Open Access Peer-reviewed Research Article

A novel role of NK3 receptor signaling in bipolar disorder

Article Sidebar

Effects of TACR3
Download PDF
Submitted   Jan 7, 2024
Published   Mar 14, 2024
Issue    Vol 5 No 1 (2023)
DOI   10.25082/JPBR.2023.01.003

Views

361

Downloads

72

Citations

PlumX Metrics

Main Article Content

Wei Zhang
School of Pharmacy, Yantai University, Yantai 264005, China
Linyao Yu
School of Pharmacy, Yantai University, Yantai 264005, China
Yaoqin Shi
School of Pharmacy, Yantai University, Yantai 264005, China
Yingtian Zhang
School of Pharmacy, Yantai University, Yantai 264005, China
Min Xu
School of Pharmacy, Yantai University, Yantai 264005, China
Yang Xu
School of Pharmacy, Yantai University, Yantai 264005, China
Chunmei Li
School of Pharmacy, Yantai University, Yantai 264005, China
Jingwei Tian corresponding author
School of Pharmacy, Yantai University, Yantai 264005, China

Abstract

Objective: Bipolar disorder (BD) affects more than 1% of the global population with limited therapeutic options. The neurokinin B (NKB)-neurokinin B receptor (NK3R) is involved in a variety of emotional activities. This study explored the role of NK3 receptor signaling in bipolar disorder.
Materials and methods: In this study, a model of intracerebroventricular (ICV) administration of OUA-induced BD was used to investigate the possible role of NK3R signaling in BD. The involvement of NK3R in the expression of OUA-induced BD was assessed by genetically knocking down the NK3R-encoding TACR3 gene with shRNA approach in the hippocampus and systemic administration of a NK3R antagonist ESN364,. Biochemical techniques were used to examine the NK3R-associated signaling changes and the oxidative stress parameters in the hippocampus of BD rats.
Results: The NK3R expression level was elevated in the hippocampus BD rats. Both TACR3 knockdown in the hippocampus and ESN364 treatment reversed the manic-like and depression-like behaviors in BD rats Inhibition of the NK3R signaling reversed oxidative stress-induced damage via upregulating the BDNF signaling pathway in the hippocampus.
Conclusion: These results demonstrated that NK3R signaling plays a key role in the pathogenesis of BD and that pharmacological antagonist of NK3R such as ESN364 could represent a novel therapeutic strategy for the management of BD.

Keywords
bipolar disorder, hippocampus, NK3R, ESN364, oxidative stress

Article Details

Supporting Agencies
This work was supported by the Natural Science Foundation of Shandong Province (No. ZR2020MH411).
How to Cite
Zhang, W., Yu, L., Shi, Y., Zhang, Y., Xu, M., Xu, Y., Li, C., & Tian, J. (2024). A novel role of NK3 receptor signaling in bipolar disorder. Journal of Pharmaceutical and Biopharmaceutical Research, 5(1), 382-395. https://doi.org/10.25082/JPBR.2023.01.003
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

References

  1. Mcgrath JJ, Alhamzawi A, Alonso J, et al. Age of onset and cumulative risk of mental disorders: a cross-national analysis of population surveys from 29 countries. The Lancet Psychiatry. 2023, 10(9): 668-681. https://doi.org/10.1016/S2215-0366(23)00193-1
  2. Cyrino LAR, Delwing-de Lima D, Ullmann OM, et al. Concepts of Neuroinflammation and Their Relationship With Impaired Mitochondrial Functions in Bipolar Disorder. Frontiers in Behavioral Neuroscience. 2021, 15. https://doi.org/10.3389/fnbeh.2021.609487
  3. Liu X, Ma X, Wang W, et al. The functional impairment of different subtypes and occupational states in euthymic patients with bipolar disorder. BMC Psychiatry. 2021, 21(1). https://doi.org/10.1186/s12888-021-03242-x
  4. Clemente AS, Diniz BS, Nicolato R, et al. Bipolar disorder prevalence: a systematic review and meta-analysis of the literature. Revista Brasileira de Psiquiatria. 2015, 37(2): 155-161. https://doi.org/10.1590/1516-4446-2012-1693
  5. Health, N.I.f., C. Excellence. Bipolar disorder: assessment and management. NICE, National Institute for Health and Care Excellence. Number of 2019.
  6. Morriss RK. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology, 2016.
  7. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disorders. 2018, 20(2): 97-170. https://doi.org/10.1111/bdi.12609
  8. Madireddy S, Madireddy S. Therapeutic Interventions to Mitigate Mitochondrial Dysfunction and Oxidative Stress–Induced Damage in Patients with Bipolar Disorder. International Journal of Molecular Sciences. 2022, 23(3): 1844. https://doi.org/10.3390/ijms23031844
  9. Rabie AM, Tantawy AS, Badr SMI. Design, Synthesis, and Biological Evaluation of Novel 5-Substituted-2-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazoles as Potent Antioxidants. American Journal of Organic Chemistry. 2016, 6(2): 54-80. https://doi.org/10.5923/j.ajoc.20160602.02
  10. Rabie AM, Tantawy AS, Badr SM. Design, synthesis, and biological evaluation of new 5-substituted-1, 3, 4-thiadiazole-2-thiols as potent antioxidants. Researcher. 2018, 10: 21-43.
  11. Ebner K, Sartori S, Singewald N. Tachykinin Receptors as Therapeutic Targets in Stress-Related Disorders. Current Pharmaceutical Design. 2009, 15(14): 1647-1674. https://doi.org/10.2174/138161209788168074
  12. Meltzer H, Prus A. NK3 receptor antagonists for the treatment of schizophrenia. Drug Discovery Today: Therapeutic Strategies. 2006, 3(4): 555-560. https://doi.org/10.1016/j.ddstr.2006.11.013
  13. Meltzer HY, Arvanitis L, Bauer D, et al. Placebo-Controlled Evaluation of Four Novel Compounds for the Treatment of Schizophrenia and Schizoaffective Disorder. American Journal of Psychiatry. 2004, 161(6): 975-984. https://doi.org/10.1176/appi.ajp.161.6.975
  14. Quartara L, Altamura M, Evangelista S, et al. Tachykinin receptor antagonists in clinical trials. Expert Opinion on Investigational Drugs. 2009, 18(12): 1843-1864. https://doi.org/10.1517/13543780903379530
  15. Spooren W, Riemer C, Meltzer H. NK3 receptor antagonists: the next generation of antipsychotics? Nature Reviews Drug Discovery. 2005, 4(12): 967-975. https://doi.org/10.1038/nrd1905
  16. Dableh LJ, Yashpal K, Rochford J, et al. Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat. European Journal of Pharmacology. 2005, 507(1-3): 99-105. https://doi.org/10.1016/j.ejphar.2004.11.024
  17. SALOME N, STEMMELIN J, COHEN C, et al. Selective blockade of NK2 or NK3 receptors produces anxiolytic- and antidepressant-like effects in gerbils. Pharmacology Biochemistry and Behavior. 2006, 83(4): 533-539. https://doi.org/10.1016/j.pbb.2006.03.013
  18. Hoveyda HR, Fraser GL, Dutheuil G, et al. Optimization of Novel Antagonists to the Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part II). ACS Medicinal Chemistry Letters. 2015, 6(7): 736-740. https://doi.org/10.1021/acsmedchemlett.5b00117
  19. Fraser GL, Ramael S, Hoveyda HR, et al. The NK3 Receptor Antagonist ESN364 Suppresses Sex Hormones in Men and Women. The Journal of Clinical Endocrinology & Metabolism. 2016, 101(2): 417-426. https://doi.org/10.1210/jc.2015-3621
  20. El-Mallakh RS. The Na,K-ATPase hypothesis for manic-depression. I. General considerations. Medical Hypotheses. 1983, 12(3): 253-268. https://doi.org/10.1016/0306-9877(83)90042-7
  21. El-Mallakh RS, Wyatt RJ. The Na,K-ATPase hypothesis for bipolar illness. Biological Psychiatry. 1995, 37(4): 235-244. https://doi.org/10.1016/0006-3223(94)00201-d
  22. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nature Neuroscience. 2010, 13(10): 1161-1169. https://doi.org/10.1038/nn.2647
  23. Broadhurst PL. The Place of Animal Psychology in the Development of Psychosomatic Research. Advances in Psychosomatic Medicine.: 63-69. https://doi.org/10.1159/000386484
  24. Ericson E, Samuelsson J, Ahlenius S. Photocell measurements of rat motor activity. Journal of Pharmacological Methods. 1991, 25(2): 111-122. https://doi.org/10.1016/0160-5402(91)90002-m
  25. Valvassori SS, Budni J, Varela RB, et al. Contributions of animal models to the study of mood disorders. Revista Brasileira de Psiquiatria. 2013, 35(suppl 2): S121-S131. https://doi.org/10.1590/1516-4446-2013-1168
  26. Valvassori SS, Resende WR, Lopes-Borges J, et al. Effects of mood stabilizers on oxidative stress-induced cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania. Journal of Psychiatric Research. 2015, 65: 63-70. https://doi.org/10.1016/j.jpsychires.2015.04.009
  27. Jornada LK, Moretti M, Valvassori SS, et al. Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain. Journal of Psychiatric Research. 2010, 44(8): 506-510. https://doi.org/10.1016/j.jpsychires.2009.11.002
  28. Lopes-Borges J, Valvassori SS, Varela RB, et al. Histone deacetylase inhibitors reverse manic-like behaviors and protect the rat brain from energetic metabolic alterations induced by ouabain. Pharmacology Biochemistry and Behavior. 2015, 128: 89-95. https://doi.org/10.1016/j.pbb.2014.11.014
  29. Riegel RE, Valvassori SS, Elias G, et al. Animal model of mania induced by ouabain: Evidence of oxidative stress in submitochondrial particles of the rat brain. Neurochemistry International. 2009, 55(7): 491-495. https://doi.org/10.1016/j.neuint.2009.05.003
  30. Riegel RE, Valvassori SS, Moretti M, et al. Intracerebroventricular ouabain administration induces oxidative stress in the rat brain. International Journal of Developmental Neuroscience. 2010, 28(3): 233-237. https://doi.org/10.1016/j.ijdevneu.2010.02.002
  31. Scaini G, Valvassori SS, Diaz AP, et al. Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings. Brazilian Journal of Psychiatry. 2020, 42(5): 536-551. https://doi.org/10.1590/1516-4446-2019-0732
  32. Valvassori SS, Dal-Pont GC, Resende WR, et al. Validation of the animal model of bipolar disorder induced by Ouabain: face, construct and predictive perspectives. Translational Psychiatry. 2019, 9(1). https://doi.org/10.1038/s41398-019-0494-6
  33. Andreazza AC, Kapczinski F, Kauer-Sant’Anna M, et al. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. Journal of Psychiatry and Neuroscience. 2009, 34: 263-271.
  34. Roda Â, Chendo I, Kunz M. Biomarkers and staging of bipolar disorder: a systematic review. Trends in Psychiatry and Psychotherapy. 2014, 37(1): 03-11. https://doi.org/10.1590/2237-6089-2014-0002
  35. Salim S. Oxidative Stress and the Central Nervous System. Journal of Pharmacology and Experimental Therapeutics. 2016, 360(1): 201-205. https://doi.org/10.1124/jpet.116.237503
  36. Andreazza AC, Kauer-Sant’Anna M, Frey BN, et al. Effects of mood stabilizers on DNA damage in an animal model of mania. Journal of Psychiatry and Neuroscience. 2008, 33: 516-524.
  37. Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. International Journal of Developmental Neuroscience. 2010, 29(3): 311-324. https://doi.org/10.1016/j.ijdevneu.2010.08.007
  38. Madireddy S, Madireddy S. Regulation of Reactive Oxygen Species-Mediated Damage in the Pathogenesis of Schizophrenia. Brain Sciences. 2020, 10(10): 742. https://doi.org/10.3390/brainsci10100742
  39. Bitanihirwe BKY, Woo TUW. Oxidative stress in schizophrenia: An integrated approach. Neuroscience & Biobehavioral Reviews. 2011, 35(3): 878-893. https://doi.org/10.1016/j.neubiorev.2010.10.008
  40. Collin F. Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases. International Journal of Molecular Sciences. 2019, 20(10): 2407. https://doi.org/10.3390/ijms20102407
  41. Morris G, Puri BK, Walker AJ, et al. The compensatory antioxidant response system with a focus on neuroprogressive disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019, 95: 109708. https://doi.org/10.1016/j.pnpbp.2019.109708
  42. Singh A, Kukreti R, Saso L, et al. Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules. 2019, 24(8): 1583. https://doi.org/10.3390/molecules24081583
  43. Steckert AV, Valvassori SS, Moretti M, et al. Role of oxidative stress in the pathophysiology of bipolar disorder. Neurochemical Research. 2010, 35(9): 1295-1301. https://doi.org/10.1007/s11064-010-0195-2
  44. Younus H. Therapeutic potentials of superoxide dismutase. International Journal of Health Sciences. 2018, 12: 88.
  45. Valvassori SS, Tonin PT, Varela RB, et al. Lithium modulates the production of peripheral and cerebral cytokines in an animal model of mania induced by dextroamphetamine. Bipolar Disorders. 2015, 17(5): 507-517. https://doi.org/10.1111/bdi.12299
  46. Humpel C, Saria A, Regoli D. Injection of tachykinins and selective neurokinin receptor ligands into the substantia nigra reticulata increases striatal dopamine and 5-hydroxytryptamine metabolism. European Journal of Pharmacology. 1991, 195(1): 107-114. https://doi.org/10.1016/0014-2999(91)90387-6
  47. Keegan KD, Woodruff GN, Pinnock RD. The selective NK3 receptor agonist senktide excites a subpopulation of dopamine‐sensitive neurones in the rat substantia nigra pars compacta in vitro. British Journal of Pharmacology. 1992, 105(1): 3-5. https://doi.org/10.1111/j.1476-5381.1992.tb14199.x
  48. Jon Stoessl A, Szczutkowski E, Glenn B, et al. Behavioural effects of selective tachykinin agonists in midbrain dopamine regions. Brain Research. 1991, 565(2): 254-262. https://doi.org/10.1016/0006-8993(91)91657-m
  49. Song M, Martinowich K, Lee FS. BDNF at the synapse: why location matters. Molecular Psychiatry. 2017, 22(10): 1370-1375. https://doi.org/10.1038/mp.2017.144
  50. Wang D, Li H, Du X, et al. Circulating Brain-Derived Neurotrophic Factor, Antioxidant Enzymes Activities, and Mitochondrial DNA in Bipolar Disorder: An Exploratory Report. Frontiers in Psychiatry. 2020, 11. https://doi.org/10.3389/fpsyt.2020.514658
  51. Fernandes BS, Molendijk ML, Köhler CA, et al. Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Medicine. 2015, 13(1). https://doi.org/10.1186/s12916-015-0529-7
  52. Lin PY. State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: A meta-analytic study. Neuroscience Letters. 2009, 466(3): 139-143. https://doi.org/10.1016/j.neulet.2009.09.044
  53. Munkholm K, Vinberg M, Kessing LV. Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis. Molecular Psychiatry. 2015, 21(2): 216-228. https://doi.org/10.1038/mp.2015.54
  54. Polyakova M, Stuke K, Schuemberg K, et al. BDNF as a biomarker for successful treatment of mood disorders: A systematic & quantitative meta-analysis. Journal of Affective Disorders. 2015, 174: 432-440. https://doi.org/10.1016/j.jad.2014.11.044
  55. Wu R, Fan J, Zhao J, et al. The relationship between neurotrophins and bipolar disorder. Expert Review of Neurotherapeutics. 2013, 14(1): 51-65. https://doi.org/10.1586/14737175.2014.863709
  56. Sigitova E, Fišar Z, Hroudová J, et al. Biological hypotheses and biomarkers of bipolar disorder. Psychiatry and Clinical Neurosciences. 2017, 71(2): 77-103. https://doi.org/10.1111/pcn.12476
  57. de Oliveira GS, Ceresér KM, Fernandes BS, et al. Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients. Journal of Psychiatric Research. 2009, 43(14): 1171-1174. https://doi.org/10.1016/j.jpsychires.2009.04.002
  58. Fernandes BS, Gama CS, Kauer-Sant’Anna M, et al. Serum brain-derived neurotrophic factor in bipolar and unipolar depression: A potential adjunctive tool for differential diagnosis. Journal of Psychiatric Research. 2009, 43(15): 1200-1204. https://doi.org/10.1016/j.jpsychires.2009.04.010