Abstract
Ilex kudingcha C.J. Tseng is a nootropic used throughout Asia that shares a number of metabolites with Ilex paraguariensis used throughout South America. Our previous study using a Drosophila melanogaster rugose model of autism spectrum disorders (ASD) showed that consumption of an Ilex kudingcha extract (IKE) mitigates phenotypic characteristics of ASD and in normal mice, alters gene expression involved in cognition, metabolism, and protein synthesis. This study investigated the effects of IKE on prenatal sodium valproate (VPA) treatment-induced ASD core behavioral deficits and ASD associated behaviors, neurochemical markers and histological changes. IKE administration significantly mitigated these behavioral deficits and damaged Purkinje cells, PTEN expression and oxidative stress and resembled treatment with methylphenidate in its effect upon social behavior. These findings extend our previous study with D. melanogaster and together, indicate that IKE consumption ameliorates ASD-like properties in two animal models of ASD with different etiologies. Potential mechanisms involve reduction of oxidative stress, increased PTEN expression and cerebral Purkinje cell health. These data support further studies of IKE and related species for treatment of ASD.
Graphical abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdelli LS, Samsam A, Naser SA (2019) Propionic acid induces gliosis and neuro-inflammation through modulation of PTEN/AKT pathway in autism spectrum disorder. Sci Rep 9:8824. https://doi.org/10.1038/s41598-019-45348-z
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Arlington
Arçari D P, Santos J C, Gambero A et al (2013). The in vitro and in vivo effects of yerba mate (Ilex paraguariensis) extract on adipogenesis. Food Chem 141:809–15. https://doi.org/10.1016/j.foodchem.2013.04.062
Bernardi A, Ballestero P, Schenk M et al (2019) Yerba mate (Ilex paraguariensis) favors survival and growth of dopaminergic neurons in culture. Mov Disord. 34:920–922. https://doi.org/10.1002/mds.27667
Bjørk MH, Zoega H, Leinonen MK et al (2022) Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA Neurol 79:672–681. https://doi.org/10.1001/jamaneurol.2022.1269
Branchi I, Santucci D, Vitale A et al (1998) Ultrasonic vocalizations by infant laboratory mice: a preliminary spectrographic characterization under different conditions. Dev Psychobiol 33:249–256. https://doi.org/10.1002/(SICI)1098-2302(199811)33:3%3c249::AID-DEV5%3e3.0.CO;2-R
Chaliha D, Albrecht M, Vaccarezza M et al (2020) A systematic review of the valproic-acid-induced rodent model of autism. Dev Neurosci 42:12–48. https://doi.org/10.1159/000509109
Chen G, Xie M, Dai Z et al (2018) Kudingcha and fuzhuan brick tea prevent obesity and modulate gut microbiota in high-fat diet fed mice. Mol Nutr Food Res 62:e1700485. https://doi.org/10.1002/mnfr.201700485
Chulikhit Y, Sukhano W, Daodee S et al (2021) Effects of pueraria candollei var mirifica (airy shaw and suvat.)niyomdham on ovariectomy-induced cognitive impairment and oxidative stress in the mouse brain. Molecules 26(11):3442. https://doi.org/10.3390/molecules26113442
Clipperton-Allen AE, Page DT (2014) Pten haploinsufficient mice show broad brain overgrowth but selective impairments in autism-relevant behavioral tests. Hum Mol Genet 23:3490–3505. https://doi.org/10.1093/hmg/ddu057
Cryan JF, O’Riordan KJ, Cowan CSM et al (2019) The microbiota-gut-brain axis. Physiol Rev 99:1877–2013. https://doi.org/10.1152/physrev.00018.2018
Cupolillo D, Hoxha E, Faralli A et al (2016) Autistic-Like traits and cerebellar dysfunction in Purkinje cell PTEN knock-out mice. Neuropsychopharmacology. https://doi.org/10.1038/npp.2015.339
de Theije CG, Wopereis H, Ramadan M et al (2014) Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav Immun 37:197–206. https://doi.org/10.1016/j.bbi.2013.12.005
de Meneses Fujii T M, Jacob P S, Yamada M et al (2014) Yerba mate (Ilex paraguariensis) modulates NF-κB pathway and AKT expression in the liver of rats fed on a high-fat diet. Int J Food Sci Nutr 65:967–976. https://doi.org/10.3109/09637486.2014.945153
DiCarlo GE, Wallace MT (2022) Modeling dopamine dysfunction in autism spectrum disorder: from invertebrates to vertebrates. Neurosci Biobehav Rev 133:104494. https://doi.org/10.1016/j.neubiorev.2021.12.017
D’Mello AM, Stoodley CJ (2015) Cerebro-cerebellar circuits in autism spectrum disorder. Front Neurosci 9:408. https://doi.org/10.3389/fnins.2015.00408
Doshi-Velez F, Ge Y, Kohane I (2014) Comorbidity clusters in autism spectrum disorders: an electronic health record time-series analysis. Pediatrics 133:e54-63. https://doi.org/10.1542/peds.2013-0819
Ebihara K, Fujiwara H, Awale S et al (2017) Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: a novel animal model of ASD. Behav Brain Res 334:6–15. https://doi.org/10.1016/j.bbr.2017.07.019
Erekat NS (2022) Programmed cell death in cerebellar Purkinje neurons. J Integr Neurosci 21:30. https://doi.org/10.31083/j.jin2101030
Eshraghi RS, Deth RC, Mittal R et al (2018) Early disruption of the microbiome leading to decreased antioxidant capacity and epigenetic changes: implications for the rise in autism. Front Cell Neurosci 12:256. https://doi.org/10.3389/fncel.2018.00256
Fan S, Zhang Y, Hu N et al (2012) Extract of kuding tea prevents high-fat diet-induced metabolic disorders in c57bl/6 mice via liver x receptor (lxr) β antagonism. PLoS ONE 7(12):e51007. https://doi.org/10.1371/journal.pone.0051007
Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates, 3rd edn. Elsevier, New York
Gao L, Li X, Meng S, Ma T et al (2020) Chlorogenic acid alleviates Aβ25-35-induced autophagy and cognitive impairment via the mTOR/TFEB signaling pathway. Drug Des Devel Ther 14:1705–1716. https://doi.org/10.2147/DDDT.S235969
Gao LJ, Dai Y, Li XQ et al (2021) Chlorogenic acid enhances autophagy by upregulating lysosomal function to protect against SH-SY5Y cell injury induced by H(2)O(2). Exp Ther Med 21:426. https://doi.org/10.3892/etm.2021.9843
Geschwind DH (2009) Advances in autism. Annu Rev Med 60:367–380. https://doi.org/10.1146/annurev.med.60.053107.121225
Guo Q, Ebihara K, Fujiwara H et al (2019) Kami-shoyo-san ameliorates sociability deficits in ovariectomized mice, a putative female model of autism spectrum disorder, via facilitating dopamine D1 and GABAA receptor functions. J Ethnopharmacol 236:231–239. https://doi.org/10.1016/j.jep.2019.03.010
Hanks AN, Dlugolenski K, Hughes ZA et al (2013) Pharmacological disruption of mouse social approach behavior: relevance to negative symptoms of schizophrenia. Behav Brain Res 252:405–414. https://doi.org/10.1016/j.bbr.2013.06.017
Hara Y, Ago Y, Taruta A et al (2016) Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism. Autism Res 9:926–939. https://doi.org/10.1002/aur.1596
Kalueff AV, Stewart AM, Song C et al (2016) Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat Rev Neurosci 17:45–59. https://doi.org/10.1038/nrn.2015.8
Kamal A, Ramakers GM, Altinbilek B et al (2014) Social isolation stress reduces hippocampal long-term potentiation: effect of animal strain and involvement of glucocorticoid receptors. Neuroscience 256:262–270. https://doi.org/10.1016/j.neuroscience.2013.10.016
Kern JK, Geier DA, Adams JB et al (2011) A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit 17(12):677–682. https://doi.org/10.12659/msm.882125
Kuo HY, Liu FC (2022) pathophysiological studies of monoaminergic neurotransmission systems in valproic acid-induced model of autism spectrum disorder. Biomedicines 10:560. https://doi.org/10.3390/biomedicines10030560
Le XT, Nguyet Pham HT, Van Nguyen T et al (2015) Protective effects of Bacopa monnieri on ischemia-induced cognitive deficits in mice: the possible contribution of bacopaside I and underlying mechanism. J Ethnopharmacol 164:37–45. https://doi.org/10.1016/j.jep.2015.01.041
Li L, Xu LJ, Ma GZ et al (2013) The large-leaved Kudingcha (Ilex latifolia Thunb and Ilex kudingcha C.J. Tseng): a traditional Chinese tea with plentiful secondary metabolites and potential biological activities. J Nat Med 67:425–437. https://doi.org/10.1007/s11418-013-0758-z
Liu F, Horton-Sparks K, Hull V et al (2018) The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism. Mol Autism 9:61. https://doi.org/10.1186/s13229-018-0251-3
Lugo JN, Smith GD, Arbuckle EP et al (2014) Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins. Front Mol Neurosci 7:27. https://doi.org/10.3389/fnmol.2014.00027
Mabunga DF, Gonzales EL, Kim JW et al (2015) Exploring the validity of valproic acid animal model of autism. Exp Neurobiol 24:285–300. https://doi.org/10.5607/en.2015.24.4.285
Manivasagam T, Arunadevi S, Essa MM et al (2020) Role of oxidative stress and antioxidants in autism. Adv Neurobiol 24:193–206. https://doi.org/10.1007/978-3-030-30402-7_7
Mardinoglu A, Shoaie S, Bergentall M et al (2015) The gut microbiota modulates host amino acid and glutathione metabolism in mice. Mol Syst Biol 11(10):834. https://doi.org/10.15252/msb.20156487
Meng Q, Zhang W, Wang X et al (2022) Human forebrain organoids reveal connections between valproic acid exposure and autism risk. Transl Psychiatry 12:130. https://doi.org/10.1038/s41398-022-01898-x
Moldrich RX, Leanage G, She D et al (2013) Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice. Behav Brain Res 257:253–264. https://doi.org/10.1016/j.bbr.2013.09.049
Mousavinejad E, Ghaffari MA, Riahi F et al (2018) Coenzyme Q(10) supplementation reduces oxidative stress and decreases antioxidant enzyme activity in children with autism spectrum disorders. Psychiatry Res 265:62–69. https://doi.org/10.1016/j.psychres.2018.03.061
Needham BD, Tang W, Wu WL (2018) Searching for the gut microbial contributing factors to social behavior in rodent models of autism spectrum disorder. Dev Neurobiol 78:474–499. https://doi.org/10.1002/dneu.22581
Nicolini C, Fahnestock M (2018) The valproic acid-induced rodent model of autism. Exp Neurol 299:217–227. https://doi.org/10.1016/j.expneurol.2017.04.017
Okada R, Fujiwara H, Mizuki D et al (2015) Involvement of dopaminergic and cholinergic systems in social isolation-induced deficits in social affiliation and conditional fear memory in mice. Neuroscience 299:134–145. https://doi.org/10.1016/j.neuroscience.2015.04.064
Pham HTN, Phi XT, Le XT et al (2018) Anti-dementia effects of Ilex kudincha leaves on olfactory bulbectomy-induced memory impairment in mice. J Med Mater 23(5):301–308
Pham HTN, Tran HN, Le XT et al (2021) Ilex kudingcha c.j. tseng mitigates phenotypic characteristics of human autism spectrum disorders in a drosophila melanogaster rugose mutant. Neurochem Res 46:1995–2007. https://doi.org/10.1007/s11064-021-03337-7
Roullet FI, Lai JK, Foster JA (2013) In utero exposure to valproic acid and autism: a current review of clinical and animal studies. Neurotoxicol Teratol 36:47–56. https://doi.org/10.1016/j.ntt.2013.01.004
Servadio M, Vanderschuren LJ, Trezza V (2015) Modeling autism-relevant behavioral phenotypes in rats and mice: do ‘autistic’ rodents exist? Behav Pharmacol 26:522–540. https://doi.org/10.1097/fbp.0000000000000163
Sgritta M, Dooling SW, Buffington SA et al (2019) mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron 101:246-259.e246. https://doi.org/10.1016/j.neuron.2018.11.018
Tartaglione AM, Schiavi S, Calamandrei G et al (2019) Prenatal valproate in rodents as a tool to understand the neural underpinnings of social dysfunctions in autism spectrum disorder. Neuropharmacology 159:107477. https://doi.org/10.1016/j.neuropharm.2018.12.024
Thuong PT, Su ND, Ngoc TM et al (2009) Antioxidant activity and principles of Vietnam bitter tea Ilex kudingcha. Food Chem 113(1):139–145. https://doi.org/10.1016/j.foodchem.2008.07.041
Vuong HE, Hsiao EY (2017) Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry 81:411–423. https://doi.org/10.1016/j.biopsych.2016.08.024
Wan P, Peng Y, Chen G et al (2019) Modulation of gut microbiota by Ilex kudingcha improves dextran sulfate sodium-induced colitis. Food Res Int 126:108595. https://doi.org/10.1016/j.foodres.2019.108595
Wohr M, Dahlhoff M, Wolf E et al (2008) Effects of genetic background, gender, and early environmental factors on isolation-induced ultrasonic calling in mouse pups: an embryo-transfer study. Behav Genet 38:579–595. https://doi.org/10.1007/s10519-008-9221-4
Wüpper S, Fischer A, Lüersen K et al (2019) High dietary kuding tea extract supplementation induces hepatic xenobiotic-metabolizing enzymes-a 6-week feeding study in mice. Nutrients 12:40. https://doi.org/10.3390/nu12010040
Xie J, Huang L, Li X et al (2017) Immunological cytokine profiling identifies TNF-α as a key molecule dysregulated in autistic children. Oncotarget 8(47):82390–82398. https://doi.org/10.18632/oncotarget.19326
Zhao Q, Niu Y, Matsumoto K et al (2012) Chotosan ameliorates cognitive and emotional deficits in an animal model of type 2 diabetes: possible involvement of cholinergic and VEGF/PDGF mechanisms in the brain. BMC Complement Altern Med 12:188. https://doi.org/10.1186/1472-6882-12-188
Zheng S, Zuo Z (2003) Isoflurane preconditioning reduces Purkinje cell death in an in vitro model of rat cerebellar ischemia. Neuroscience 118:99–106. https://doi.org/10.1016/s0306-4522(02)00767-4
Funding
This study was funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 108.05-2018.319
Author information
Authors and Affiliations
Contributions
Hang Thi Nguyet Pham: Conceptualization, Methodology, Formal analysis and investigation, validation, resources, Writing original draft preparation, Writing review and editing, Visualization, Project Administration, Funding Acquisition; Ly Thi Nguyen: Formal analysis, Investigation; Xoan Le Thi: Investigation, Ha Do Thi: Formal analysis, Chien Le Nguyen: Software, Formal analysis; Zhentian Lei: Metabolite Analyses; Kinzo Matsumoto and William R. Folk: Supervision, Visualization, Writing, Review and Editing.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no competing interests to declare that are relevant to the content of this article.
Ethical approval and Consent to Participate
All procedures were performed according to ethical principles in accordance with the Guiding Principles for (NIH publication #85-23, revised in 1985) and approved by the Institutional Animal Use and Care Committee of the National Institute of Medicinal Materials, Hanoi, Vietnam (Approval number No. DLSH.012021).
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Pham, H.T.N., Nguyen, L.T., Le, X.T. et al. Ilex kudingcha extract ameliorates alterations in behaviors, neurochemical markers and Purkinje cells in the sodium valproate murine model of autism spectrum disorder. ADV TRADIT MED (ADTM) (2024). https://doi.org/10.1007/s13596-024-00758-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s13596-024-00758-x