{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T17:12:49Z","timestamp":1781629969396,"version":"3.54.5"},"reference-count":88,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T00:00:00Z","timestamp":1671408000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    \u00a0Asiatic acid (AA) is a naturally occurring triterpenoid derivative of\n                    <ns4:italic>Centella asiatica<\/ns4:italic>\n                    (CA) with neuroprotective effect.\u00a0The study aimed to design an ideal oral drug delivery system to treat Alzheimer's disease (AD) and develop chitosan-embedded liposomes comprising an extract of CA (CLCAE) and compare them with the chitosan-coated liposomes of asiatic acid (CLAA) for oral delivery to treat the initial phases of AD.\u00a0\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    \u00a0The solvent evaporation technique was used to develop CLCAE and CLAA, optimised with the experiment's design, and was further evaluated.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    \u00a0Nuclear magnetic resonance (NMR) studies confirmed coating with chitosan.\n                    <ns4:italic>Transmission electron microscopy<\/ns4:italic>\n                    \u00a0(TEM) and atomic force microscopy (AFM) indicated the successful formation of CLCAE and CLAA. Differential scanning colorimetry (DSC) confirmed the drug-phospholipid complex. Furthermore, the rate of\u00a0\n                    <ns4:italic>in vitro<\/ns4:italic>\n                    \u00a0release of CLCAE and CLAA was found to be 69.43\u00b10.3 % and 85.3\u00b10.3 %, respectively, in 24 h.\u00a0\n                    <ns4:italic>Ex vivo<\/ns4:italic>\n                    \u00a0permeation of CLCAE and CLAA was found to be 48\u00b10.3 % and 78\u00b10.3 %, respectively. In the Alcl3-induced AD model in rats, disease progression was confirmed by Y-maze, the preliminary histopathology evaluation showed significantly higher efficacy of the prepared liposomes (CLCAE and CLAA) compared to the\n                    <ns4:italic>Centella asiatica<\/ns4:italic>\n                    extract (CAE) and they were found to have equivalent efficacy to the standard drug (rivastigmine tartrate). The considerable increase in pharmacodynamic parameters in terms of neuronal count in the CLAA group indicated the protective role against Alcl3 toxicity and was also confirmed by assessing acetylcholine (Ach) levels. The pharmacokinetic study, such as C\n                    <ns4:sub>max<\/ns4:sub>\n                    , T\n                    <ns4:sub>max<\/ns4:sub>\n                    , and area under curve (AUC) parameters, proved an increase in AA bioavailability in the form of CLAA compared to the pure AA and CLCAE forms.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusion:<\/ns4:bold>\n                    \u00a0The preclinical study suggested that CLAA was found to have better stability and an ideal oral drug delivery system to treat AD.\n                  <\/ns4:p>","DOI":"10.12688\/f1000research.128874.1","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T14:10:07Z","timestamp":1671459007000},"page":"1535","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Cationic biopolymer decorated Asiatic Acid and Centella asiatica extract incorporated liposomes for treating early-stage Alzheimer\u2019s disease: An In-vitro and In-vivo investigation"],"prefix":"10.12688","volume":"11","author":[{"given":"Akhilesh","family":"Dubey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namdev","family":"Dhas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anup","family":"Naha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9290-7854","authenticated-orcid":false,"given":"Usha","family":"Rani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"GS","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amitha","family":"Shetty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaithra","family":"R Shetty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2459-4937","authenticated-orcid":false,"given":"Srinivas","family":"Hebbar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"135-139","DOI":"10.1097\/WAD.0b013e31821f5787","article-title":"Apolipoprotein E polymorphism and behavioral and psychological symptoms of dementia in patients with Alzheimer disease.","volume":"26","author":"C Chen","year":"2012","journal-title":"Alzheimer Dis. 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A hypothetical graphical abstract is required so that readers can quickly understand the whole theme in a single glance. <\/b> Graphical abstract is submitted already while submitting the manuscript. Please see the PDF file linked here.   \n<b>2. Additional information on the rationale of using Centella asiatica extracts is required in the introduction; especially on phyto-mapping constituents of this plan (which is required).<\/b>   \n<b>Role of CA in AD.<\/b> CA (\n<i>Centella asiatica<\/i>) is the most studied herb for its nootropic action. It is believed to be a promising agent for treating AD in the future because of its anti-amyloid property, cholinergic and antioxidant property. Oxidative damage is the main reason for many age-related disorders. Free radicals like hydroxyl (OH), hydrogen peroxide, peroxynitrite, and superoxide dismutase are responsible for cell damages during AD condition. CA\n<i>&nbsp;<\/i>extract (CAE) selectively decreases amyloid levels in the hippocampus of AD animal model.\n<b>&nbsp;<\/b>Dhanasekaran M\n<b>&nbsp;<\/b>\n<i>et al<\/i>&nbsp;(2009) have shown that CAE can impact the amyloid cascade altering amyloid \u03b2 pathology in the brains of PSAPP mice and modulating oxidative stress components response that has been implicated in the neurodegenerative changes that occur with AD. The study resulted in a decrease in amyloid-beta with 2.5mg\/kg of CA extract for the treatment period of 8 months. It also confirmed that CA extract acts as an antioxidant agent&nbsp;\n<i>in-vitro<\/i>&nbsp;by scavenging the free radicals and offers protection against DNA damage. Role of CA against D-galactose induced cognitive impairment, oxidative and mitochondrial dysfunction in mice were conducted by Anil Kumar \n<i>et al<\/i>\n<b>. <\/b>Chronic administration of D-galactose (100 mg\/kg s.c.) for a period of six weeks significantly impaired cognitive task and oxidative defense (Increased lipid peroxidation, nitrite concentration and decreased activity of superoxide dismutase, catalase and non-protein thiols) and impaired mitochondrial complex (I, II and III) enzymes activities. The study concluded that six weeks CA\n<i> <\/i>(150 and 300 mg\/kg, p.o) treatment significantly improved behavioural alterations, oxidative damage and mitochondrial enzyme complex activities as compared to control l (D-galactose). The role of CA\n<i> <\/i>fresh leaf extract treatment on the dendritic morphology of hippocampal CA3 neurons was studied by Gadahad\n<i> et al<\/i> . Rats (2.5 months old) were fed with 2, 4 and 6 ml\/kg body weight of fresh leaf juice extract of CA\n<i> <\/i>for 2, 4 and 6 weeks, respectively. The results showed a significant increase in the dendritic length (intersections) and dendritic branching points along the length of both apical and basal dendrites in rats treated with 6 ml\/kg body weight\/day of CA\n<i> <\/i>for 6 weeks. However, the rats treated with 2 and 4 ml\/kg body weight\/day for 2 and 4 weeks did not show any significant change in hippocampal CA3 neuronal dendritic arborisation    \n<b>3. Did the investigators use whole plant including roots or some selective parts for extraction procedure?<\/b> For the extraction process, only leaf and stem part of the \n<i>Centella asiatica<\/i> plant was used. It was dried and extracted through Soxhlet apparuts.  \n<b>4. The detailed procedures on formulation of conventional as well as chitosan-coated liposomes of CAE are required.<\/b>  \n<u>Formulation of Chitosan coated liposome of CAE (CLCAE)<\/u> The liposome of CAE (LCAE) was formulated by the solvent evaporation method, with some modifications. Different ratios of CAE, soya phosphatidylcholine (SPC) and cholesterol were dissolved in dichloromethane (20 ml) in 100 ml round bottom flask. It was subjected to the rotary flash evaporator (Superfit rotavap series, 6-BU, continental Pvt. Ltd., Mumbai, India), and the flask was rotated with 60 rpm speed at 55 &deg;C to obtain a thin film. The film was hydrated with phosphate buffer pH 6.5 at room temperature. CLCAE was prepared as per the improved ionotropic gelation method. Chitosan was dissolved in acetic acid (0.5% w\/v) and kept overnight at room temperature. An appropriate amount of chitosan solution was added drop-wise using a syringe to the optimised CAE liposomal suspension under continuous magnetic stirring at room temperature for one hour. It was undisturbed for three-four hour to get a proper swelling of the liposomes.  \n<b>5. Replace figure 2 with peak only representations.<\/b> Replaced (Not able to paste in this section).   \n<b>6. Scale bar is missing in TEM (Fig. 4) of CLCAE and CLAA.<\/b> The scale bar of the Fig 4. Is 200 nm.   \n<b>7. Fig. 10: what is the magnification?<\/b> The magnification of fig 10 is 40x  \n<b>8. Some more points on the mechanism of actions of phytoconstitutents and AD is required in the discussion.<\/b>  Asiatic acid (AA) is a natural aglycone of pentacyclic triterpenoids of the ursane type. It is abundantly present in CA and many edible and medicinal plants. It is a reputed herb for neuropsychiatric disorders and wound healing in many traditional medicinal formulations. AA can modulate various enzymes, receptors, growth factors, cell signalling etc \n<u>Role of AA in AD<\/u> AD is a neurodegenerative disease caused due to multifactorial pathogenesis reactions, mainly oxidative stress and inflammation in the neuron triggers amyloid plaque formation. As per the study conducted by Jew \n<i>et al<\/i> (2000), AA was showed most effective 97% potent against amyloid plaque. AA modulates the enzymatical pathways such as BACE1, (Beta site APP cleaving enzyme 1) ADAM10,(A disintegrin and metalloproteinase 10),IDE (Insulin degrading enzyme), NEP (Neprilysin) BACE1 enzyme is responsible for regulating the formation of A\u03b2 from A\u03b2 precursor protein. However, ADAM10 controls the rate of non-amyloidgenic formation of A\u03b2PP. Effective degradation of A\u03b2 was done using IDE and NEP enzymes. The AA inhibits the A\u03b2 plaque formation by reducing BACE1 and regulates the enzymatic action of IDE, NEP and ADAM10 and also helps in neurogenesis. Aluminium ion is a neurotoxic molecule responsible for regulating A\u03b2PP AA shows neuroprotection against aluminium maltolate \u2013induced neurotoxicity by inhibiting acetylcholinesterase, gamma secretases sideways with amyloid \u03b2 1-42 (insoluble protein) and glial fibrillary acidic protein. AA shows potent antioxidant activity inhibiting H2O2 induced cytotoxicity and reduces apoptosis by reducing&nbsp; BAX&nbsp; and capase 3 gene expressions responsible for ROS production (Reactive oxygen species)","URL":"https:\/\/f1000research.com\/articles\/11-1535\/v1#referee-comment-9219","order":1,"name":"referee-comment-9219","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.141508.r159536, Manodeep Chakraborty, Pharmacology Department, Himalayan Pharmacy Institute, Majitar, Sikkim, 25 Jan 2023, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/11-1535\/v1#referee-response-159536","order":2,"name":"referee-response-159536","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.141508.r159533, Udit J. Chaube, Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, 30 Jan 2023, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/11-1535\/v1#referee-response-159533","order":3,"name":"referee-response-159533","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}