Neuroprotective Effect of Cudrania tricuspidata Fruit Extracts on Scopolamine-Induced Learning and Memory Impairment
Open accessAbstract
Cudrania tricuspidata has diverse biological activities, such as antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. This study investigated the protective effects of C. tricuspidata fruit extracts (CTFE) against scopolamine (SCO)-induced neuron impairment. The neuroprotective effects of CTFE on SCO-induced memory dysfunction were confirmed in mice using the Barnes maze test. The results showed that co-treatment of SCO and CTFE increased the stay time in the target zone compared with SCO treatment alone. Similarly, the results obtained by the fear conditioning test revealed that SCO-CTFE co-treatment induced the freezing action time under both the contextual fear condition and the cued fear condition compared with SCO treatment alone. Moreover, we showed that CTFE reduced the SCO-induced acetylcholinesterase (AChE) activity, thereby increasing the acetylcholine concentration in mice hippocampal tissues. Consistent with the improvement of memory and recognition function in vivo, our in vitro results showed that CTFE induced cAMP response element binding protein (CREB) and extracellular regulated kinase 1/2 (ERK1/2) activity in PC12 cells and reduced SCO-induced AChE activity. In addition, the microarray results of the hippocampal tissue support our data showing that CTFE affects gene expressions associated with neurogenesis and neuronal cell differentiation markers such as spp1 and klk6. Overall, CTFE exerts a neuroprotective effect via regulation of the CREB and ERK1/2 signaling pathways and could be a therapeutic candidate for neurodegenerative diseases.
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Extracts from Amygdalus spinosissima roots, Peganum harmala, Trianthema portulastrum, Centella asiatica, Citrus reticulata, and Cudrania tricuspidata reduced AChE activity and improved cognitive function in scopolamine-treated mice.
“Extracts from Amygdalus spinosissima roots, Peganum harmala, Trianthema portulastrum, Centella asiatica, and other plants, including Citrus reticulata and Cudrania tricuspidata, have also shown promising results in reducing AChE activity and improving cognitive function in SCO-treated mice [30,31,32,33,34,35].”
From Cholinesterase Inhibitors from Plants and Their Potential in Alzheimer’s Treatment: Systematic Review (2025) · cites this paper as [35]
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“A previous study supported the fact that large amounts of ACh were found to prevent SCO-induced memory dysfunction [51].”
ResultRay, R. S., Rai, S., & Katyal, A. (2014) · Nitric Oxide · doi:10.1016/j.niox.2014.08.009 · Cited by 31 · cited 2× · see citing works
“In conclusion, SCO blocks the stimulation of postsynaptic acetylcholine receptors [13] and induces learning and memory dysfunction.”
BackgroundEbrahimzadeh, A., Moghadam, S. Y., Rahimi, H., Motaghinejad, M., Motevalian, M., Safari, S., & Mesrabadi, M. A. (2020) · Acta Neurobiologiae Experimentalis · doi:10.21307/ane-2019-033 · Cited by 30 · see citing works
Lee, T.-H., Kwon, J., Lee, D., & Mar, W. (2015) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5b00903 · Cited by 23 · see citing works
Weon, J. B., Yun, B.-R., Lee, J., Eom, M. R., Ko, H., Lee, H.-Y., Park, D., Chung, H., Chung, J. Y., & Ma, C. J. (2014) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2014/319436 · Cited by 20 · cited 1× · see citing works
“Acetylcholine (ACh) is a neurotransmitter that plays an important role in learning and memory [8].”
BackgroundValbonesi, P., Franzellitti, S., Bersani, F., Contin, A., & Fabbri, E. (2015) · International Journal of Radiation Biology · doi:10.3109/09553002.2016.1114188 · Cited by 18 · cited 1× · see citing works
“AChE has three variants known as AChE-S, AChE-R, and AChE-E and they have multiple biological effects [39].”
BackgroundQin, Q.-F., Li, X., Li, Y.-S., Zhang, W. K., Tian, G.-H., Shang, H., & Tang, H. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01247 · Cited by 18 · cited 1× · see citing works
“Moreover, autophagy was down-regulated in neurodegenerative diseases in accordance with the regulation of ERK [64,65].”
BackgroundThapalia, B. A., Zhou, Z., & Lin, X. (2016) · PubMed · Cited by 12 · see citing works
Chinnadurai, R. K., Ponne, S., & Boopathy, R. (2017) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-017-3167-x · Cited by 5 · cited 1× · see citing works
“Previous studies showed that AChE was related to neuronal differentiation and mineralization, as well as extension of neurite outgrowth [40,41].”
BackgroundYoon, S. Y., Kim, S. J., Sim, S. J., & Lee, H. (2016) · Journal of the Korean Wood Science and Technology · doi:10.5658/wood.2016.44.3.337 · Cited by 4 · see citing works
Self-citationShin, Y., & Cho, N. J. (2014) · Neurochemical Research · doi:10.1007/s11064-014-1268-4 · Cited by 3 · cited 2× · see citing works
“nAChRs are ion channels composed of five subunits [10].”
Background
Flagged first, then by citations
2 of the 82 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Zhao, X., Zhu, H., Wang, X., Lu, X., Pan, C., Xu, L., Liu, X., Xu, N., & Zhang, Z. (2022) · Journal of Neurotrauma · doi:10.1089/neu.2021.0466 · Cited by 34 · see citing works
“A FCT was used to analyze memory behaviors of the mice, as previously described, 18 with the FCT machine LE116 (Panlab, Barcelona, Spain) ( n = 6–7 for behavioral tests; n = 4 for BBB evaluation).”
ALNasser, M. N., Alboraiy, G. M., Alsowig, E. M., & Alqattan, F. M. (2025) · Brain Sciences · doi:10.3390/brainsci15020215 · Cited by 35 · see citing works
“…from Amygdalus spinosissima roots, Peganum harmala , Trianthema portulastrum , Centella asiatica , and other plants, including Citrus reticulata and Cudrania tricuspidata , have also shown promising results in reducing AChE activity and improving cognitive function in SCO-treated mice [30–35].”
Effect of ivabradine on cognitive functions of rats with scopolamine-induced dementia
Assi, A.-A. A., Abdelnabi, S., Attaai, A., & Abd-ellatief, R. B. (2022) · Scientific Reports · doi:10.1038/s41598-022-20963-5 · Cited by 24 · see citing works
Song, J., Song, G., Park, S., & Lim, W. (2022) · Antioxidants · doi:10.3390/antiox11010171 · Cited by 22 · see citing works
Elbaz, E. M., Ibrahim, S. M., Rashad, E., Yasin, N. A. E., Ghaiad, H. R., & Mehana, N. A. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00351 · Cited by 21 · see citing works
Hussein, H. M., Abdelkawy, M. A., Eltanany, B. M., Pont, L., Benavente, F., Fayez, A. M., Alnajjar, R. A., Al-Karmalawy, A. A., Abdel-Monem, A. R., & Mohsen, E. (2024) · RSC Advances · doi:10.1039/d4ra06991a · Cited by 10 · see citing works
Lu, Q., Gouda, N. A., Quan, G., Nada, H., Elkamhawy, A., Lee, D., Lee, C. H., Cho, J., & Lee, K. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114692 · Cited by 7 · see citing works
Self-citationTopçu, A., Saral, S., Öztürk, A., Saral, Ö., & Kaya, A. K. (2023) · Neurological Research · doi:10.1080/01616412.2022.2164452 · Cited by 7 · see citing works
Trân, N. B., Lee, H., Ji, M.-G., Hoang, L. N., & Lee, S.-J. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1566621 · Cited by 5 · see citing works
“Scopolamine suppresses AMPK activation by inhibiting autophagy and increasing oxidative stress (Jee et al., 2020).”
InfluentialKo, W., Baek, J.-S., Liu, Z., Dong, L., Kim, N., Lee, H., Yoon, C., Kim, N. Y., Kim, S. C., & Lee, D. (2023) · Molecules · doi:10.3390/molecules28217299 · Cited by 5 · see citing works
“Furthermore, it has been reported that the fruit extract of C. tricuspidata exhibits neuroprotective effects against scopolamine-induced neuronal damage by regulating the CREB and ERK1/2 signaling pathways [21].”
Self-citationKang, J.-Y., Noh, H.-R., Yoone, Y., & Kim, B.-G. (2025) · Separations · doi:10.3390/separations12110298 · Cited by 4 · see citing works
Jeong, Y. H., Li, W., Yang, H. J., Kim, S.-G., Choi, H. M., Choi, J., & Oh, Y.-C. (2024) · Antioxidants · doi:10.3390/antiox13111346 · Cited by 3 · see citing works
Self-citationEffect of Cocos nucifera L. Water on Scopolamine-Induced Memory Impairment in the Wistar Rat
Oladun, B. T., Oyerinde, A., Oyadeyi, A., Badmus, H. A., & Onasanwo, S. A. (2023) · NIgerian Journal of Neuroscience · doi:10.47081/njn2023.14.1/003
Beneficial Fruit-Derived Phytochemicals in Treating Alzheimer’s Disease – A Review
Annisa, Y. N., Samor, V. A., Ikawati, M., & Yuniarti, N. (2023) · Journal of Pharmaceutical Sciences and Community · doi:10.24071/jpsc.004491
Shang, X., Gao, W., Zhao, C., LI, B. H., Guo, J., Wang, J., Zhang, M., & Fu, Y. (2026) · Food Safety and Health · doi:10.1002/fsh3.70087
- Authors
- Jee, S.-C., Lee, K. M., Kim, M., Lee, Y.-J., Kim, S., Park, J.-O., & Sung, J.-S.
- Affiliations
- Dongguk University (KR)
- Corresponding author
- Sung, Jung-Suk
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2020-12-02
- Volume
- 21
- Issue
- 23
- Pages
- 9202
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7730846
- OpenAlex
- W3108065221
- Cited by
- 15
- References
- 82
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 4
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Forest Science (2015)
- Dongguk University (2019)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Cudrania tricuspidata, fruit extract, neuroprotection, scopolamine-induced neurotoxicity, learning and memory impairment, acetylcholinesterase inhibition, acetylcholine, CREB signaling, ERK signaling, hippocampus, fear conditioning, neurogenesis, neurodegenerative diseases, PC12 cells
- MeSH terms
- Animals, Cholinesterase Inhibitors, Fruit, Hippocampus, Learning, Memory, Memory Disorders, Plant Extracts, Scopolamine, PC12 Cells, Cyclic AMP Response Element-Binding Protein, Neuroprotective Agents, Gene Expression Profiling, Maclura, Mice, Rats, Sirtuin 3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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