Smilagenin Protects Dopaminergic Neurons in Chronic MPTP/Probenecid—Lesioned Parkinson’s Disease Models
Open accessAbstract
Current therapies for Parkinson's disease only offer limited symptomatic alleviation but fail to hamper the progress of the disease. Thus it is imperative to establish new approaches aiming at protecting or reversing neurodegeneration in PD. Recent work elucidates whether smilagenin (abbreviated SMI), a steroidal sapogenin from traditional Chinese medicinal herbs, can take neuroprotective effect on dopaminergic neurons in a chronic model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) conjuncted with probenecid mice. We reported for the first time that SMI significantly improved the locomotor ability of chronic MPTP-lesioned mice. SMI increased the TH positive and Nissl positive neuron number in the substantia nigra pars compacta（SNpc）, augmented striatal DA and its metabolites concentration and elevated striatal dopamine transporter density (DAT). In addition, dopamine receptor D2R not D1R was down-regulated by MPTP and slightly raised by SMI prevention. What’s more, we discovered that SMI markedly elevated striatal GDNF and BDNF protein levels in SMI prevented mice. And we found that SMI increased GDNF and BDNF mRNA level by promoting CREB phosphorylation in MPP+ treated SH-SY5Y cells. The results illustrated that SMI could prevent the impairment of dopaminergic neurons in chronic MPTP-induced mouse model.
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CREB is directly involved in regulating TH expression in PD.
“Among the mechanisms related to exercise-dependent neuroplasticity, CREB is directly involved in regulating TH expression in PD [193,194].”
From BDNF as a Promising Therapeutic Agent in Parkinson’s Disease (2020) · cites this paper as [193]
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1 retracted
Anandhan, A., Janakiraman, U., & Manivasagam, T. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.05.039 · Cited by 40 · see citing works
RetractedNon-motor features of Parkinson disease
Schapira, A. H. V., Chaudhuri, K. R., & Jenner, P. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.62 · Cited by 2,053 · see citing works
Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease
Gill, S. S., Patel, N. K., Hotton, G. R., O'Sullivan, K., McCarter, R., Bunnage, M., Brooks, D. J., Svendsen, C. N., & Heywood, P. (2003) · Nature Medicine · doi:10.1038/nm850 · Cited by 1,290 · see citing works
Lang, A. E., Gill, S., Patel, N., Lozano, A., Nutt, J. G., Penn, R., Brooks, D. J., Hotton, G. R., Moro, E., Heywood, P., et al. (2006) · Annals of Neurology · doi:10.1002/ana.20737 · Cited by 987 · see citing works
α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies
Wong, Y. C., & Krainc, D. (2017) · Nature Medicine · doi:10.1038/nm.4269 · Cited by 897 · see citing works
BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases
Lu, B., Nagappan, G., Guan, X.-M., Nathan, P. J., & Wren, P. B. (2013) · Nature reviews. Neuroscience · doi:10.1038/nrn3505 · Cited by 747 · see citing works
The two-century journey of Parkinson disease research
Przedborski, S. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.25 · Cited by 344 · see citing works
Thoenen, H., & Sendtner, M. (2002) · Nature Neuroscience · doi:10.1038/nn938 · Cited by 336 · see citing works
Petroske, E., Meredith, G. E., Callen, S. E., Totterdell, S., & Lau, Y.-S. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00295-0 · Cited by 331 · see citing works
Glial cell line–derived neurotrophic factor induces neuronal sprouting in human brain
Love, S., Plaha, P., Patel, N. K., Hotton, G. R., Brooks, D. J., & Gill, S. S. (2005) · Nature Medicine · doi:10.1038/nm0705-703 · Cited by 285 · see citing works
Erratum: Non-motor features of Parkinson disease
Schapira, A. H. V., Chaudhuri, К. R., & Jenner, P. G. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.91 · Cited by 271 · see citing works
Biology of GDNF and its receptors — Relevance for disorders of the central nervous system
Ibáñez, C. F., & Andressoo, J. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.01.021 · Cited by 234 · see citing works
The overall rod performance test in the MPTP-treated-mouse model of Parkinsonism
Rozas, G., López-Martín, M. E., Guerra, M. J., & Labandeira-García, J. L. (1998) · Journal of Neuroscience Methods · doi:10.1016/s0165-0270(98)00078-8 · Cited by 225 · see citing works
Zhang, N., Yan, F., Liang, X., Wu, M., Shen, Y., Chen, M., Xu, Y., Zou, G., Jiang, P., Tang, C., et al. (2018) · Theranostics · doi:10.7150/thno.23734 · Cited by 180 · see citing works
GDNF–Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease
Kramer, E. R., & Liss, B. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.11.006 · Cited by 120 · see citing works
Fan, C., Ting, C.-Y., Lin, C., Chan, H., Chang, Y., Chen, Y., Liu, H.-L., & Yeh, C. (2016) · Scientific Reports · doi:10.1038/srep19579 · Cited by 115 · see citing works
Biju, K. C., Zhou, Q., Li, G., Imam, S. Z., Roberts, J. L., Morgan, W. W., Clark, R. A., & Li, S. (2010) · Molecular Therapy · doi:10.1038/mt.2010.107 · Cited by 106 · see citing works
Emerging therapies for Parkinson's disease: From bench to bedside
Tarazi, F. I., Sahli, Z. T., Wolny, M., & Mousa, S. A. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.05.010 · Cited by 96 · see citing works
Tipping Points and Endogenous Determinants of Nigrostriatal Degeneration by MPTP
Schildknecht, S., Monte, D. A. D., Pape, R., Tieu, K., & Leist, M. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.03.010 · Cited by 96 · see citing works
Old and new challenges in Parkinson's disease therapeutics
Pires, A. O., Teixeira, F. G., Mendes-Pinheiro, B., Serra, S. C., Sousa, N., & Salgado, A. J. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.04.006 · Cited by 94 · see citing works
Naskar, A., Prabhakar, V., Singh, R. P., Dutta, D., & Mohanakumar, K. P. (2015) · Journal of Pineal Research · doi:10.1111/jpi.12212 · Cited by 78 · see citing works
Visanji, N. P., Orsi, A., Johnston, T. H., Howson, P. A., Dixon, K., Callizot, N., Brotchie, J. M., & Rees, D. D. (2008) · The FASEB Journal · doi:10.1096/fj.07-095398 · Cited by 78 · see citing works
Zhang, G., Xiong, N., Zhang, Z., Liu, L., Huang, J., Yang, J., Wu, J., Lin, Z., & Wang, T. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118498 · Cited by 73 · see citing works
Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons
Hong, J., Sha, S., Zhou, L., Wang, C., Yin, J., & Chen, L. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.194 · Cited by 65 · see citing works
MPTP-induced parkinsonism: an historical case series
Nonnekes, J. H., Post, B., Tetrud, J. W., Langston, J. W., & Bloem, B. R. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30072-3 · Cited by 64 · see citing works
Su, P., Wang, C., Ma, J., Jiang, K., Jiang, Y., Gu, X., & Sun, C. (2017) · British Journal of Pharmacology · doi:10.1111/bph.14110 · Cited by 60 · see citing works
Xu, G., Xiong, Z., Yong, Y., Wang, Z., Ke, Z., Xia, Z., & Hu, Y. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.01.048 · Cited by 56 · see citing works
Liang, Y., & Tang, X.-C. (2006) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2006.00411.x · Cited by 55 · see citing works
Towards universal therapeutics for memory disorders
Sun, M., Nelson, T. J., & Alkon, D. L. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.04.004 · Cited by 50 · see citing works
Plasmalogen Augmentation Reverses Striatal Dopamine Loss in MPTP Mice
Miville-Godbout, E., Bourque, M., Morissette, M., Al-Sweidi, S., Smith, T. M., Mochizuki, A., Senanayake, V. K., Jayasinghe, D., Wang, L., Goodenowe, D. B., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151020 · Cited by 49 · see citing works
Morissette, M., Goulet, M., Calon, F., Falardeau, P., Blanchet, P. J., Bédard, P. J., & Paolo, T. D. (1996) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09534-3 · Cited by 48 · see citing works
Alam, G., Edler, M. K., Burchfield, S. L., & Richardson, J. R. (2017) · NeuroToxicology · doi:10.1016/j.neuro.2017.03.008 · Cited by 48 · see citing works
Sun, Z., Jia, J., Gong, X., Jia, Y., Deng, J., Wang, X., & Wang, X. (2012) · Neuroscience Letters · doi:10.1016/j.neulet.2012.05.021 · Cited by 45 · see citing works
Cass, W. A., Peters, L. E., Harned, M. E., & Seroogy, K. B. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1369.024 · Cited by 44 · see citing works
Cen, X., Nitta, A., Ohya, S., Zhao, Y., Ozawa, N., Mouri, A., Ibi, D., Wang, L., Suzuki, M., Saito, K., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5010-05.2006 · Cited by 42 · see citing works
The effect of dopamine on MPTP-induced rotarod disability
Ayton, S., George, J. L., Adlard, P. A., Bush, A. I., Cherny, R. A., & Finkelstein, D. I. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.02.066 · Cited by 38 · see citing works
Ren, Z., Wang, J., Wang, S., Zou, C., Li, X., Guan, Y., Chen, Z., & Zhang, Y. A. (2013) · Scientific Reports · doi:10.1038/srep02786 · Cited by 36 · see citing works
Survival of Dopaminergic Amacrine Cells after Near-Infrared Light Treatment in MPTP-Treated Mice
Peoples, C. L., Shaw, V. E., Stone, J., Jeffery, G., Baker, G. E., & Mitrofanis, J. (2012) · ISRN Neurology · doi:10.5402/2012/850150 · Cited by 33 · see citing works
Age-related alteration of the adenosine/dopamine balance in the rat striatum
Popoli, P., Betto, P., Rimondini, R., Reggio, R., Pèzzola, A., Ricciarello, G., Fuxé, K., & Ferré, S. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00356-4 · Cited by 25 · see citing works
Regulation of CREB Functions by Phosphorylation and Sumoylation in Nervous and Visual Systems
Wang, L., Hu, X., Huang, Z.-X., Nie, Q., Chen, Z.-G., Xiang, J., Qi, R., Yang, T., Xiao, Y., Qing, W., et al. (2017) · Current Molecular Medicine · doi:10.2174/1566524016666161223110106 · Cited by 24 · see citing works
Sy, L., Lok, C., Wang, J., Liu, Y., Cheng, L., Wan, P., Leung, C.-T., Cao, B., Kwong, W., Chang, R. C., et al. (2016) · Chemical Science · doi:10.1039/c5sc02377g · Cited by 19 · see citing works
Zhang, Y., Xia, Z., Hu, Y., Orsi, A., & Rees, D. D. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.02.039 · Cited by 16 · see citing works
Reversal of dopamine neurons and locomotor ability degeneration in aged rats with smilagenin
Li, J., Xia, Z., Sun, X., Zhang, R., Huang, G., Hickling, R. I., Xia, Z., Hu, Y., & Zhang, Y. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.04.028 · Cited by 5 · see citing works
Flagged first, then by citations
1 of the 44 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
BDNF as a Promising Therapeutic Agent in Parkinson’s Disease
Palasz, E., Wysocka, A., Gasiorowska, A., Chalimoniuk, M., Niewiadomski, W., & Niewiadomska, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031170 · Cited by 504 · see citing works
Nanoformulations of Herbal Extracts in Treatment of Neurodegenerative Disorders
Moradi, S. Z., Momtaz, S., Bayrami, Z., Farzaei, M. H., & Abdollahi, M. R. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00238 · Cited by 181 · see citing works
Polyphenols and neurodegenerative diseases: focus on neuronal regeneration
Moradi, S. Z., Jalili, F., Farhadian, N., Joshi, T., Wang, M., Zou, L., Cao, H., Farzaei, M. H., & Xiao, J. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2020.1865870 · Cited by 62 · see citing works
Advances in animal models of Parkinson's disease
He, S., Ru, Q., Chen, L., Xu, G., & Wu, Y. (2024) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2024.111024 · Cited by 46 · see citing works
The dopaminergic system and Alzheimer’s disease
Zhang, Y., Liang, Y., & Gu, Y. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00230 · Cited by 45 · see citing works
Effects of Acupuncture on Neurological Disease in Clinical- and Animal-Based Research
Guo, X., & Ma, T. (2019) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2019.00047 · Cited by 33 · see citing works
Gong, X., Huang, M., & Chen, L. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14441 · Cited by 29 · see citing works
Al‐Shuhaib, M. B. S., & Al‐Shuhaib, J. M. B. (2024) · Chemistry & Biodiversity · doi:10.1002/cbdv.202401754 · Cited by 29 · see citing works
Herbal Resources to Combat a Progressive & Degenerative Nervous System Disorder- Parkinson’s Disease
Singla, R. K., Agarwal, T., He, X., & Shen, B. (2020) · Current Drug Targets · doi:10.2174/1389450121999201013155202 · Cited by 19 · see citing works
Okyere, S. K., Zeng, C., Dong, Y., & Hu, Y. (2020) · Venoms and Toxins · doi:10.2174/2666121701999201104163407 · Cited by 16 · see citing works
Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice
Cui, K., Fan, Y., Tufan, T., Raza, M. U., Zhan, Y., Fan, Y., Zeng, F., Brown, R. W., Price, J. B., Jones, T. C., et al. (2021) · ASN NEURO · doi:10.1177/17590914211009730 · Cited by 15 · see citing works
Neurotoxicological Profiling of Paraquat in Zebrafish Model
Kim, S. S., Hwang, K.-S., Kan, H., Yang, J. Y., Son, Y., Shin, D., Lee, B. H., Chae, C. H., & Bae, M. A. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03615-y · Cited by 15 · see citing works
Wang, Y., Wei, L., Tan, M., Yang, Z., Gao, B., Li, J., Liu, Y., Zikereya, T., Shi, K., & Chen, W. (2024) · Scientific Reports · doi:10.1038/s41598-024-63045-4 · Cited by 14 · see citing works
Li, X., Zhang, Z., & Wu, J. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202500341 · Cited by 12 · see citing works
Fukuyama, Y., Kubo, M., & Harada, K. (2024) · Fortschritte der Chemie Organischer Naturstoffe/Fortschritte der Chemie organischer Naturstoffe/Progress in the chemistry of organic natural products · doi:10.1007/978-3-031-42422-9_1 · Cited by 7 · see citing works
Li, J., Ni, Y., Huang, L., Yu, X., & Zhu, J. (2022) · Acta Cirúrgica Brasileira · doi:10.1590/acb371104 · Cited by 5 · see citing works
Behavioral, biochemical, and molecular characterization of MPTP/p-intoxicated mice
Tang, X., Xue, J., Chen, R., Xing, J., Lu, X., & Cui, L. (2025) · Experimental Neurology · doi:10.1016/j.expneurol.2025.115168 · Cited by 5 · see citing works
Haiyang, W., Wang, Y., Han, W., Huihui, L. I., Haisheng, J. I., & Xiuxiu, L. (2023) · PubMed Central · doi:10.19852/j.cnki.jtcm.20230214.005 · Cited by 4 · see citing works
Tiwari, U., Akhtar, S., Mir, S. S., & Khan, M. K. A. (2025) · Molecular Diversity · doi:10.1007/s11030-025-11122-9 · Cited by 4 · see citing works
Lorek, K., Chalimoniuk, M., Langfort, J., Mączewska, J., Królicki, L., Markowska, K., Budrewicz, S. P., Koszewicz, M. A., Wroński, Z., & Marusiak, J. (2025) · Neurorehabilitation and neural repair · doi:10.1177/15459683251360729 · Cited by 3 · see citing works
In silico identification and characterization of small molecule binding to the CD1d immunoreceptor
Rathakrishnan, P., & McShan, A. C. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2294388 · Cited by 2 · see citing works
Li, X., Zhang, Z., & Wu, J. (2025) · Angewandte Chemie · doi:10.1002/ange.202500341 · Cited by 2 · see citing works
Rong, H., Li, X., Chun-lei, Y., Wang, W., Li, L., Xu, T., Ding, Y., Su, Y., & Wang, X. (2023) · Folia Neuropathologica · doi:10.5114/fn.2023.133039 · Cited by 1 · see citing works
Anand, A. V., & Sukumaran, S. T. (2026) · New Zealand Journal of Botany · doi:10.1002/nzb2.70037 · Cited by 1 · see citing works
Okyere, S. K., & Hu, Y. (2021) · Venoms and Toxins · doi:10.2174/2666121701666211213100634
Keshri, P. K., Rathore, A. S., Singh, R., Dilnashin, H., Singh, S., Gupta, N. K., Satyaprakash, S. A., & Singh, S. P. (2026) · 3 Biotech · doi:10.1007/s13205-026-04757-4
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Liu, T., Zhang, M., & Wei, J. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.115744
- Authors
- He, X., Yang, S., Zhang, R., Hou, L., Xu, J., Hu, Y., Xu, R., Wang, H., & Zhang, Y.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Xu, Rang
- Wang, Hao
- Zhang, Yongfang
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2019-02-05
- Volume
- 13
- Pages
- 18-18
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC6371654
- OpenAlex
- W2911517111
- Cited by
- 27
- References
- 44
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 1
- FWCI
- 1.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- Parkinson's disease, neuroprotection, dopaminergic neurons, MPTP, probenecid, substantia nigra pars compacta, dopamine transporter, dopamine D2 receptor, glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, CREB phosphorylation, MPP+, SH-SY5Y cells, locomotor function, sapogenins
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