(1): 320-6.
[http://dx.doi.org/10.3892/etm.2012.798] [PMID: 29375691 ]
[76]
Wang J, Li D, Hou J, Lei H. Protective effects of geniposide and ginsenoside Rg1 combination treatment on rats following cerebral ischemia are mediated via microglial microRNA1555p inhibition. Mol Med Rep 2018; 17(2): 3186-93.
[PMID: 29257264 ]
[77]
Tang B, Qu Y, Wang D, Mu D. Targeting hypoxia inducible factor-1α: a novel mechanism of ginsenoside Rg1 for brain repair after hypoxia/ischemia brain damage. CNS Neurol Disord Drug Targets 2011; 10(2): 235-8.
[http://dx.doi.org/10.2174/187152711794480456] [PMID: 20874696 ]
[78]
Xie CL, Li JH, Wang WW, Zheng GQ, Wang LX. Neuroprotective effect of ginsenoside-Rg1 on cerebral ischemia/reperfusion injury in rats by downregulating protease-activated receptor-1 expression. Life Sci 2015; 121: 145-51.
[http://dx.doi.org/10.1016/j.lfs.2014.12.002] [PMID: 25498890 ]
[79]
Zheng T, Jiang H, Jin R, et al. Ginsenoside Rg1 attenuates protein aggregation and inflammatory response following cerebral ischemia and reperfusion injury. Eur J Pharmacol 2019; 853: 65-73.
[http://dx.doi.org/10.1016/j.ejphar.2019.02.018] [PMID: 30794781 ]
[80]
Chen J, Zhang X, Liu X, et al. Ginsenoside Rg1 promotes cerebral angiogenesis via the PI3K/Akt/mTOR signaling pathway in ischemic mice. Eur J Pharmacol 2019; 856 172418
[http://dx.doi.org/10.1016/j.ejphar.2019.172418] [PMID: 31132356 ]
[81]
Hu BR, Janelidze S, Ginsberg MD, et al. Protein aggregation after focal brain ischemia and reperfusion. J Cereb Blood Flow Metab 2001; 21(7): 865-75.
[http://dx.doi.org/10.1097/00004647-200107000-00012] [PMID: 11435799 ]
[82]
Yang J, Huang J, Shen C, et al. Resveratrol treatment in different time-attenuated neuronal apoptosis after oxygen and glucose deprivation/reoxygenation via enhancing the activation of Nrf-2 signaling pathway in vitro. Cell Transplant 2018; 27(12): 1789-97.
[http://dx.doi.org/10.1177/0963689718780930] [PMID: 30008229 ]
[83]
Gao Y, Fu R, Wang J, Yang X, Wen L, Feng J. Resveratrol mitigates the oxidative stress mediated by hypoxic-ischemic brain injury in neonatal rats via Nrf2/HO-1 pathway. Pharm Biol 2018; 56(1): 440-9.
[http://dx.doi.org/10.1080/13880209.2018.1502326] [PMID: 30460866 ]
[84]
Wei H, Wang S, Zhen L, et al. Resveratrol attenuates the blood-brain barrier dysfunction by regulation of the MMP-9/TIMP-1 balance after cerebral ischemia reperfusion in rats. J Mol Neurosci 2015; 55(4): 872-9.
[http://dx.doi.org/10.1007/s12031-014-0441-1] [PMID: 25330860 ]
[85]
Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech 2017; 10(5): 499-502.
[http://dx.doi.org/10.1242/dmm.030205] [PMID: 28468935 ]
[86]
Skovronsky DM, Lee VM-Y, Trojanowski JQ. Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol 2006; 1: 151-70.
[http://dx.doi.org/10.1146/annurev.pathol.1.110304.100113] [PMID: 18039111 ]
[87]
Dugger BN, Dickson DW. Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol 2017; 9(7): 1-22.
[http://dx.doi.org/10.1101/cshperspect.a028035] [PMID: 28062563 ]
[88]
Solleiro-Villavicencio H, Rivas-Arancibia S. Effect of chronic oxidative stress on neuroinflammatory response mediated by CD4+T cells in neurodegenerative diseases. Front Cell Neurosci 2018; 12: 114.
[http://dx.doi.org/10.3389/fncel.2018.00114] [PMID: 29755324 ]
[89]
Lilienfeld S. Galantamine-a novel cholinergic drug with a unique dual mode of action for the treatment of patients with Alzheimer’s disease. CNS Drug Rev 2002; 8(2): 159-76.
[http://dx.doi.org/10.1111/j.1527-3458.2002.tb00221.x] [PMID: 12177686 ]
[90]
Chen Y, Cheng G, Hu R, et al. A nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of huperzine a: formulation, evaluation, and in vivo pharmacokinetic study. AAPS PharmSciTech 2019; 20(7): 301.
[http://dx.doi.org/10.1208/s12249-019-1513-x] [PMID: 31485857 ]
[91]
Yang G, Wang Y, Tian J, Liu JP. Huperzine a for alzheimer’s disease: a systematic review and meta-analysis of randomized clinical trials. PLoS One 2013; 8(9) e74916
[http://dx.doi.org/10.1371/journal.pone.0074916] [PMID: 24086396 ]
[92]
Meng Q, Wang A, Hua H, et al. Intranasal delivery of Huperzine a to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease. Int J Nanomedicine 2018; 13: 705-18.
[http://dx.doi.org/10.2147/IJN.S151474] [PMID: 29440896 ]
[93]
Li J, Yue M, Zhou D, Wang M, Zhang H. Abcb1a but not Abcg2 played a predominant role in limiting the brain distribution of Huperzine A in mice Food Chem Toxicol 2017; 107(Pt. A): 68-73.
[http://dx.doi.org/10.1016/j.fct.2017.06.005] [PMID: 28587984 ]
[94]
Fei Z, Hu M, Baum L, Kwan P, Hong T, Zhang C. The potential role of human multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 2 (MRP2) in the transport of Huperzine A in vitro. Xenobiotica 2019; 50(3): 354-62.
[http://dx.doi.org/10.1080/00498254.2019.1623935] [PMID: 31132291 ]
[95]
Gong EJ, Park HR, Kim ME, et al. Morin attenuates tau hyperphosphorylation by inhibiting GSK3β. Neurobiol Dis 2011; 44(2): 223-30.
[http://dx.doi.org/10.1016/j.nbd.2011.07.005] [PMID: 21782947 ]
[96]
Yu KC, Kwan P, Cheung SKK, Ho A, Baum L. Effects of resveratrol and morin on insoluble tau in tau transgenic mice. Transl Neurosci 2018; 9: 54-60.
[http://dx.doi.org/10.1515/tnsci-2018-0010] [PMID: 30479844 ]
[97]
Jhang KA, Park JS, Kim HS, Chong YH. Resveratrol ameliorates tau hyperphosphorylation at ser396 site and oxidative damage in rat hippocampal slices exposed to vanadate: implication of ERK1/2 and GSK-3β signaling cascades. J Agric Food Chem 2017; 65(44): 9626-34.
[http://dx.doi.org/10.1021/acs.jafc.7b03252] [PMID: 29022339 ]
[98]
Wang H, Sui H, Zheng Y, et al. Curcumin-primed exosomes potently ameliorate cognitive function in AD mice by inhibiting hyperphosphorylation of the Tau protein through the AKT/GSK-3β pathway. Nanoscale 2019; 11(15): 7481-96.
[http://dx.doi.org/10.1039/C9NR01255A] [PMID: 30942233 ]
[99]
Rane JS, Bhaumik P, Panda D. Curcumin inhibits tau aggregation and disintegrates preformed tau filaments in vitro. J Alzheimers Dis 2017; 60(3): 999-1014.
[http://dx.doi.org/10.3233/JAD-170351] [PMID: 28984591 ]
[100]
Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005; 280(7): 5892-901.
[http://dx.doi.org/10.1074/jbc.M404751200] [PMID: 15590663 ]
[101]
Lemkul JA, Bevan DR. Morin inhibits the early stages of amyloid β-peptide aggregation by altering tertiary and quaternary interactions to produce “off-pathway” structures. Biochemistry 2012; 51(30): 5990-6009.
[http://dx.doi.org/10.1021/bi300113x] [PMID: 22762350 ]
[102]
Jia Y, Wang N, Liu X. Resveratrol and amyloid-beta: mechanistic insights. Nutrients 2017; 9(10): 1-13.
[http://dx.doi.org/10.3390/nu9101122] [PMID: 29036903 ]
[103]
Nasr M. Development of an optimized hyaluronic acid-based lipidic nanoemulsion co-encapsulating two polyphenols for nose to brain delivery. Drug Deliv 2016; 23(4): 1444-52.
[http://dx.doi.org/10.3109/10717544.2015.1092619] [PMID: 26401600 ]
[104]
Lee KM, Lee Y, Chun HJ, et al. Neuroprotective and anti-inflammatory effects of morin in a murine model of Parkinson’s disease. J Neurosci Res 2016; 94(10): 865-78.
[http://dx.doi.org/10.1002/jnr.23764] [PMID: 27265894 ]
[105]
Lindner G da R, Santos DB, Colle D, Moreira ELG, Prediger RD, Farina M, et al. Improved neuroprotective effects of poly(lactide) nanoparticles in MPTP-induced Parkinsonism. Nanomedicine (Lond) 2015; 10: 1127-38.
[http://dx.doi.org/10.2217/nnm.14.165] [PMID: 25929569 ]
[106]
Sang Q, Liu X, Wang L, et al. Curcumin protects an SH-SY5Y cell model of Parkinson’s disease against toxic injury by regulating HSP90. Cell Physiol Biochem 2018; 51(2): 681-91.
[http://dx.doi.org/10.1159/000495326] [PMID: 30463061 ]
[107]
Liu LX, Chen WF, Xie JX, Wong MS. Neuroprotective effects of genistein on dopaminergic neurons in the mice model of Parkinson’s disease. Neurosci Res 2008; 60(2): 156-61.
[http://dx.doi.org/10.1016/j.neures.2007.10.005] [PMID: 18054104 ]
[108]
Sharma N, Nehru B. Curcumin affords neuroprotection and inhibits α-synuclein aggregation in lipopolysaccharide-induced parkinson’s disease model. Inflammopharmacology 2018; 26(2): 349-60.
[http://dx.doi.org/10.1007/s10787-017-0402-8] [PMID: 29027056 ]
[109]
Langasco R, Fancello S, Rassu G, et al. Increasing protective activity of genistein by loading into transfersomes: A new potential adjuvant in the oxidative stress-related neurodegenerative diseases? Phytomedicine 2019; 52: 23-31.
[http://dx.doi.org/10.1016/j.phymed.2018.09.207] [PMID: 30599903 ]
[110]
Wu HC, Hu QL, Zhang SJ, et al. Neuroprotective effects of genistein on SH-SY5Y cells overexpressing A53T mutant α-synuclein. Neural Regen Res 2018; 13(8): 1375-83.
[http://dx.doi.org/10.4103/1673-5374.235250] [PMID: 30106049 ]
[111]
Pierzynowska K, Gaffke L, Cyske Z, Węgrzyn G. Genistein induces degradation of mutant huntingtin in fibroblasts from Huntington’s disease patients. Metab Brain Dis 2019; 34(3): 715-20.
[http://dx.doi.org/10.1007/s11011-019-00405-4] [PMID: 30850940 ]
[112]
Bhatt R, Singh D, Prakash A, Mishra N. Development, characterization and nasal delivery of rosmarinic acid-loaded solid lipid nanoparticles for the effective management of Huntington’s disease. Drug Deliv 2015; 22(7): 931-9.
[http://dx.doi.org/10.3109/10717544.2014.880860] [PMID: 24512295 ]
[113]
De Somma E, Jain RW, Poon KWC, Tresidder KA, Segal JP, Ghasemlou N. Chronobiological regulation of psychosocial and physiological outcomes in multiple sclerosis. Neurosci Biobehav Rev 2018; 88: 73-83.
[http://dx.doi.org/10.1016/j.neubiorev.2018.03.011] [PMID: 29548931 ]
[114]
Iruretagoyena MI, Tobar JA, González PA, et al. Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse. J Pharmacol Exp Ther 2005; 312(1): 366-72.
[http://dx.doi.org/10.1124/jpet.104.072512] [PMID: 15331658 ]
[115]
Bertoglio JC, Baumgartner M, Palma R, et al. Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study. BMC Neurol 2016; 16: 77.
[http://dx.doi.org/10.1186/s12883-016-0595-2] [PMID: 27215274 ]
[116]
Giacoppo S, Bramanti P, Mazzon E. Sativex in the management of multiple sclerosis-related spasticity: an overview of the last decade of clinical evaluation. Mult Scler Relat Disord 2017; 17: 22-31.
[http://dx.doi.org/10.1016/j.msard.2017.06.015] [PMID: 29055461 ]
[117]
Otero-Romero S, Sastre-Garriga J, Comi G, et al. Pharmacological management of spasticity in multiple sclerosis: systematic review and consensus paper. Mult Scler 2016; 22(11): 1386-96.
[http://dx.doi.org/10.1177/1352458516643600] [PMID: 27207462 ]
[118]
Duchi S, Ovadia H, Touitou E. Nasal administration of drugs as a new non-invasive strategy for efficient treatment of multiple sclerosis. J Neuroimmunol 2013; 258(1-2): 32-40.
[http://dx.doi.org/10.1016/j.jneuroim.2013.02.013] [PMID: 23517929 ]
[119]
Zhang K, Ge Z, Xue Z, et al. Chrysin suppresses human CD14(+) monocyte-derived dendritic cells and ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 2015; 288: 13-20.
[http://dx.doi.org/10.1016/j.jneuroim.2015.08.017] [PMID: 26531689 ]
[120]
Del Fabbro L, de Gomes MG, Souza LC, et al. Chrysin suppress immune responses and protects from experimental autoimmune encephalomyelitis in mice. J Neuroimmunol 2019; 335577007
[http://dx.doi.org/10.1016/j.jneuroim.2019.577007] [PMID: 31376787 ]
[121]
Lungare S, Hallam K, Badhan RKS. Phytochemical-loaded mesoporous silica nanoparticles for nose-to-brain olfactory drug delivery. Int J Pharm 2016; 513(1-2): 280-93.
[http://dx.doi.org/10.1016/j.ijpharm.2016.09.042] [PMID: 27633279 ]
[122]
Tao L, Zhang L, Gao R, Jiang F, Cao J, Liu H. Andrographolide alleviates acute brain injury in a rat model of traumatic brain injury: possible involvement of inflammatory signaling. Front Neurosci 2018; 12: 657.
[http://dx.doi.org/10.3389/fnins.2018.00657] [PMID: 30294256 ]
[123]
Rashno M, Sarkaki A, Farbood Y, et al. Therapeutic effects of chrysin in a rat model of traumatic brain injury: a behavioral, biochemical, and histological study. Life Sci 2019; 228: 285-94.
[http://dx.doi.org/10.1016/j.lfs.2019.05.007] [PMID: 31063733 ]
[124]
Ding H, Wang H, Zhu L, Wei W. Ursolic acid ameliorates early brain injury after experimental traumatic brain injury in mice by activating the Nrf2 pathway. Neurochem Res 2017; 42(2): 337-46.
[http://dx.doi.org/10.1007/s11064-016-2077-8] [PMID: 27734181 ]
[125]
Zhang J-J, Gao T-T, Wang Y, et al. Andrographolide exerts significant antidepressant-like effects involving the hippocampal BDNF system in mice. Int J Neuropsychopharmacol 2019; 22(9): 585-600.
[http://dx.doi.org/10.1093/ijnp/pyz032] [PMID: 31181145 ]
[126]
Geng J, Liu J, Yuan X, Liu W, Guo W. Andrographolide triggers autophagy-mediated inflammation inhibition and attenuates chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in mice. Toxicol Appl Pharmacol 2019; 379114688
[http://dx.doi.org/10.1016/j.taap.2019.114688] [PMID: 31340160 ]
[127]
Filho CB, Jesse CR, Donato F, et al. Chrysin promotes attenuation of depressive-like behavior and hippocampal dysfunction resulting from olfactory bulbectomy in mice. Chem Biol Interact 2016; 260: 154-62.
[http://dx.doi.org/10.1016/j.cbi.2016.11.005] [PMID: 27818124 ]
[128]
Colombo M, Figueiró F, de Fraga Dias A, Teixeira HF, Battastini AMO, Koester LS. Kaempferol-loaded mucoadhesive nanoemulsion for intranasal administration reduces glioma growth in vitro. Int J Pharm 2018; 543(1-2): 214-23.
[http://dx.doi.org/10.1016/j.ijpharm.2018.03.055] [PMID: 29605695 ]
[129]
Ramos-Hryb AB, Pazini FL, Kaster MP, Rodrigues ALS. Therapeutic potential of ursolic acid to manage neurodegenerative and psychiatric diseases. CNS Drugs 2017; 31(12): 1029-41.
[http://dx.doi.org/10.1007/s40263-017-0474-4] [PMID: 29098660 ]
[130]
Pearn ML, Niesman IR, Egawa J, et al. Pathophysiology associated with traumatic brain injury: current treatments and potential novel therapeutics. Cell Mol Neurobiol 2017; 37(4): 571-85.
[http://dx.doi.org/10.1007/s10571-016-0400-1] [PMID: 27383839 ]
[131]
Zhao J, Moore AN, Redell JB, Dash PK. Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci 2007; 27(38): 10240-8.
[http://dx.doi.org/10.1523/JNEUROSCI.1683-07.2007] [PMID: 17881530 ]
[132]
Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: from monoamines to the neurogenesis hypothesis model - are we there yet? Behav Brain Res 2018; 341: 79-90.
[http://dx.doi.org/10.1016/j.bbr.2017.12.025] [PMID: 29284108 ]
[133]
Liang X, Xu N, Cui S, et al. Antidepressant-like effect of asiaticoside in mice. Pharmacol Biochem Behav 2008; 89(3): 444-9.
[http://dx.doi.org/10.1016/j.pbb.2008.01.020] [PMID: 18325568 ]
[134]
Luo L, Liu XL, Mu RH, et al. Hippocampal BDNF signaling restored with chronic asiaticoside treatment in depression-like mice. Brain Res Bull 2015; 114: 62-9.
[http://dx.doi.org/10.1016/j.brainresbull.2015.03.006] [PMID: 25857945 ]
[135]
Hou T, Li X, Peng C. Borneol enhances the antidepressant effects of asiaticoside by promoting its distribution into the brain. Neurosci Lett 2017; 646: 56-61.
[http://dx.doi.org/10.1016/j.neulet.2017.02.068] [PMID: 28263826 ]
[136]
Hurley LL, Akinfiresoye L, Kalejaiye O, Tizabi Y. Antidepressant effects of resveratrol in an animal model of depression. Behav Brain Res 2014; 268: 1-7.
[http://dx.doi.org/10.1016/j.bbr.2014.03.052] [PMID: 24717328 ]
[137]
de Oliveira MR, Chenet AL, Duarte AR, Scaini G, Quevedo J. Molecular mechanisms underlying the anti-depressant effects of resveratrol: a review. Mol Neurobiol 2018; 55(6): 4543-59.
[http://dx.doi.org/10.1007/s12035-017-0680-6] [PMID: 28695536 ]
[138]
Ramos-Hryb AB, Cunha MP, Pazini FL, et al. Ursolic acid affords antidepressant-like effects in mice through the activation of PKA, PKC, CAMK-II and MEK1/2. Pharmacol Rep 2017; 69(6): 1240-6.
[http://dx.doi.org/10.1016/j.pharep.2017.05.009] [PMID: 29128805 ]
[139]
Chen WJ, Du JK, Hu X, et al. Protective effects of resveratrol on mitochondrial function in the hippocampus improves inflammation-induced depressive-like behavior. Physiol Behav 2017; 182: 54-61.
[http://dx.doi.org/10.1016/j.physbeh.2017.09.024] [PMID: 28964807 ]
[140]
Brolis M, Gabetta B, Fuzzati N, Pace R, Panzeri F, Peterlongo F. Identification by high-performance liquid chromatography-diode array detection-mass spectrometry and quantification by high-performance liquid chromatography - UV absorbance detection of active constituents of hypericum perforatum. J Chromatogr A 1998; 825: 9-16.
[http://dx.doi.org/10.1016/S0021-9673(98)00697-9]
[141]
Nöldner M, Schötz K. Rutin is essential for the antidepressant activity of Hypericum perforatum extracts in the forced swimming test. Planta Med 2002; 68(7): 577-80.
[http://dx.doi.org/10.1055/s-2002-32908] [PMID: 12142988 ]
[142]
Holzmann I, da Silva LM, Corrêa da Silva JA, Steimbach VMB, de Souza MM. Antidepressant-like effect of quercetin in bulbectomized mice and involvement of the antioxidant defenses, and the glutamatergic and oxidonitrergic pathways. Pharmacol Biochem Behav 2015; 136: 55-63.
[http://dx.doi.org/10.1016/j.pbb.2015.07.003] [PMID: 26196245 ]
[143]
Rinwa P, Kumar A. Quercetin suppress microglial neuroinflammatory response and induce antidepressent-like effect in olfactory bulbectomized rats. Neuroscience 2013; 255: 86-98.
[http://dx.doi.org/10.1016/j.neuroscience.2013.09.044] [PMID: 24095694 ]
[144]
WHO. monographs on selected medicinal plants - volume 2: herba hyperici. WHO Monogr Sel Med Plants 2002; 1: 149-71.
[145]
Machado DG, Bettio LEB, Cunha MP, et al. Antidepressant-like effect of rutin isolated from the ethanolic extract from Schinus molle L. in mice: evidence for the involvement of the serotonergic and noradrenergic systems. Eur J Pharmacol 2008; 587(1-3): 163-8.
[http://dx.doi.org/10.1016/j.ejphar.2008.03.021] [PMID: 18457827 ]
[146]
Ahmad N, Ahmad R, Naqvi AA, et al. Intranasal delivery of quercetin-loaded mucoadhesive nanoemulsion for treatment of cerebral ischaemia. Artif Cells Nanomed Biotechnol 2018; 46(4): 717-29.
[http://dx.doi.org/10.1080/21691401.2017.1337024] [PMID: 28604104 ]
[147]
Hillaireau H, Couvreur P. Nanocarriers’ entry into the cell: relevance to drug delivery. Cell Mol Life Sci 2009; 66(17): 2873-96.
[http://dx.doi.org/10.1007/s00018-009-0053-z] [PMID: 19499185 ]
[148]
Gänger S, Schindowski K. Tailoring formulations for intranasal nose-to-brain delivery: a review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics 2018; 10(3): 1-28.
[http://dx.doi.org/10.3390/pharmaceutics10030116] [PMID: 30081536 ]
[149]
van Woensel M, Wauthoz N, Rosière R, et al. Formulations for intranasal delivery of pharmacological agents to combat brain disease: a new opportunity to tackle GBM? Cancers (Basel) 2013; 5(3): 1020-48.
[http://dx.doi.org/10.3390/cancers5031020] [PMID: 24202332 ]
[150]
Martignoni I, Trotta V, Lee WH, et al. Resveratrol solid lipid microparticles as dry powder formulation for nasal delivery, characterization and in vitro deposition study. J Microencapsul 2016; 33(8): 735-42.
[http://dx.doi.org/10.1080/02652048.2016.1260659] [PMID: 27841060 ]
[151]
Lu Y, Du SY, Chen XL, et al. Enhancing effect of natural borneol on the absorption of geniposide in rat via intranasal administration. J Zhejiang Univ Sci B 2011; 12(2): 143-8.
[http://dx.doi.org/10.1631/jzus.B1000121] [PMID: 21265046 ]
[152]
Lu Y, Du S, Bai J, Li P, Wen R, Zhao X. Bioavailability and brain-targeting of geniposide in gardenia-borneol co-compound by different administration routes in mice. Int J Mol Sci 2012; 13(11): 14127-35.
[http://dx.doi.org/10.3390/ijms131114127] [PMID: 23203054 ]
[153]
Chen Z, Gong X, Lu Y, et al. Enhancing effect of borneol and muscone on geniposide transport across the human nasal epithelial cell monolayer. PLoS One 2014; 9(7)e101414
[http://dx.doi.org/10.1371/journal.pone.0101414] [PMID: 24992195 ]
[154]
Wang Y, Jiang S, Wang H, Bie H. A mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases. PLoS One 2017; 12(12)e0189478
[http://dx.doi.org/10.1371/journal.pone.0189478] [PMID: 29240797 ]
[155]
Wang L, Zhao X, Du J, Liu M, Feng J, Hu K. Improved brain delivery of pueraria flavones via intranasal administration of borneol-modified solid lipid nanoparticles. Nanomedicine (Lond) 2019; 14(16): 2105-19.
[http://dx.doi.org/10.2217/nnm-2018-0417] [PMID: 31397219 ]
[156]
Ferri P, Angelino D, Gennari L, et al. Enhancement of flavonoid ability to cross the blood-brain barrier of rats by co-administration with α-tocopherol. Food Funct 2015; 6(2): 394-400.
[http://dx.doi.org/10.1039/C4FO00817K] [PMID: 25474041 ]
[157]
Zhang L, Du SY, Lu Y, et al. Puerarin transport across rat nasal epithelial cells and the influence of compatibility with peoniflorin and menthol. Drug Des Devel Ther 2017; 11: 2581-93.
[http://dx.doi.org/10.2147/DDDT.S143029] [PMID: 28919709 ]
[158]
Zhang QL, Fu BM, Zhang ZJ. Borneol, a novel agent that improves central nervous system drug delivery by enhancing blood-brain barrier permeability. Drug Deliv 2017; 24(1): 1037-44.
[http://dx.doi.org/10.1080/10717544.2017.1346002] [PMID: 28687052 ]
[159]
Gao C, Liang J, Zhu Y, et al. Menthol-modified casein nanoparticles loading 10-hydroxycamptothecin for glioma targeting therapy. Acta Pharm Sin B 2019; 9(4): 843-57.
[http://dx.doi.org/10.1016/j.apsb.2019.01.006] [PMID: 31384543 ]
[160]
Bruni N, Della Pepa C, Oliaro-Bosso S, Pessione E, Gastaldi D, Dosio F. Cannabinoid delivery systems for pain and inflammation treatment. Molecules 2018; 23(10): 23.
[http://dx.doi.org/10.3390/molecules23102478] [PMID: 30262735 ]
[161]
Xiao XY, Zhu YX, Bu JY, Li GW, Zhou JH, Zhou SP. Evaluation of neuroprotective effect of thymoquinone nanoformulation in the rodent cerebral ischemia-reperfusion model Biomed Res Int 2016; (2016): 2571060.
[http://dx.doi.org/10.1155/2016/2571060]
[162]
Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers (Basel) 2011; 3(3): 1377-97.
[http://dx.doi.org/10.3390/polym3031377] [PMID: 22577513 ]
[163]
Pan L, Zhou J, Ju F, Zhu H. Intranasal delivery of α-asarone to the brain with lactoferrin-modified mPEG-PLA nanoparticles prepared by premix membrane emulsification. Drug Deliv Transl Res 2018; 8(1): 83-96.
[http://dx.doi.org/10.1007/s13346-017-0438-8] [PMID: 29134552 ]
[164]
Sonvico F, Clementino A, Buttini F, et al. Surface-modified nanocarriers for nose-to-brain delivery: from bioadhesion to targeting. Pharmaceutics 2018; 10(1): 1-34.
[http://dx.doi.org/10.3390/pharmaceutics10010034] [PMID: 29543755 ]
[165]
Li Y, Wang C, Zong S, et al. The trigeminal pathway dominates the nose-to-brain transportation of intact polymeric nanoparticles: evidence from aggregation-caused quenching probes. J Biomed Nanotechnol 2019; 15(4): 686-702.
[http://dx.doi.org/10.1166/jbn.2019.2724] [PMID: 30841963 ]
[166]
Ahmad N, Ahmad R, Alam MA, Ahmad FJ. Quantification and brain targeting of eugenol-loaded surface modified nanoparticles through intranasal route in the treatment of cerebral ischemia. Drug Res (Stuttg) 2018; 68(10): 584-95.
[http://dx.doi.org/10.1055/a-0596-7288] [PMID: 29669380 ]
[167]
Chawla JS, Amiji MM. Biodegradable poly(ε -caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen. Int J Pharm 2002; 249(1-2): 127-38.
[http://dx.doi.org/10.1016/S0378-5173(02)00483-0] [PMID: 12433441 ]
[168]
Jesus S, Soares E, Borges O. Poly-ε-caprolactone/chitosan and chitosan particles: two recombinant antigen delivery systems for intranasal vaccination. Methods Mol Biol 2016; 1404: 697-713.
[http://dx.doi.org/10.1007/978-1-4939-3389-1_45] [PMID: 27076331 ]
[169]
Li W, Zhou Y, Zhao N, Hao B, Wang X, Kong P. Pharmacokinetic behavior and efficiency of acetylcholinesterase inhibition in rat brain after intranasal administration of galanthamine hydrobromide loaded flexible liposomes. Environ Toxicol Pharmacol 2012; 34(2): 272-9.
[http://dx.doi.org/10.1016/j.etap.2012.04.012] [PMID: 22613079 ]
[170]
Yu A, Wang H, Wang J, et al. Formulation optimization and bioavailability after oral and nasal administration in rabbits of puerarin-loaded microemulsion. J Pharm Sci 2011; 100(3): 933-41.
[http://dx.doi.org/10.1002/jps.22333] [PMID: 20862776 ]
[171]
Pangeni R, Sharma S, Mustafa G, Ali J, Baboota S. Vitamin E loaded resveratrol nanoemulsion for brain targeting for the treatment of Parkinson’s disease by reducing oxidative stress. Nanotechnology 2014; 25(48)485102
[http://dx.doi.org/10.1088/0957-4484/25/48/485102] [PMID: 25392203 ]
[172]
Ahmad N, Ahmad R, Alam MA, Samim M, Iqbal Z, Ahmad FJ. Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia. Int J Biol Macromol 2016; 88: 320-32.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.03.019] [PMID: 26976069 ]
[173]
Vaz GR, Hädrich G, Bidone J, et al. Development of nasal lipid nanocarriers containing curcumin for brain targeting. J Alzheimers Dis 2017; 59(3): 961-74.
[http://dx.doi.org/10.3233/JAD-160355] [PMID: 28731428 ]
[174]
Madane RG, Mahajan HS. Curcumin-loaded nanostructured lipid carriers (NLCs) for nasal administration: design, characterization, and in vivo study. Drug Deliv 2016; 23(4): 1326-34.
[PMID: 25367836 ]
[175]
Puri A, Loomis K, Smith B, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: from concepts to clinic. Crit Rev Ther Drug Carrier Syst 2009; 26(6): 523-80.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.v26.i6.10] [PMID: 20402623 ]
[176]
Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles in brain targeting. J Control Release 2008; 127(2): 97-109.
[http://dx.doi.org/10.1016/j.jconrel.2007.12.018] [PMID: 18313785 ]
[177]
Karavasili C, Fatouros DG. Smart materials: in situ gel-forming systems for nasal delivery. Drug Discov Today 2016; 21(1): 157-66.
[http://dx.doi.org/10.1016/j.drudis.2015.10.016] [PMID: 26563428 ]
[178]
Khan K, Aqil M, Imam SS, et al. Ursolic acid loaded intra nasal nano lipid vesicles for brain tumour: formulation, optimization, in-vivo brain/plasma distribution study and histopathological assessment. Biomed Pharmacother 2018; 106: 1578-85.
[http://dx.doi.org/10.1016/j.biopha.2018.07.127] [PMID: 30119233 ]
[179]
Salem HF, Kharshoum RM, Abou-Taleb HA, Naguib DM. Nanosized transferosome-based intranasal in situ gel for brain targeting of resveratrol: formulation, optimization, in vitro evaluation, and in vivo pharmacokinetic study. AAPS PharmSciTech 2019; 20(5): 181.
[http://dx.doi.org/10.1208/s12249-019-1353-8] [PMID: 31049748 ]
[180]
Hao J, Zhao J, Zhang S, et al. Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery. Colloids Surf B Biointerfaces 2016; 147: 376-86.
[http://dx.doi.org/10.1016/j.colsurfb.2016.08.011] [PMID: 27566226 ]
[181]
Barriga HMG, Holme MN, Stevens MM. Cubosomes: the next generation of smart lipid nanoparticles? Angew Chem Int Ed Engl 2019; 58(10): 2958-78.
[http://dx.doi.org/10.1002/anie.201804067] [PMID: 29926520 ]
[182]
Sun D, Zhuang X, Xiang X, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 2010; 18(9): 1606-14.
[http://dx.doi.org/10.1038/mt.2010.105] [PMID: 20571541 ]
[183]
Tian T, Zhang HX, He CP, et al. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials 2018; 150: 137-49.
[http://dx.doi.org/10.1016/j.biomaterials.2017.10.012] [PMID: 29040874 ]
[184]
Zhuang X, Xiang X, Grizzle W, et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 2011; 19(10): 1769-79.
[http://dx.doi.org/10.1038/mt.2011.164] [PMID: 21915101 ]
[185]
Kalani A, Chaturvedi P, Kamat PK, et al. Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury. Int J Biochem Cell Biol 2016; 79: 360-9.
[http://dx.doi.org/10.1016/j.biocel.2016.09.002] [PMID: 27594413 ]
[186]
Lakhal S, Wood MJA. Intranasal exosomes for treatment of neuroinflammation? Prospects and limitations. Mol Ther 2011; 19(10): 1754-6.
[http://dx.doi.org/10.1038/mt.2011.198] [PMID: 21964306 ]
[187]
Zhang L, Du SY, Lu Y, et al. Puerarin transport across a Calu-3 cell monolayer - an in vitro model of nasal mucosa permeability and the influence of paeoniflorin and menthol. Drug Des Devel Ther 2016; 10: 2227-37.
[http://dx.doi.org/10.2147/DDDT.S110247] [PMID: 27468226 ]
[188]
Fatouh AM, Elshafeey AH, Abdelbary A. Agomelatine-based in situ gels for brain targeting via the nasal route: statistical optimization, in vitro, and in vivo evaluation. Drug Deliv 2017; 24(1): 1077-85.
[http://dx.doi.org/10.1080/10717544.2017.1357148] [PMID: 28745530 ]
[189]
Li P, Bai J, Dong B, et al. In vivo pharmacokinetics of puerarin via different drug administration routes based on middle cerebral artery occlusion model. Eur J Drug Metab Pharmacokinet 2017; 42(4): 719-27.
[http://dx.doi.org/10.1007/s13318-016-0388-4] [PMID: 27928655 ]
[190]
Hammarlund-Udenaes M. Microdialysis as an important technique in systems pharmacology - a historical and methodological review. AAPS J 2017; 19(5): 1294-303.
[http://dx.doi.org/10.1208/s12248-017-0108-2] [PMID: 28762127 ]
[191]
Agrawal M, Saraf S, Saraf S, et al. Nose-to-brain drug delivery: an update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J Control Release 2018; 281: 139-77.
[http://dx.doi.org/10.1016/j.jconrel.2018.05.011] [PMID: 29772289 ]
[192]
Lee HJ, Ahn SM, Pak ME, et al. Positive effects of α-asarone on transplanted neural progenitor cells in a murine model of ischemic stroke. Phytomedicine 2018; 51: 151-61.
[http://dx.doi.org/10.1016/j.phymed.2018.09.230] [PMID: 30466612 ]
[193]
Kim BW, Koppula S, Kumar H, et al. α-Asarone attenuates microglia-mediated neuroinflammation by inhibiting NF kappa B activation and mitigates MPTP-induced behavioral deficits in a mouse model of Parkinson’s disease. Neuropharmacology 2015; 97: 46-57.
[http://dx.doi.org/10.1016/j.neuropharm.2015.04.037] [PMID: 25983275]
[194]
Chellian R, Pandy V, Mohamed Z. Pharmacology and toxicology of α- and β-Asarone: a review of preclinical evidence. Phytomedicine 2017; 32: 41-58.
[http://dx.doi.org/10.1016/j.phymed.2017.04.003] [PMID: 28732807 ]
[195]
Graverini G, Piazzini V, Landucci E, et al. Solid lipid nanoparticles for delivery of andrographolide across the blood-brain barrier: in vitro and in vivo evaluation. Colloids Surf B Biointerfaces 2018; 161: 302-13.
[http://dx.doi.org/10.1016/j.colsurfb.2017.10.062] [PMID: 29096375 ]
[196]
Bilia AR, Nardiello P, Piazzini V, et al. Successful brain delivery of andrographolide loaded in human albumin nanoparticles to TgCRND8 mice, an Alzheimer’s disease mouse model. Front Pharmacol 2019; 10: 910.
[http://dx.doi.org/10.3389/fphar.2019.00910] [PMID: 31507412 ]
[197]
Lu J, Ma Y, Wu J, et al. A review for the neuroprotective effects of andrographolide in the central nervous system. Biomed Pharmacother 2019; 117109078
[http://dx.doi.org/10.1016/j.biopha.2019.109078] [PMID: 31181444 ]
[198]
Chiu S-P, Batsaikhan B, Huang H-M, Wang J-Y. Application of electric cell-substrate impedance sensing to investigate the cytotoxic effects of andrographolide on U-87 MG glioblastoma cell migration and apoptosis. Sensors (Basel) 2019; 19(10): 1-15.
[http://dx.doi.org/10.3390/s19102275] [PMID: 31100944 ]
[199]
Paudel KS, Hammell DC, Agu RU, Valiveti S, Stinchcomb AL. Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers. Drug Dev Ind Pharm 2010; 36(9): 1088-97.
[http://dx.doi.org/10.3109/03639041003657295] [PMID: 20545522 ]
[200]
Goes ATR, Jesse CR, Antunes MS, et al. Protective role of chrysin on 6-hydroxydopamine-induced neurodegeneration a mouse model of Parkinson’s disease: involvement of neuroinflammation and neurotrophins. Chem Biol Interact 2018; 279: 111-20.
[http://dx.doi.org/10.1016/j.cbi.2017.10.019] [PMID: 29054324 ]
[201]
Krishnamoorthy A, Sevanan M, Mani S, Balu M, Balaji S. P R. Chrysin restores MPTP induced neuroinflammation, oxidative stress and neurotrophic factors in an acute Parkinson’s disease mouse model. Neurosci Lett 2019; 709134382
[http://dx.doi.org/10.1016/j.neulet.2019.134382] [PMID: 31325581 ]
[202]
Huang L, Chen C, Zhang X, et al. Neuroprotective effect of curcumin against cerebral ischemia-reperfusion via mediating autophagy and inflammation. J Mol Neurosci 2018; 64(1): 129-39.
[http://dx.doi.org/10.1007/s12031-017-1006-x] [PMID: 29243061 ]
[203]
Hanafy AS, Farid RM, ElGamal SS. Complexation as an approach to entrap cationic drugs into cationic nanoparticles administered intranasally for Alzheimer’s disease management: preparation and detection in rat brain. Drug Dev Ind Pharm 2015; 41(12): 2055-68.
[http://dx.doi.org/10.3109/03639045.2015.1062897] [PMID: 26133084 ]
[204]
Heinrich M. Galanthamine from galanthus and other amaryllidaceae - chemistry and biology based on traditional use. In: Alkaloids Chem Biol 2010; 68: 157-65.
[205]
Rassu G, Porcu EP, Fancello S, et al. Intranasal delivery of genistein-loaded nanoparticles as a potential preventive system against neurodegenerative disorders. Pharmaceutics 2018; 11(1): 11.
[http://dx.doi.org/10.3390/pharmaceutics11010008] [PMID: 30597930 ]
[206]
Kuang X, Zhou HJ, Thorne AH, Chen XN, Li LJ, Du JR. Neuroprotective effect of ligustilide through induction of α-secretase processing of both APP and Klotho in a mouse model of Alzheimer’s disease. Front Aging Neurosci 2017; 9: 353.
[http://dx.doi.org/10.3389/fnagi.2017.00353] [PMID: 29163135]
[207]
Kuang X, Wang LF, Yu L, et al. Ligustilide ameliorates neuroinflammation and brain injury in focal cerebral ischemia/reperfusion rats: involvement of inhibition of TLR4/peroxiredoxin 6 signaling. Free Radic Biol Med 2014; 71: 165-75.
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.03.028] [PMID: 24681253 ]
[208]
Sharma D, Singh M, Kumar P, Vikram V, Mishra N. Development and characterization of morin hydrate loaded microemulsion for the management of Alzheimer’s disease. Artif Cells Nanomed Biotechnol 2017; 45(8): 1620-30.
[http://dx.doi.org/10.1080/21691401.2016.1276919] [PMID: 28102083 ]
[209]
Rodriguez AAM, Carvalho LJM, Kimura EA, Katzin AM. Perillyl alcohol exhibits in vitro inhibitory activity against plasmodium falciparum and protects against experimental cerebral malaria. Int J Antimicrob Agents 2018; 51(3): 370-7.
[http://dx.doi.org/10.1016/j.ijantimicag.2017.08.025] [PMID: 28843818 ]
[210]
Chen TC, Da Fonseca CO, Schönthal AH. Perillyl alcohol and its drug-conjugated derivatives as potential novel methods of treating brain metastases. Int J Mol Sci 2016; 17(9): 17.
[http://dx.doi.org/10.3390/ijms17091463] [PMID: 27598140 ]
[211]
Elnaggar YSR, Etman SM, Abdelmonsif DA, Abdallah OY. Intranasal piperine-loaded chitosan nanoparticles as brain-targeted therapy in Alzheimer’s disease: optimization, biological efficacy, and potential toxicity. J Pharm Sci 2015; 104: 3544-56.
[http://dx.doi.org/10.1002/jps.24557]
[212]
Yang JA, Li JQ, Shao LM, et al. Puerarin inhibits proliferation and induces apoptosis in human glioblastoma cell lines. Int J Clin Exp Med 2015; 8(6): 10132-42.
[PMID: 26309712 ]
[213]
Li Y, Yao J, Han C, et al. Quercetin, inflammation and immunity. Nutrients 2016; 8(3): 167.
[http://dx.doi.org/10.3390/nu8030167] [PMID: 26999194 ]
[214]
Hommoss G, Pyo SM, Müller RH. Mucoadhesive tetrahydrocannabinol-loaded NLC - Formulation optimization and long-term physicochemical stability. Eur J Pharm Biopharm 2017; 117: 408-17.
[http://dx.doi.org/10.1016/j.ejpb.2017.04.009] [PMID: 28433786 ]
[215]
Al-Ghananeem AM, Malkawi AH, Crooks PA. Bioavailability of Δ-tetrahydrocannabinol following intranasal administration of a mucoadhesive gel spray delivery system in conscious rabbits. Drug Dev Ind Pharm 2011; 37(3): 329-34.
[http://dx.doi.org/10.3109/03639045.2010.513009] [PMID: 21244195 ]
[216]
Günther G, Berríos E, Pizarro N, et al. Flavonoids in microheterogeneous media, relationship between their relative location and their reactivity towards singlet oxygen. PLoS One 2015; 10(6)e0129749
[http://dx.doi.org/10.1371/journal.pone.0129749] [PMID: 26098745 ]
[217]
Lu T, Jiang Y, Zhou Z, et al. Intranasal ginsenoside Rb1 targets the brain and ameliorates cerebral ischemia/reperfusion injury in rats. Biol Pharm Bull 2011; 34(8): 1319-24.
[http://dx.doi.org/10.1248/bpb.34.1319] [PMID: 21804225 ]
[218]
Zhao Y, Yue P, Tao T, Chen QH. Drug brain distribution following intranasal administration of Huperzine A in situ gel in rats. Acta Pharmacol Sin 2007; 28(2): 273-8.
[http://dx.doi.org/10.1111/j.1745-7254.2007.00486.x] [PMID: 17241531 ]
[219]
Yue P, Tao T, Zhao Y, Ren J, Chai X. Huperzine A in rat plasma and CSF following intranasal administration. Int J Pharm 2007; 337(1-2): 127-32.
[http://dx.doi.org/10.1016/j.ijpharm.2006.12.029] [PMID: 17241758 ]
[220]
Trotta V, Pavan B, Ferraro L, et al. Brain targeting of resveratrol by nasal administration of chitosan-coated lipid microparticles. Eur J Pharm Biopharm 2018; 127: 250-9.
[http://dx.doi.org/10.1016/j.ejpb.2018.02.010] [PMID: 29486302 ]
[221]
Pires PC, Santos AO. Nanosystems in nose-to-brain drug delivery: A review of non-clinical brain targeting studies. J Control Release 2018; 270: 89-100.
[http://dx.doi.org/10.1016/j.jconrel.2017.11.047] [PMID: 29199063 ]
[222]
Costa C, Moreira JN, Amaral MH, Sousa Lobo JM, Silva AC. Nose-to-brain delivery of lipid-based nanosystems for epileptic seizures and anxiety crisis. J Control Release 2019; 295: 187-200.
[http://dx.doi.org/10.1016/j.jconrel.2018.12.049] [PMID: 30610952 ]
[223]
Battaglia L, Panciani PP, Muntoni E, et al. Lipid nanoparticles for intranasal administration: application to nose-to-brain delivery. Expert Opin Drug Deliv 2018; 15(4): 369-78.
[http://dx.doi.org/10.1080/17425247.2018.1429401] [PMID: 29338427 ]
[224]
Li X, Corbett AL, Taatizadeh E, et al. Challenges and opportunities in exosome research-perspectives from biology, engineering, and cancer therapy. APL Bioeng 2019; 3(1)011503
[http://dx.doi.org/10.1063/1.5087122] [PMID: 31069333 ]

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