Open Access Peer-reviewed Research Article

LPM570065 ameliorates anxiety-like and depressive-like behaviors in CUMS rats through regulating DNA methylation in hippocampus

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Density of dendritic spines
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Submitted   Jan 23, 2023
Published   Apr 17, 2023
Issue    Vol 4 No 2 (2022)
DOI   10.25082/JPBR.2022.02.005

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Shengmin Ji
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China
Chunmei Li
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China
Wei Zhang
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China
Linyao Yu
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China
Yue Yang
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China
Yaoqin Shi
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China
Hongbo Wang
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China
Jingwei Tian corresponding author
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China

Abstract

Objective: This study aims to analyze the effects and underlying mechanisms of LPM570065 on behavioral phenotypes in rats with generalized anxiety disorder (GAD).
Methods: The chronic unpredictable mild stress (CUMS) rats were used to observe the results of LPM570065. Total 72 male Sprague Dawley rats were divided into control, vehicle (0.5% CMC-Na), LPM570065 (32 mg/kg) and diazepam (3 mg/kg) groups, 12 rats in each group. Anxiety-like behaviors of rats were observed by elevated zero maze test and novelty-suppressed feeding test. Depressive-like behaviors of rats were detected by forced swimming test. DNA methylation in hippocampi of rats were measured by reduced representation bisulfite sequencing (RRBS). In hippocampi of rats, expressions of DNA methyltransferase (DNMT) 1 and DNMT3a proteins were measured by western blot, and density of dendritic spines was observed by Golgi staining.
Results: Compared with the control group, the weights of rats were obviously decreased (p < 0.001) and the rats showed anxiety-like and depressive-like behaviors (p < 0.001) in the vehicle group. Compared with the vehicle group, the weights of rats were significantly increased (p < 0.001) and the anxiety-like and depressive-like behaviors were improved (p < 0.001) in the LPM570065 group. The results of RRBS showed that there were 49964 promoters showed hypermethylation in the LPM570065 treatment rats contrasted to the vehicle treatment rats. In addition, these promoters were enriched in signal transduction and immune function. Furthermore, the expressions of DNMT1 and DNMT3a were significantly decreased, the density of dendritic spines was significantly increased in hippocampi of LPM570065 treatment rats compared with the vehicle treatment rats.
Conclusions: LPM570065 ameliorates anxiety-like and depressive-like behaviors in CUMS rats, and its mechanism is possible associated with downregulating DNA methylation in hippocampus.

Keywords
LPM570065, generalized anxiety disorder, western blot

Article Details

How to Cite
Ji, S., Li, C., Zhang, W., Yu, L., Yang, Y., Shi, Y., Wang, H., & Tian, J. (2023). LPM570065 ameliorates anxiety-like and depressive-like behaviors in CUMS rats through regulating DNA methylation in hippocampus. Journal of Pharmaceutical and Biopharmaceutical Research, 4(2), 340-348. https://doi.org/10.25082/JPBR.2022.02.005
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References

  1. Andreescu C and Lee S. Anxiety disorders in the elderly. Anxiety Disorders: Rethinking and Understanding Recent Discoveries, 2020, 1191: 561-576. http://doi.org/10.1007/978-981-32-9705-0_28
  2. Arango-Dávila CA and Rincón-Hoyos HG. Depressive disorder, anxiety disorder and chronic pain: multiple manifestations of a common clinical and pathophysiological core. Revista Colombiana de Psiquiatría (English ed.), 2018, 47(1): 46-55. https://doi.org/10.1016/j.rcp.2016.10.007
  3. Liu Y, Zhao J and Guo W. Emotional roles of mono-aminergic neurotransmitters in major depressive disorder and anxiety disorders. Frontiers in psychology, 2018, 9: 2201. https://doi.org/10.3389/fpsyg.2018.02201
  4. Murrough JW, Yaqubi S, Sayed S, et al. Emerging drugs for the treatment of anxiety. Expert opinion on emerging drugs, 2015, 20(3): 393-406. https://doi.org/10.1517/14728214.2015.1049996
  5. Zhu J, Klein-Fedyshin M and Stevenson JM. Serotonin transporter gene polymorphisms and selective serotonin reuptake inhibitor tolerability: review of pharmacogenetic evidence. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 2017, 37(9): 1089-1104. https://doi.org/10.1002/phar.1978
  6. Li C, Jiang W, Gao Y, et al. Acute, subchronic oral toxicity, and genotoxicity evaluations of LPM570065, a new potent triple reuptake inhibitor. Regulatory Toxicology and Pharmacology, 2018, 98: 129-139. https://doi.org/10.1016/j.yrtph.2018.07.011
  7. Meng P, Li C, Duan S, et al. Epigenetic mechanism of 5-HT/NE/DA triple reuptake inhibitor on adult depression susceptibility in early stress mice. Frontiers in Pharmacology, 2022, 13: 848251. https://doi.org/10.3389/fphar.2022.848251
  8. Pillai-Kastoori L, Schutz-Geschwender AR and Harford JA. A systematic approach to quantitative Western blot analysis. Analytical biochemistry, 2020, 593: 113608. https://doi.org/10.1016/j.ab.2020.113608
  9. Du F. Golgi-Cox staining of neuronal dendrites and dendritic spines with FD rapid GolgiStain™ kit. Current protocols in neuroscience, 2019, 88(1): e69. https://doi.org/10.1002/cpns.69
  10. Bartlett AA, Singh R and Hunter RG. Anxiety and epigenetics. Neuroepigenomics in Aging and Disease, 2017, 978: 145-166. https://doi.org/10.1007/978-3-319-53889-1_8
  11. Liu W, Xue X, Xia J, et al. Swimming exercise reverses CUMS-induced changes in depression-like behaviors and hippocampal plasticity-related proteins. Journal of Affective Disorders, 2018, 227: 126-135. https://doi.org/10.1016/j.jad.2017.10.019
  12. Kulkarni SK, Singh K and Bishnoi M. Elevated zero maze: a paradigm to evaluate antianxiety effects of drugs. Methods and findings in experimental and clinical pharmacology, 2007, 29(5): 343-348. https://doi.org/10.1358/mf.2007.29.5.1117557
  13. Pellow S, Chopin P, File SE, et al. Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of neuroscience methods, 1985, 14(3): 149-167. https://doi.org/10.1016/0165-0270(85)90031-7
  14. Blasco-Serra A, González-Soler EM, Cervera-Ferri A, et al. A standardization of the novelty-suppressed feeding test protocol in rats. Neuroscience Letters, 2017, 658: 73-78. https://doi.org/10.1016/j.neulet.2017.08.019
  15. Yankelevitch-Yahav R, Franko M, Huly A, et al. The forced swim test as a model of depressive-like behavior. Journal of Visualized Experiments, 2015, 97: e52587. https://doi.org/10.3791/52587
  16. von Känel T and Huber AR. DNA methylation analysis. Swiss Med Wkly, 2013, 143: w13799. https://doi.org/10.4414/smw.2013.13799
  17. Nakabayashi K, Yamamura M, Haseagawa K, et al. Reduced representation bisulfite sequencing (RRBS). Epigenomics: Methods and Protocols. New York, NY: Springer US, 2022, 2577: 39-51. https://doi.org/10.1007/978-1-0716-2724-2_3
  18. Poh WJ, Wee CP and Gao Z. DNA Methyltransferase Activity Assays: Advances and Challenges. Theranostics, 2016, 6(3): 369-391. https://doi.org/10.7150/thno.13438
  19. Jin B and Robertson KD. DNA methyltransferases, DNA damage repair, and cancer. Epigenetic alterations in oncogenesis, 2012, 754: 3-29. https://doi.org/10.1007/978-1-4419-9967-2_1
  20. Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nature Reviews Genetics, 2018, 19(2): 81-92. https://doi.org/10.1038/nrg.2017.80
  21. Magee JC and Grienberger C. Synaptic plasticity forms and functions. Annual review of neuroscience, 2020, 43: 95-117. https://doi.org/10.1146/annurev-neuro-090919-022842
  22. Citri A and Malenka RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology, 2008, 33(1): 18-41. https://doi.org/10.1038/sj.npp.1301559