Aerial part of Houttuynia cordata reverses memory impairment by regulating amyloid beta accumulation and neuroinflammation in Alzheimer's disease model
In Gyoung Ju
Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorSeungmin Lee
Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorJin Gyu Choi
Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorNamkwon Kim
Department of Life and Nanopharmaceutical Sciences, Graduate school, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorEugene Huh
Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorJong Kil Lee
Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorCorresponding Author
Myung Sook Oh
Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
Department of Life and Nanopharmaceutical Sciences, Graduate school, Kyung Hee University, Seoul, Republic of Korea
Department of Integrated Drug Development and Natural Products, Graduate School, Kyung Hee University, Seoul, Republic of Korea
Correspondence
Myung Sook Oh, Department of Biomedical and Pharmaceutical Sciences, Graduate school, Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea.
Email: [email protected]
Search for more papers by this authorIn Gyoung Ju
Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorSeungmin Lee
Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorJin Gyu Choi
Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorNamkwon Kim
Department of Life and Nanopharmaceutical Sciences, Graduate school, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorEugene Huh
Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorJong Kil Lee
Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Search for more papers by this authorCorresponding Author
Myung Sook Oh
Department of Oriental Pharmaceutical Science and Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, Republic of Korea
Department of Life and Nanopharmaceutical Sciences, Graduate school, Kyung Hee University, Seoul, Republic of Korea
Department of Integrated Drug Development and Natural Products, Graduate School, Kyung Hee University, Seoul, Republic of Korea
Correspondence
Myung Sook Oh, Department of Biomedical and Pharmaceutical Sciences, Graduate school, Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea.
Email: [email protected]
Search for more papers by this authorAbstract
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by amyloid-β (Aβ) deposition, accompanied by neuroinflammation and memory dysfunction. Houttuyniae Herba (aerial parts of Houttuynia cordata, also known as fish mint; HH), an herbal medicine traditionally used to treat fever, urinary disorders, and pus, is revealed to protect neurons from Aβ toxicity and regulate cholinergic dysfunction in AD models. In this study, we aimed to investigate the effects of HH on excessive accumulation of Aβ followed by neuroinflammation, synaptic degeneration, and memory impairment. Two-month-old 5xFAD transgenic mice were administered HH at 100 mg/kg for 4 months. We observed that HH treatment ameliorated memory impairment and reduced Aβ deposits in the brains of the mice. HH directly inhibited Aβ aggregation in vitro using the Thioflavin T assay and indirectly suppressed the amyloidogenic pathway by increasing alpha-secretase expression in the mice brain. In addition, HH exerted antineuroinflammatory effects by reducing of glial activation and p38 phosphorylation. Moreover, HH treatment increased the expression of synaptophysin, a presynaptic marker protein. Overall, HH alleviates memory impairment in AD by facilitating nonamyloidogenic pathway and inhibiting neuroinflammation. Therefore, we suggest that HH can be a promising herbal drug for patients with AD requiring multifaceted improvement.
CONFLICT OF INTEREST STATEMENT
The authors declare that there are no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| ptr7781-sup-0001-FigureS1.docxWord 2007 document , 149.6 KB | Figure S1. Effects of HHE on Aβ-degrading enzymes expression in the hippocampus of 5xFAD mice. Representative band images (a) and the quantifications of insulin-degrading enzyme (IDE) (b) and neprilysin (NEP) (c) in the hippocampus (n = 3–5 per group). Values are indicated as the mean ± SEM. The data were analyzed by the one-way analysis of variance followed by Dunnett's multiple comparisons test. ns, not significant |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- Cai, D. S., Zhou, H., Liu, W. W., & Pei, L. (2013). Protective effects of bone marrow-derived endothelial progenitor cells and Houttuynia cordata in lipopolysaccharide-induced acute lung injury in rats. Cellular Physiology and Biochemistry, 32(6), 1577–1586. https://doi.org/10.1159/000356594
- Chiow, K. H., Phoon, M. C., Putti, T., Tan, B. K., & Chow, V. T. (2016). Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pacific Journal of Tropical Medicine, 9(1), 1–7. https://doi.org/10.1016/j.apjtm.2015.12.002
- Chung, M. S., Bae, W. J., Choi, S. W., Lee, K. W., Jeong, H. C., Bashraheel, F., Jeon, S. H., Jung, J., Yoon, B., Kwon, E., Oh, H., Hwang, S., & Kim, S. W. (2017). An Asian traditional herbal complex containing Houttuynia cordata Thunb, Perilla frutescens var. acuta and green tea stimulates hair growth in mice. BMC Complementary and Alternative Medicine, 17(1), 515. https://doi.org/10.1186/s12906-017-2003-x
- Chung, W. S., Welsh, C. A., Barres, B. A., & Stevens, B. (2015). Do glia drive synaptic and cognitive impairment in disease? Nature Neuroscience, 18(11), 1539–1545. https://doi.org/10.1038/nn.4142
- Cummings, J., Lee, G., Zhong, K., Fonseca, J., & Taghva, K. (2021). Alzheimer's disease drug development pipeline: 2021. Alzheimers Dementia (N Y), 7(1), e12179. https://doi.org/10.1002/trc2.12179
- Cummings, J., Ritter, A., & Zhong, K. (2018). Clinical trials for disease-modifying therapies in Alzheimer's disease: A primer, lessons learned, and a blueprint for the future. Journal of Alzheimer's Disease, 64(s1), S3–S22. https://doi.org/10.3233/JAD-179901
- Fakhoury, M. (2018). Microglia and astrocytes in Alzheimer's disease: Implications for therapy. Current Neuropharmacology, 16(5), 508–518. https://doi.org/10.2174/1570159X15666170720095240
- Falcicchia, C., Tozzi, F., Arancio, O., Watterson, D. M., & Origlia, N. (2020). Involvement of p38 MAPK in synaptic function and dysfunction. International Journal of Molecular Sciences, 21(16), 5624. https://doi.org/10.3390/ijms21165624
- Gee, M. S., Son, S. H., Jeon, S. H., Do, J., Kim, N., Ju, Y. J., Lee, S. J., Chung, E. K., Inn, K.-S., Kim, N.-J., & Lee, J. K. (2020). A selective p38alpha/beta MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse. Alzheimer's Research & Therapy, 12(1), 45. https://doi.org/10.1186/s13195-020-00617-2
- Huh, E., Kim, H. G., Park, H., Kang, M. S., Lee, B., & Oh, M. S. (2014). Houttuynia cordata improves cognitive deficits in cholinergic dysfunction Alzheimer's disease-like models. Biomolecules and Therapeutics (Seoul), 22(3), 176–183. https://doi.org/10.4062/biomolther.2014.040
- Ibrahim, M. M., & Gabr, M. T. (2019). Multitarget therapeutic strategies for Alzheimer's disease. Neural Regeneration Research, 14(3), 437–440. https://doi.org/10.4103/1673-5374.245463
- Im, H., Ju, I. G., Kim, J. H., Lee, S., & Oh, M. S. (2022). Trichosanthis semen and Zingiberis rhizoma mixture ameliorates lipopolysaccharide-induced memory dysfunction by inhibiting neuroinflammation. International Journal of Molecular Sciences, 23(22), 14015. https://doi.org/10.3390/ijms232214015
- Ju, I. G., Hong, S. M., Yun, S. W., Huh, E., Kim, D. H., Kim, S. Y., & Oh, M. S. (2021). CCL01, a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, enhances memory function via nerve growth factor-mediated neurogenesis. Food & Function, 12(21), 10690–10699. https://doi.org/10.1039/d1fo01403j
- Ju, I. G., Huh, E., Kim, N., Lee, S., Choi, J. G., Hong, J., & Oh, M. S. (2021). Artemisiae Iwayomogii Herba inhibits lipopolysaccharide-induced neuroinflammation by regulating NF-kappaB and MAPK signaling pathways. Phytomedicine, 84, 153501. https://doi.org/10.1016/j.phymed.2021.153501
- Ju, I. G., Kim, N., Choi, J. G., Lee, J. K., & Oh, M. S. (2019). Cuscutae Japonicae Semen ameliorates memory dysfunction by rescuing synaptic damage in Alzheimer's disease models. Nutrients, 11(11), 2591. https://doi.org/10.3390/nu11112591
- Ju, I. G., Lee, M. Y., Jeon, S. H., Huh, E., Kim, J. H., Lee, J. K., Lee, C. H., & Oh, M. S. (2020). GC-TOF-MS-based metabolomic analysis and evaluation of the effects of HX106, a nutraceutical, on ADHD-like symptoms in prenatal alcohol exposed mice. Nutrients, 12(10), 3027. https://doi.org/10.3390/nu12103027
- Ju, I. G., Son, S. Y., Lee, S., Im, H., Huh, E., Eo, H., Choi, J. G., Sohn, M. W., Yim, S. V., Kim, S. Y., Kim, D. H., Lee, C. H., & Oh, M. S. (2022). Protective effects of CCL01 against Abeta-induced neurotoxicity in 5xFAD transgenic mouse model of Alzheimer's disease. Biomedicine & Pharmacotherapy, 158, 114105. https://doi.org/10.1016/j.biopha.2022.114105
- Kheiri, G., Dolatshahi, M., Rahmani, F., & Rezaei, N. (2018). Role of p38/MAPKs in Alzheimer's disease: Implications for amyloid beta toxicity targeted therapy. Reviews in the Neurosciences, 30(1), 9–30. https://doi.org/10.1515/revneuro-2018-0008
- Kim, N., Do, J., Ju, I. G., Jeon, S. H., Lee, J. K., & Oh, M. S. (2020). Picrorhiza kurroa prevents memory deficits by inhibiting NLRP3 inflammasome activation and BACE1 expression in 5xFAD mice. Neurotherapeutics, 17(1), 189–199. https://doi.org/10.1007/s13311-019-00792-7
- Kim, H. G., Jeong, H. U., Hong, S. I., & Oh, M. S. (2015). Houttuyniae Herba attenuates kainic acid-induced neurotoxicity via calcium response modulation in the mouse hippocampus. Planta Medica, 81(18), 1697–1704. https://doi.org/10.1055/s-0035-1557832
- Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018). Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dementia (N Y), 4, 575–590. https://doi.org/10.1016/j.trci.2018.06.014
- Lim, S., Choi, J. G., Moon, M., Kim, H. G., Lee, W., Bak, H. R., Sung, H., Park, C. H., Kim, S. Y., & Oh, M. S. (2016). An optimized combination of ginger and Peony root effectively inhibits amyloid-beta accumulation and amyloid-beta-mediated pathology in AbetaPP/PS1 double-transgenic mice. Journal of Alzheimer's Disease, 50(1), 189–200. https://doi.org/10.3233/JAD-150839
- Long, J. M., & Holtzman, D. M. (2019). Alzheimer disease: An update on pathobiology and treatment strategies. Cell, 179(2), 312–339. https://doi.org/10.1016/j.cell.2019.09.001
- Lu, H. M., Liang, Y. Z., Yi, L. Z., & Wu, X. J. (2006). Anti-inflammatory effect of Houttuynia cordata injection. Journal of Ethnopharmacology, 104(1–2), 245–249. https://doi.org/10.1016/j.jep.2005.09.012
- Michelon, C., Michels, M., Abatti, M., Vieira, A., Borges, H., Dominguini, D., Barichello, T., & Dal-Pizzol, F. (2020). The role of secretase pathway in long-term brain inflammation and cognitive impairment in an animal model of severe sepsis. Molecular Neurobiology, 57(2), 1159–1169. https://doi.org/10.1007/s12035-019-01808-1
- Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 7(2), 27–31. https://doi.org/10.4103/0976-0105.177703
- Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., Berry, R., & Vassar, R. (2006). Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: Potential factors in amyloid plaque formation. The Journal of Neuroscience, 26(40), 10129–10140. https://doi.org/10.1523/JNEUROSCI.1202-06.2006
- Obregon, D., Hou, H., Deng, J., Giunta, B., Tian, J., Darlington, D., Shahaduzzaman, M., Zhu, Y., Mori, T., Mattson, M. P., & Tan, J. (2012). Soluble amyloid precursor protein-alpha modulates beta-secretase activity and amyloid-beta generation. Nature Communications, 3, 777. https://doi.org/10.1038/ncomms1781
- Park, H., & Oh, M. S. (2012). Houttuyniae Herba protects rat primary cortical cells from Abeta(25-35)-induced neurotoxicity via regulation of calcium influx and mitochondria-mediated apoptosis. Human & Experimental Toxicology, 31(7), 698–709. https://doi.org/10.1177/0960327111433898
- Russell, C. L., Semerdjieva, S., Empson, R. M., Austen, B. M., Beesley, P. W., & Alifragis, P. (2012). Amyloid-beta acts as a regulator of neurotransmitter release disrupting the interaction between synaptophysin and VAMP2. PLoS One, 7(8), e43201. https://doi.org/10.1371/journal.pone.0043201
- Singh, S. K., Srivastav, S., Yadav, A. K., Srikrishna, S., & Perry, G. (2016). Overview of Alzheimer's disease and some therapeutic approaches targeting Abeta by using several synthetic and herbal compounds. Oxidative Medicine and Cellular Longevity, 2016, 7361613. https://doi.org/10.1155/2016/7361613
- Tarawneh, R., & Holtzman, D. M. (2012). The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harbor Perspectives in Medicine, 2(5), a006148. https://doi.org/10.1101/cshperspect.a006148
- Zhang, Y., & He, M. L. (2017). Deferoxamine enhances alternative activation of microglia and inhibits amyloid beta deposits in APP/PS1 mice. Brain Research, 1677, 86–92. https://doi.org/10.1016/j.brainres.2017.09.019
- Zhang, Y. H., Ren, L. M., & Wang, X. Y. (2019). Inhibitory effect of Houttuynia cordata Thunb on LPS-induced retinal microglial activation. International Journal of Ophthalmology, 12(7), 1095–1100. https://doi.org/10.18240/ijo.2019.07.07
