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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2023

Open Access 01-12-2023 | Alzheimer's Disease | Research

Neuroprotective effect of nose-to-brain delivery of Asiatic acid in solid lipid nanoparticles and its mechanisms against memory dysfunction induced by Amyloid Beta1-42 in mice

Authors: Ridho Islamie, Su Lwin Lwin Myint, Tissana Rojanaratha, Garnpimol Ritthidej, Oraphan Wanakhachornkrai, Onsurang Wattanathamsan, Ratchanee Rodsiri

Published in: BMC Complementary Medicine and Therapies | Issue 1/2023

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Abstract

Background

Amyloid-β1-42 (Aβ1-42) plays an essential role in the development of the early stage of Alzheimer’s disease (AD). Asiatic acid (AA), an active compound in Centella asiatica L, exhibit neuroprotective properties in previous studies. Due to its low bioavailability, the nose-to-brain delivery technique was used to enhance AA penetration in the brain. In this study, AA was also loaded in solid lipid nanoparticles (SLNs) as a strategy to increase its absorption in the nasal cavity.

Methods

Memory impairment was induced via direct intracerebroventricular injection of Aβ1-42 oligomer into mouse brain. The neuroprotective effect and potential underlying mechanisms were investigated using several memory behavioral examinations and molecular techniques.

Results

The intranasal administration of AA in SLNs attenuated learning and memory impairment induced by Aβ1-42 in Morris water maze and novel object recognition tests. AA significantly inhibited tau hyperphosphorylation of pTau-S396 and pTau-T231 and prevented astrocyte reactivity and microglial activation in the hippocampus of Aβ1-42-treated mice. It is also decreased the high levels of IL-1β, TNF-α, and malondialdehyde (MDA) in mouse brain.

Conclusions

These results suggested that nose-to-brain delivery of AA in SLNs could be a promising strategy to treat the early stage of AD.
Appendix
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Literature
1.
Yin X, Qiu Y, Zhao C, Zhou Z, Bao J, Qian W. The Role of Amyloid-Beta and Tau in the Early Pathogenesis of Alzheimer’s Disease. Med Sci Monit. 2021;27:e933084.
2.
Niikura T, Tajima H, Kita Y. Neuronal cell death in Alzheimer’s disease and a neuroprotective factor, humanin. Curr Neuropharmacol. 2006;4(2):139–47.
3.
Stancu I-C, Vasconcelos B, Terwel D, Dewachter I. Models of β-amyloid induced Tau-pathology: the long and “folded” road to understand the mechanism. Mol Neurodegener. 2014;9(1):51.PubMedPubMedCentral
4.
Song T, Song X, Zhu C, Patrick R, Skurla M, Santangelo I, et al. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer’s disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies. Ageing Res Rev. 2021;72:101503.PubMedPubMedCentral
5.
Tönnies E, Trushina E. Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease. J Alzheimers Dis. 2017;57(4):1105–21.
6.
Yiannopoulou KG, Papageorgiou SG. Current and Future Treatments in Alzheimer Disease: An Update. Journal of central nervous system disease. 2020;12:1179573520907397-.
7.
Lee MK, Kim SR, Sung SH, Lim D, Kim H, Choi H, et al. Asiatic acid derivatives protect cultured cortical neurons from glutamate-induced excitotoxicity. Res Commun Mol Pathol Pharmacol. 2000;108(1–2):75–86.PubMed
8.
Xu MF, Xiong YY, Liu JK, Qian JJ, Zhu L, Gao J. Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells. Acta Pharmacol Sin. 2012;33(5):578–87.PubMedPubMedCentral
9.
Park J-H, Seo YH, Jang J-H, Jeong C-H, Lee S, Park B. Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB/STAT3/ERK and mitochondria-mediated apoptosis pathway. J Neuroinflammation. 2017;14(1):240.PubMedPubMedCentral
10.
Ahmad Rather M, Justin Thenmozhi A, Manivasagam T, Nataraj J, Essa MM, Chidambaram SB. Asiatic acid nullified aluminium toxicity in in vitro model of Alzheimer’s disease. Front Biosci (Elite Ed). 2018;10(2):287–99.
11.
Umka Welbat J, Sirichoat A, Chaijaroonkhanarak W, Prachaney P, Pannangrong W, Pakdeechote P, et al. Asiatic Acid Prevents the Deleterious Effects of Valproic Acid on Cognition and Hippocampal Cell Proliferation and Survival. Nutrients. 2016;8(5):303.PubMedPubMedCentral
12.
Chaisawang P, Sirichoat A, Chaijaroonkhanarak W, Pannangrong W, Sripanidkulchai B, Wigmore P, et al. Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy. PLoS ONE. 2017;12(7):e0180650.PubMedPubMedCentral
13.
Loganathan C, Thayumanavan P. Asiatic acid prevents the quinolinic acid-induced oxidative stress and cognitive impairment. Metab Brain Dis. 2018;33(1):151–9.PubMed
14.
Yuan Y, Zhang H, Sun F, Sun S, Zhu Z, Chai Y. Biopharmaceutical and pharmacokinetic characterization of asiatic acid in Centella asiatica as determined by a sensitive and robust HPLC-MS method. J Ethnopharmacol. 2015;163:31–8.PubMed
15.
Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614–28.PubMed
16.
Espinoza LC, Silva-Abreu M, Clares B, Rodríguez-Lagunas MJ, Halbaut L, Cañas MA, et al. Formulation Strategies to Improve Nose-to-Brain Delivery of Donepezil. Pharmaceutics. 2019;11(2):64.PubMedPubMedCentral
17.
Shah B, Khunt D, Bhatt HS, Misra M, Padh H. Intranasal delivery of venlafaxine loaded nanostructured lipid carrier: Risk assessment and QbD based optimization. J Drug Deliv Sci Technol. 2016;33:37–50.
18.
Baltzley S, Mohammad A, Malkawi AH, Al-Ghananeem AM. Intranasal drug delivery of olanzapine-loaded chitosan nanoparticles. AAPS PharmSciTech. 2014;15(6):1598–602.PubMedPubMedCentral
19.
Liu S, Yang S, Ho PC. Intranasal administration of carbamazepine-loaded carboxymethyl chitosan nanoparticles for drug delivery to the brain. Asian J Pharm Sci. 2018;13(1):72–81.PubMed
20.
Tapeinos C, Battaglini M, Ciofani G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. J Control Release. 2017;264:306–32.PubMedPubMedCentral
21.
Patel S, Chavhan S, Soni H, Babbar AK, Mathur R, Mishra AK, et al. Brain targeting of risperidone-loaded solid lipid nanoparticles by intranasal route. J Drug Target. 2011;19(6):468–74.PubMed
22.
Yasir M, Sara UV. Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation. Acta Pharm Sin B. 2014;4(6):454–63.PubMedPubMedCentral
23.
Yasir M, Sara UVS, Chauhan I, Gaur PK, Singh AP, Puri D, et al. Solid lipid nanoparticles for nose to brain delivery of donepezil: formulation, optimization by Box-Behnken design, in vitro and in vivo evaluation. Artif Cells Nanomedicine Biotechnol. 2018;46(8):1838–51.
24.
Wang R, Zhang Y, Li J, Zhang C. Resveratrol ameliorates spatial learning memory impairment induced by Aβ(1–42) in rats. Neuroscience. 2017;344:39–47.PubMed
25.
Kim HY, Lee DK, Chung BR, Kim HV, Kim Y. Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits. J Vis Exp. 2016(109).
26.
Hanson LR, Fine JM, Svitak AL, Faltesek KA. Intranasal administration of CNS therapeutics to awake mice. J Vis Exp. 2013(74).
27.
Bonferoni MC, Rossi S, Sandri G, Ferrari F, Gavini E, Rassu G, et al. Nanoemulsions for “Nose-to-Brain” Drug Delivery. Pharmaceutics. 2019;11(2):84.PubMedPubMedCentral
28.
Erdő F, Bors LA, Farkas D, Bajza Á, Gizurarson S. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Res Bull. 2018;143:155–70.PubMed
29.
Benya-Aphikul H, Pongrakhananon V, Chetprayoon P, Sooksawate T, Rodsiri R. Neuronal growth and synaptogenesis are inhibited by prenatal methamphetamine exposure leading to memory impairment in adolescent and adult mice. Toxicol Lett. 2021;351:99–110.PubMed
30.
Euaruksakul P, Tansawat R, Rodsiri R. Ginseng extract G115 improves locomotor function in rotenone-induced parkinsonism rats via an antioxidant effect. Songklanakarin J Sci Technol. 2015;37(2):163–9.
31.
Zhang LL, Sui HJ, Liang B, Wang HM, Qu WH, Yu SX, et al. Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway. Acta Pharmacologica Sinica. 2014;35(6):716–26.PubMedPubMedCentral
32.
Figueiredo CP, Clarke JR, Ledo JH, Ribeiro FC, Costa CV, Melo HM, et al. Memantine Rescues Transient Cognitive Impairment Caused by High-Molecular-Weight Aβ Oligomers But Not the Persistent Impairment Induced by Low-Molecular-Weight Oligomers. J Neurosci. 2013;33(23):9626–34.PubMedPubMedCentral
33.
Sirichoat A, Chaijaroonkhanarak W, Prachaney P, Pannangrong W, Leksomboon R, Chaichun A, et al. Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus. Nutrients. 2015;7(10):8413–23.PubMedPubMedCentral
34.
Wong JH, Muthuraju S, Reza F, Senik MH, Zhang J, Mohd Yusuf Yeo NAB, et al. Differential expression of entorhinal cortex and hippocampal subfields α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors enhanced learning and memory of rats following administration of Centella asiatica. Biomed Pharmacother. 2019;110:168–80.PubMed
35.
Bourganis V, Kammona O, Alexopoulos A, Kiparissides C. Recent advances in carrier mediated nose-to-brain delivery of pharmaceutics. Eur J Pharm Biopharm. 2018;128:337–62.PubMed
36.
Costantino HR, Illum L, Brandt G, Johnson PH, Quay SC. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007;337(1–2):1–24.PubMed
37.
Hanapi NA, Mohamad Arshad AS, Abdullah JM, Tengku Muhammad TS, Yusof SR. Blood-Brain Barrier Permeability of Asiaticoside, Madecassoside and Asiatic Acid in Porcine Brain Endothelial Cell Model. J Pharm Sci. 2021;110(2):698–706.PubMed
38.
Gizurarson S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr Drug Deliv. 2012;9(6):566–82.PubMedPubMedCentral
39.
Watanabe K, Kondo K, Yamasoba T, Kaga K. Age-related change in the axonal diameter of the olfactory nerve in mouse lamina propria. Acta Otolaryngol Suppl. 2007;559:108–12.
40.
Lesniak A, Kilinc D, Blasiak A, Galea G, Simpson JC, Lee GU. Rapid Growth Cone Uptake and Dynein-Mediated Axonal Retrograde Transport of Negatively Charged Nanoparticles in Neurons Is Dependent on Size and Cell Type. Small. 2019;15(2):1803758.
41.
Maryam T, Rana NF, Alshahrani SM, Batool F, Fatima M, Tanweer T, et al. Silymarin Encapsulated Liposomal Formulation: An Effective Treatment Modality against Copper Toxicity Associated Liver Dysfunction and Neurobehavioral Abnormalities in Wistar Rats. Molecules. 2023;28(3):1514.PubMedPubMedCentral
42.
Ali T, Yoon GH, Shah SA, Lee HY, Kim MO. Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. Sci Rep. 2015;5(1):11708.PubMedPubMedCentral
43.
Xia Y, Prokop S, Giasson BI. “Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies. Mol Neurodegener. 2021;16(1):37.
44.
Noble W, Hanger DP, Miller CC, Lovestone S. The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol. 2013;4:83.PubMedPubMedCentral
45.
Barthélemy NR, Mallipeddi N, Moiseyev P, Sato C, Bateman RJ. Tau Phosphorylation Rates Measured by Mass Spectrometry Differ in the Intracellular Brain vs. Extracellular Cerebrospinal Fluid Compartments and Are Differentially Affected by Alzheimer’s Disease. Front Aging Neurosci. 2019;11:121.
46.
Russell CL, Mitra V, Hansson K, Blennow K, Gobom J, Zetterberg H, et al. Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by Mass Spectrometry Provides New Biomarker Candidates. J Alzheimers Dis. 2017;55(1):303–13.PubMed
47.
Ahmad Rather M, Justin-Thenmozhi A, Manivasagam T, Saravanababu C, Guillemin GJ, Essa MM. Asiatic Acid Attenuated Aluminum Chloride-Induced Tau Pathology, Oxidative Stress and Apoptosis Via AKT/GSK-3β Signaling Pathway in Wistar Rats. Neurotox Res. 2019;35(4):955–68.PubMed
48.
Cheng W, Chen W, Wang P, Chu J. Asiatic acid protects differentiated PC12 cells from Aβ(25–35)-induced apoptosis and tau hyperphosphorylation via regulating PI3K/Akt/GSK-3β signaling. Life Sci. 2018;208:96–101.PubMed
49.
Chun H, Marriott I, Lee CJ, Cho H. Elucidating the Interactive Roles of Glia in Alzheimer’s Disease Using Established and Newly Developed Experimental Models. Front Neurol. 2018;9:797.
50.
Kwon HS, Koh S-H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020;9(1):42.PubMedPubMedCentral
51.
Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang H-Y. Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971(2):197–209.PubMed
52.
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation. 2005;2(1):22.PubMedPubMedCentral
53.
Olabarria M, Noristani HN, Verkhratsky A, Rodríguez JJ. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia. 2010;58(7):831–8.
54.
Ledo JH, Azevedo EP, Clarke JR, Ribeiro FC, Figueiredo CP, Foguel D, et al. Amyloid-β oligomers link depressive-like behavior and cognitive deficits in mice. Mol Psychiatry. 2013;18(10):1053–4.PubMed
55.
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405.
56.
Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med. 2015;3(10):136.
57.
Mishra A, Kim HJ, Shin AH, Thayer SA. Synapse loss induced by interleukin-1β requires pre- and post-synaptic mechanisms. J Neuroimmune Pharmacol. 2012;7(3):571–8.PubMedPubMedCentral
58.
Chao PC, Lee HL, Yin MC. Asiatic acid attenuated apoptotic and inflammatory stress in the striatum of MPTP-treated mice. Food Funct. 2016;7(4):1999–2005.PubMed
59.
Qian Y, Xin Z, Lv Y, Wang Z, Zuo L, Huang X, et al. Asiatic acid suppresses neuroinflammation in BV2 microglia via modulation of the Sirt1/NF-κB signaling pathway. Food Funct. 2018;9(2):1048–57.PubMed
60.
Legiawati L, Fadilah F, Bramono K, Indriatmi W. In silico study of centella asiatica active compounds as anti-inflammatory agent by decreasing IL-1 and IL-6 activity, promoting IL-4 activity. J Pharm Sci Res. 2018;10:2142–7.
61.
Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018;14:450–64.
62.
Jhoo JH, Kim H-C, Nabeshima T, Yamada K, Shin E-J, Jhoo W-K, et al. β-Amyloid (1–42)-induced learning and memory deficits in mice: involvement of oxidative burdens in the hippocampus and cerebral cortex. Behav Brain Res. 2004;155(2):185–96.PubMed
63.
Althobaiti NA, Menaa F, Albalawi AE, Dalzell JJ, Warnock ND, McCammick EM, et al. Assessment and Validation of Globodera pallida as a Novel In Vivo Model for Studying Alzheimer’s Disease. Cells. 2021;10(9):2481.
64.
Althobaiti NA, Menaa F, Dalzell JJ, Albalawi AE, Ismail H, Alghuthaymi MA, et al. Ethnomedicinal Plants with Protective Effects against Beta-Amyloid Peptide (Aβ)1–42 Indicate Therapeutic Potential in a New In Vivo Model of Alzheimer's Disease. Antioxidants (Basel). 2022;11(10).
65.
Althobaiti NA, Menaa F, Dalzell JJ, Green BD. Globodera pallida, a non-transgenic invertebrate as a new model for investigating Alzheimer’s disease (and other proteinopathies)? Neural Regen Res. 2023;18(1):113–4.
66.
Kontush A. Lipid peroxidation and Alzheimer’s disease: Key role of Amyloid-β. OCL. 2006;13(1):46–53.
67.
Alavi Naini SM, Soussi-Yanicostas N. Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies? Oxid Med Cell Longev. 2015;2015:151979.PubMedPubMedCentral
68.
Suryavanshi J, Prakash C, Sharma D. Asiatic acid attenuates aluminium chloride-induced behavioral changes, neuronal loss and astrocyte activation in rats. Metab Brain Dis. 2022;37(6):1773–85.PubMed
69.
Klein WL. Abeta toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int. 2002;41(5):345–52.
70.
Kasza Á, Penke B, Frank Z, Bozsó Z, Szegedi V, Hunya Á, et al. Studies for Improving a Rat Model of Alzheimer’s Disease: Icv Administration of Well-Characterized β-Amyloid 1–42 Oligomers Induce Dysfunction in Spatial Memory. Molecules. 2017;22(11):2007.PubMedPubMedCentral
71.
Yang Y, Ji WG, Zhu ZR, Wu Y, Zhang ZY, Qu SC. Rhynchophylline suppresses soluble Aβ1–42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B-containing NMDA receptors. Neuropharmacology. 2018;135:100–12.PubMed
72.
Kang S, Kim J, Chang K-A. Spatial memory deficiency early in 6xTg Alzheimer’s disease mouse model. Sci Rep. 2021;11(1):1334.PubMedPubMedCentral
73.
Calvo-Flores Guzmán B, Elizabeth Chaffey T, Hansika Palpagama T, Waters S, Boix J, Tate WP, et al. The Interplay Between Beta-Amyloid 1–42 (Aβ(1–42))-Induced Hippocampal Inflammatory Response, p-tau, Vascular Pathology, and Their Synergistic Contributions to Neuronal Death and Behavioral Deficits. Front Mol Neurosci. 2020;13:522073.PubMedPubMedCentral
Metadata
Title
Neuroprotective effect of nose-to-brain delivery of Asiatic acid in solid lipid nanoparticles and its mechanisms against memory dysfunction induced by Amyloid Beta1-42 in mice
Authors
Ridho Islamie
Su Lwin Lwin Myint
Tissana Rojanaratha
Garnpimol Ritthidej
Oraphan Wanakhachornkrai
Onsurang Wattanathamsan
Ratchanee Rodsiri
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2023
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-023-04125-2

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