Icariside II protects dopaminergic neurons from 1‑methyl‑4‑phenylpyridinium‑induced neurotoxicity by downregulating HDAC2 to restore mitochondrial function

Fan,Wenbo; Zhou,Jianwu

doi:10.3892/etm.2023.12328

Icariside II protects dopaminergic neurons from 1‑methyl‑4‑phenylpyridinium‑induced neurotoxicity by downregulating HDAC2 to restore mitochondrial function

Authors:
- Wenbo Fan
- Jianwu Zhou
View Affiliations

Affiliations: Pharmaceutical Technology Department, Chemical Engineering School, Jiuquan Vocational Technical College, Jiuquan, Gansu 735000, P.R. China, Medical Laboratory of Qinghai Provincial People's Hospital, Xining, Qinghai 810000, P.R. China
Published online on: November 28, 2023 https://doi.org/10.3892/etm.2023.12328
Article Number: 40
Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Icariside II (ICS II) is known to confer notable therapeutic effects against a variety of neurodegenerative diseases, such as AD. Therefore, the present study aimed to evaluate the possible effects of ICS II on 1‑methyl‑4‑phenylpyridinium (MPP⁺)‑induced SK‑N‑SH cell injury, in addition to understanding the underlying mechanism of action. The MPP⁺‑induced SK‑N‑SH cell model was used to simulate PD in vitro. The viability and mitochondrial membrane potential of SK‑N‑SH cells were detected by MTT assay and JC‑1 staining, respectively. Lactate dehydrogenase (LDH) release, ATP levels and complex I activity in treated SK‑N‑SH cells were measured using LDH activity, ATP and Complex I assay kits, respectively. The protein expression levels of histone deacetylase 2 (HDAC2) and γ‑H2A histone family member X and the copy number of mitochondrial DNA were measured by western blotting or reverse transcription‑quantitative PCR, respectively. Autodock 4.2 was used to predict the molecular docking site of ICS II on HDAC2. The results of the present study demonstrated that ICS II mitigated SK‑N‑SH cytotoxicity induced by MPP⁺. Specifically, ICS II alleviated DNA damage and restored mitochondrial function in SK‑N‑SH cells treated with MPP⁺. In addition, ICS II reduced the HDAC2 protein expression levels in MPP⁺‑induced SK‑N‑SH cells. However, overexpression of HDAC2 reversed the protective effects of ICS II on DNA damage and mitochondrial dysfunction in MPP⁺‑induced SK‑N‑SH cells. In conclusion, the results of the present study suggest that ICS II can protect dopaminergic neurons from MPP⁺‑induced neurotoxicity by downregulating HDAC2 expression to restore mitochondrial function.

View Figures

View References

1	Sharma S, Awasthi A and Singh S: Altered gut microbiota and intestinal permeability in Parkinson's disease: Pathological highlight to management. Neurosci Lett. 712(134516)2019.PubMed/NCBI View Article : Google Scholar
2	Nair AT, Ramachandran V, Joghee NM, Antony S and Ramalingam G: Gut microbiota dysfunction as reliable non-invasive early diagnostic biomarkers in the pathophysiology of Parkinson's disease: A critical review. J Neurogastroenterol Motil. 24:30–42. 2018.PubMed/NCBI View Article : Google Scholar
3	Xu X, Wang R, Hao Z, Wang G, Mu C, Ding J, Sun W and Ren H: DJ-1 regulates tyrosine hydroxylase expression through CaMKKβ/CaMKIV/CREB1 pathway in vitro and in vivo. J Cell Physiol. 235:869–879. 2020.PubMed/NCBI View Article : Google Scholar
4	Yin C, Deng Y, Liu Y, Gao J, Yan L and Gong Q: Icariside II ameliorates cognitive impairments induced by chronic cerebral hypoperfusion by inhibiting the amyloidogenic pathway: Involvement of BDNF/TrkB/CREB signaling and up-regulation of PPARα and PPARγ in rats. Front Pharmacol. 9(1211)2018.PubMed/NCBI View Article : Google Scholar
5	Deng Y, Xiong D, Yin C, Liu B, Shi J and Gong Q: Icariside II protects against cerebral ischemia-reperfusion injury in rats via nuclear factor-κB inhibition and peroxisome proliferator-activated receptor up-regulation. Neurochem Int. 96:56–61. 2016.PubMed/NCBI View Article : Google Scholar
6	Yan BY, Pan CS, Mao XW, Yang L, Liu YY, Yan L, Mu HN, Wang CS, Sun K, Liao FL, et al: Icariside II improves cerebral microcirculatory disturbance and alleviates hippocampal injury in gerbils after ischemia-reperfusion. Brain Res. 1573:63–73. 2014.PubMed/NCBI View Article : Google Scholar
7	Yin C, Deng Y, Gao J, Li X, Liu Y and Gong Q: Icariside II, a novel phosphodiesterase-5 inhibitor, attenuates streptozotocin-induced cognitive deficits in rats. Neuroscience. 328:69–79. 2016.PubMed/NCBI View Article : Google Scholar
8	Deng Y, Long L, Wang K, Zhou J, Zeng L, He L and Gong Q: Icariside II, a broad-spectrum anti-cancer agent, reverses beta-amyloid-induced cognitive impairment through reducing inflammation and apoptosis in rats. Front Pharmacol. 8(39)2017.PubMed/NCBI View Article : Google Scholar
9	Xiao HH, Chen JC, Li H, Li RH, Wang HB, Song HP, Li HY, Shan GS, Tian Y, Zhao YM, et al: Icarisid II rescues cognitive dysfunction via activation of Wnt/β-catenin signaling pathway promoting hippocampal neurogenesis in APP/PS1 transgenic mice. Phytother Res. 36:2095–2108. 2022.PubMed/NCBI View Article : Google Scholar
10	Yan L, Deng Y, Gao J, Liu Y, Li F, Shi J and Gong Q: Icariside II effectively reduces spatial learning and memory impairments in Alzheimer's disease model mice targeting beta-amyloid production. Front Pharmacol. 8(106)2017.PubMed/NCBI View Article : Google Scholar
11	Li Y, Gu Z, Lin S, Chen L, Dzreyan V, Eid M, Demyanenko S and He B: Histone deacetylases as epigenetic targets for treating Parkinson's disease. Brain Sci. 12(672)2022.PubMed/NCBI View Article : Google Scholar
12	Ma P and Schultz RM: HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation. Cell Death Differ. 23:1119–1127. 2016.PubMed/NCBI View Article : Google Scholar
13	Stoddard SV, May XA, Rivas F, Dodson K, Vijayan S, Adhika S, Parker K and Watkins DL: Design of potent panobinostat histone deacetylase inhibitor derivatives: Molecular considerations for enhanced isozyme selectivity between HDAC2 and HDAC8. Mol Inform. 38(e1800080)2019.PubMed/NCBI View Article : Google Scholar
14	Chen J, Li N, Liu B, Ling J, Yang W, Pang X and Li T: Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathways. Life Sci. 248(117469)2020.PubMed/NCBI View Article : Google Scholar
15	Tan Y, Delvaux E, Nolz J, Coleman PD, Chen S and Mastroeni D: Upregulation of histone deacetylase 2 in laser capture nigral microglia in Parkinson's disease. Neurobiol Aging. 68:134–141. 2018.PubMed/NCBI View Article : Google Scholar
16	Choong CJ, Sasaki T, Hayakawa H, Yasuda T, Baba K, Hirata Y, Uesato S and Mochizuki H: A novel histone deacetylase 1 and 2 isoform-specific inhibitor alleviates experimental Parkinson's disease. Neurobiol Aging. 37:103–116. 2016.PubMed/NCBI View Article : Google Scholar
17	Singer TP and Ramsay RR: Mechanism of the neurotoxicity of MPTP. An update. FEBS Lett. 274:1–8. 1990.PubMed/NCBI View Article : Google Scholar
18	Yuan X, Wu Y, Lu L and Feng J: Long noncoding RNA SNHG14 knockdown exerts a neuroprotective role in MPP⁺-induced Parkinson's disease cell model through mediating miR-135b-5p/KPNA4 axis. Metab Brain Dis. 37:2363–2373. 2022.PubMed/NCBI View Article : Google Scholar
19	Xu F, Lv C, Deng Y, Liu Y, Gong Q, Shi J and Gao J: Icariside II, a PDE5 inhibitor, suppresses oxygen-glucose deprivation/reperfusion-induced primary hippocampal neuronal death through activating the PKG/CREB/BDNF/TrkB signaling pathway. Front Pharmacol. 11(523)2020.PubMed/NCBI View Article : Google Scholar
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
21	Halczuk KM, Boguszewska K, Urbaniak SK, Szewczuk M and Karwowski BT: 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a cause of autoimmune thyroid diseases (AITD) during pregnancy? Yale J Biol Med. 93:501–515. 2020.PubMed/NCBI
22	Perelman A, Wachtel C, Cohen M, Haupt S, Shapiro H and Tzur A: JC-1: Alternative excitation wavelengths facilitate mitochondrial membrane potential cytometry. Cell Death Dis. 3(e430)2012.PubMed/NCBI View Article : Google Scholar
23	Jiang DQ, Ma YJ, Wang Y, Lu HX, Mao SH and Zhao SH: Microglia activation induces oxidative injury and decreases SIRT3 expression in dopaminergic neuronal cells. J Neural Transm (Vienna). 126:559–568. 2019.PubMed/NCBI View Article : Google Scholar
24	Harrington JS, Ryter SW, Plataki M, Price DR and Choi AMK: Mitochondria in health, disease, and aging. Physiol Rev. 103:2349–2422. 2023.PubMed/NCBI View Article : Google Scholar
25	Golpich M, Amini E, Mohamed Z, Azman Ali R, Mohamed Ibrahim N and Ahmadiani A: Mitochondrial dysfunction and biogenesis in neurodegenerative diseases: Pathogenesis and treatment. CNS Neurosci Ther. 23:5–22. 2017.PubMed/NCBI View Article : Google Scholar
26	Grimm A and Eckert A: Brain aging and neurodegeneration: From a mitochondrial point of view. J Neurochem. 143:418–431. 2017.PubMed/NCBI View Article : Google Scholar
27	Park JS, Davis RL and Sue CM: Mitochondrial dysfunction in Parkinson's disease: New mechanistic insights and therapeutic perspectives. Curr Neurol Neurosci Rep. 18(21)2018.PubMed/NCBI View Article : Google Scholar
28	Kim HY, Bae CH, Kim J, Lee Y, Jeon H, Kim H and Kim S: Rumex japonicus houtt. protects dopaminergic neurons by regulating mitochondrial function and gut-brain axis in in vitro and in vivo models of Parkinson's disease. Antioxidants (Basel). 11(141)2022.PubMed/NCBI View Article : Google Scholar
29	Wu LK, Agarwal S, Kuo CH, Kung YL, Day CH, Lin PY, Lin SZ, Hsieh DJ, Huang CY and Chiang CY: Artemisia leaf extract protects against neuron toxicity by TRPML1 activation and promoting autophagy/mitophagy clearance in both in vitro and in vivo models of MPP+/MPTP-induced Parkinson's disease. Phytomedicine. 104(154250)2022.PubMed/NCBI View Article : Google Scholar
30	Liu Y, Wang Y, Chen Q, Jiao F, Wang L and Gong Z: HDAC2 inhibitor CAY10683 reduces intestinal epithelial cell apoptosis by inhibiting mitochondrial apoptosis pathway in acute liver failure. Histol Histopathol. 34:1173–1184. 2019.PubMed/NCBI View Article : Google Scholar
31	Frankowski H, Yeboah F, Berry BJ, Kinoshita C, Lee M, Evitts K, Davis J, Kinoshita Y, Morrison RS and Young JE: Knock-down of HDAC2 in human induced pluripotent stem cell derived neurons improves neuronal mitochondrial dynamics, neuronal maturation and reduces amyloid beta peptides. Int J Mol Sci. 22(2526)2021.PubMed/NCBI View Article : Google Scholar
32	Li Y, Feng L, Xie D, Lin M, Li Y, Chen N, Yang D, Gao J, Zhu Y and Gong Q: Icariside II, a naturally occurring SIRT3 agonist, protects against myocardial infarction through the AMPK/PGC-1α/apoptosis signaling pathway. Antioxidants (Basel). 11(1465)2022.PubMed/NCBI View Article : Google Scholar
33	Feng L, Gao J, Liu Y, Shi J and Gong Q: Icariside II alleviates oxygen-glucose deprivation and reoxygenation-induced PC12 cell oxidative injury by activating Nrf2/SIRT3 signaling pathway. Biomed Pharmacother. 103:9–17. 2018.PubMed/NCBI View Article : Google Scholar