{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T03:17:40Z","timestamp":1773371860307,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2022YFE0104000"],"award-info":[{"award-number":["2022YFE0104000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a prevalent chronic neurodegenerative disorder; the progression of this disease is driven by cellular determinants such as oxidative stress and dysregulated neurotrophic signaling. Lavender essential oil is traditionally used in aromatherapy for neuronal regulation and neuroprotection, suggesting its potential neuroprotective effects for chronic neurodegenerative disorders like AD. However, the key active constituents responsible for its benefits and the specific molecular pharmacological mechanisms remain unclear. In this study, we isolated myrtenol from lavender essential oil under the guidance of activity evaluation. Its neuroprotective effects were evaluated in PC12 cells via neurite outgrowth, anti-A\u03b2\/H2O2 cytotoxicity, and antioxidant assays. Targets and pathways were explored using inhibitor experiments, cell thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and Western blot. Myrtenol significantly induced neurite outgrowth in PC12 cells and effectively mitigated cytotoxicity and oxidative stress damage induced by A\u03b225\u201335 and H2O2. Mechanistic studies revealed that myrtenol\u2019s effects are associated with the modulation of tyrosine kinase receptor A (TrkA) and insulin-like growth factor-1 receptor (IGF-1R), activating phospholipase C (PLC)\/protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)\/protein kinase B (AKT) signaling pathways to jointly mediate neuroprotection effects against the pathology of AD. This study demonstrates that myrtenol as a highly active component of lavender essential oil possesses NGF-like neuritogenic activity and neuroprotective effects. It provides a foundation for understanding the cellular mechanisms of myrtenol as a small-molecule lead for further investigation in neurodegeneration-related research.<\/jats:p>","DOI":"10.3390\/ijms27062615","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T16:27:51Z","timestamp":1773332871000},"page":"2615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Myrtenol from Lavender Essential Oil Possesses Neuroprotective Effects and Promotes Neurite Outgrowth by Potentially Targeting TrkA and IGF-1R in PC12 Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"Ting","family":"Jiang","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6595-2836","authenticated-orcid":false,"given":"Lan","family":"Xiang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Qi","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Yu Hang Tang Road 866, Hangzhou 310058, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2024). 2024 Alzheimer\u2019s disease facts and figures. Alzheimer\u2019s Dement., 20, 3708\u20133821.","DOI":"10.1002\/alz.13809"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Cui, J., Li, M., Wei, Y., Li, H., He, X., Yang, Q., Li, Z., Duan, J., Wu, Z., and Chen, Q. (2022). Inhalation Aromatherapy via Brain-Targeted Nasal Delivery: Natural Volatiles or Essential Oils on Mood Disorders. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.860043"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1002\/ptr.8512","article-title":"Harnessing Essential Oils for Acetylcholinesterase Inhibition: A Literature Review","volume":"39","author":"Asnaashari","year":"2025","journal-title":"Phytother. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1021\/acschemneuro.4c00768","article-title":"The Use of Natural Volatile Compounds on the Fibrillation Domain of Amyloid Beta (GSNKGAIIGLM)\u2014Towards Promising Agents to Combat Alzheimer\u2019s Disease","volume":"16","author":"Dindar","year":"2025","journal-title":"ACS Chem. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.psychres.2005.12.012","article-title":"Smelling lavender and rosemary increases free radical scavenging activity and decreases cortisol level in saliva","volume":"150","author":"Atsumi","year":"2007","journal-title":"Psychiatry Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101619","DOI":"10.1016\/j.arr.2022.101619","article-title":"Oxidative stress: The core pathogenesis and mechanism of Alzheimer\u2019s disease","volume":"77","author":"Bai","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"977","DOI":"10.3233\/JAD-210497","article-title":"A Review of Oxidative Stress Products and Related Genes in Early Alzheimer\u2019s Disease","volume":"83","author":"Cioffi","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/ptr.6827","article-title":"Lavender and coriander essential oils and their main component linalool exert a protective effect against amyloid-\u03b2 neurotoxicity","volume":"35","author":"Caputo","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100696","DOI":"10.1016\/j.hermed.2023.100696","article-title":"Neuroprotective, neurite enhancing, and cholinesterase inhibitory effects of Lamiaceae family essential oils in Alzheimer\u2019s disease model","volume":"41","author":"Chen","year":"2023","journal-title":"J. Herb. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s12264-011-1149-7","article-title":"Aqueous extract of lavender (Lavandula angustifolia) improves the spatial performance of a rat model of Alzheimer\u2019s disease","volume":"27","author":"Kashani","year":"2011","journal-title":"Neurosci. Bull."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e202301294","DOI":"10.1002\/cbdv.202301294","article-title":"Brazilian Green Propolis\u2019 Artepillin C and Its Acetylated Derivative Activate the NGF-Signaling Pathways and Induce Neurite Outgrowth in NGF-Deprived PC12 Cells","volume":"20","year":"2023","journal-title":"Chem. Biodivers."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1126\/science.8420006","article-title":"Blood-Brain Barrier Penetration and in Vivo Activity of an NGF Conjugate","volume":"259","author":"Friden","year":"1993","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s11064-025-04470-3","article-title":"Activation of the TrkA\/Ras-MAPK\/ERK Signaling Pathway via Carbon Quantum Dot Mimetics for Enhanced Peripheral Nerve Regeneration","volume":"50","author":"Hasanpour","year":"2025","journal-title":"Neurochem. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/s41419-022-04963-x","article-title":"The role of the PI3K\/AKT signalling pathway in the corneal epithelium: Recent updates","volume":"13","author":"Chen","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1128\/MCB.21.8.2695-2705.2001","article-title":"Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression","volume":"21","author":"Choi","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Fanlo-Ucar, H., Pic\u00f3n-Pag\u00e8s, P., Herrera-Fern\u00e1ndez, V., ILL-Raga, G., and Mu\u00f1oz, F.J. (2024). The Dual Role of Amyloid Beta-Peptide in Oxidative Stress and Inflammation: Unveiling Their Connections in Alzheimer\u2019s Disease Etiopathology. Antioxidants, 13.","DOI":"10.3390\/antiox13101208"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1046\/j.1471-4159.1997.68030927.x","article-title":"Induction of a Distinct Morphology and Signal Transduction in TrkB\/PC12 Cells by Nerve Growth Factor and Brain-Derived Neurotrophic Factor","volume":"68","author":"Iwasaki","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lejri, I., Grimm, A., and Eckert, A. (2019). Ginkgo biloba extract increases neurite outgrowth and activates the Akt\/mTOR pathway. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0225761"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6283","DOI":"10.1111\/jcmm.14514","article-title":"Cucurbitacin B induces neurogenesis in PC12 cells and protects memory in APP\/PS1 mice","volume":"23","author":"Li","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"An, C., Gao, L., Xiang, L., and Qi, J. (2024). IGF-1 and Glucocorticoid Receptors Are Potential Target Proteins for the NGF-Mimic Effect of \u03b2-Cyclocitral from Lavandula angustifolia Mill. in PC12 Cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25189763"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ejphar.2008.01.051","article-title":"Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair","volume":"585","author":"Nelson","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.exger.2006.08.009","article-title":"The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer\u2019s Disease","volume":"42","author":"Cole","year":"2007","journal-title":"Exp. Gerontol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gabbouj, S., Ryh\u00e4nen, S., Marttinen, M., Wittrahm, R., Takalo, M., Kemppainen, S., Martiskainen, H., Tanila, H., Haapasalo, A., and Hiltunen, M. (2019). Altered Insulin Signaling in Alzheimer\u2019s Disease Brain-Special Emphasis on PI3K-Akt Pathway. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00629"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2174\/1381612829666221222121041","article-title":"Biological and Pharmacological Properties of Myrtenol: A Review","volume":"29","author":"Imane","year":"2023","journal-title":"Curr. Pharm. Des."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1080\/13880209.2021.1917626","article-title":"Myrtenol improves brain damage and promotes angiogenesis in rats with cerebral infarction by activating the ERK1\/2 signalling pathway","volume":"59","author":"Huang","year":"2021","journal-title":"Pharm. Biol."},{"key":"ref_26","first-page":"100067","article-title":"Myrtenol: A promising terpene with potent pharmacological properties","volume":"4","author":"Barbhuiya","year":"2024","journal-title":"Pharmacol. Res.-Nat. Prod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.expneurol.2009.09.005","article-title":"Subcellular and metabolic examination of amyloid-\u03b2 peptides in Alzheimer disease pathogenesis: Evidence for A\u03b225\u201335","volume":"221","author":"Kaminsky","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s41598-017-19106-y","article-title":"Nanostructural Differentiation and Toxicity of Amyloid-\u03b225\u201335 Aggregates Ensue from Distinct Secondary Conformation","volume":"8","author":"Song","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1002\/syn.20789","article-title":"Neurites from PC12 cells are connected to each other by synapse-like structures","volume":"64","author":"Jeon","year":"2010","journal-title":"Synapse"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Xie, D., Deng, T., Zhai, Z., Sun, T., and Xu, Y. (2023). The cellular model for Alzheimer\u2019s disease research: PC12 cells. Front. Mol. Neurosci., 15.","DOI":"10.3389\/fnmol.2022.1016559"},{"key":"ref_31","first-page":"371","article-title":"K252a is a selective inhibitor of the tyrosine protein kinase activity of the trk family of oncogenes and neurotrophin receptors","volume":"7","author":"Tapley","year":"1992","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1042\/BJ20061489","article-title":"Exploring the specificity of the PI3K family inhibitor LY294002","volume":"404","author":"Gharbi","year":"2007","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Song, J. (2025). Applications of the Cellular Thermal Shift Assay to Drug Discovery in Natural Products: A Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26093940"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1039\/C5NP00107B","article-title":"Advances in identification and validation of protein targets of natural products without chemical modification","volume":"33","author":"Chang","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/adsc.201000781","article-title":"N-Heterocyclic Carbene Piano-Stool Iron Complexes as Efficient Catalysts for Hydrosilylation of Carbonyl Derivatives","volume":"353","author":"Jiang","year":"2011","journal-title":"Adv. Synth. Catal."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2615\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T16:31:16Z","timestamp":1773333076000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,12]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062615"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062615","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,12]]}}}