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Mechanism of Antidepressant Action of (2R,6R)-6-Hydroxynorketamine (HNK) and Its Compounds: Insights from Proteomic Analysis

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Abstract

The effects of HNK, I5, and I6 on the expression of protein in hippocampus of depressed mice were studied by isobaric tags for relative and absolute quantitation (iTRAQ) to explore the mechanism of their antidepressant action. HNK, I5, and I6 were administered intragastric administration once a day in the morning for 7 days. The drug was subsequently discontinued for 7 days (without any treatment). On the 15th day, mice in each group were given the drug (1.0, 10.0, 30.0 mg/kg) intragastric stimulation and mouse hippocampal tissues were taken to perform iTRAQ to identify differentially expressed proteins, and bioinformatics was used to analyze the functional enrichment of the differentially expressed proteins. Compared with Ctr group, the number of differentially expressed proteins in HNK, I5, and I6 treatment groups was 158, 88, and 105, respectively. The three groups shared 29 differentially expressed proteins. In addition, compared with HNK group, the number of differentially expressed proteins in I5 and I6 groups was 201 and 203, respectively. A total of 47 and 56 differentially expressed proteins were co-expressed in I5 and I6 groups. Bioinformatics analysis showed that these differentially expressed proteins mainly had the functions of binding, biocatalysis, and transport, and mainly participated in cellular process, biological regulation process, biological metabolism process, and stress reaction process. GO and KEGG pathway analysis found that these differentially expressed proteins were involved long-term potentiation, G13 pathway, platelet activation pathway, and MAPK signaling pathway. HNK, I5, and I6 antidepressants are closely related to sudden stress sensitivity, stress resistance, neurotransmitter, and metabolic pathways. This study provides a scientific basis to further elucidate the mechanism and clinical application of HNK, I5, and I6 antidepressants.

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Data Availability

Data is available from the corresponding author on request.

References

  1. Fries GR et al (2023) Molecular pathways of major depressive disorder converge on the synapse. Mol Psychiatry 28(1):284–297

    Article  CAS  PubMed  Google Scholar 

  2. Christian C et al (2023) A Pilot, Time-series investigation of depression, anxiety, and eating disorder symptoms in adults experiencing major depressive symptoms: the need for eating disorder assessment and research in depression. Behav Ther 54(2):214–229

    Article  PubMed  Google Scholar 

  3. Correia-Melo FS et al (2020) Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: a randomized, double-blind, non-inferiority study. J Affect Disord 264:527–534

    Article  CAS  PubMed  Google Scholar 

  4. Kheirabadi D et al (2020) Comparison of rapid antidepressant and antisuicidal effects of intramuscular ketamine, oral ketamine, and electroconvulsive therapy in patients with major depressive disorder: a pilot study. J Clin Psychopharmacol 40(6):588–593

    Article  CAS  PubMed  Google Scholar 

  5. Papadimitropoulou K et al (2017) Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis. Curr Med Res Opin 33(4):701–711

    Article  CAS  PubMed  Google Scholar 

  6. Romeo B et al (2015) Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Res 230(2):682–688

    Article  CAS  PubMed  Google Scholar 

  7. McKnight RF et al (2012) Lithium toxicity profile: a systematic review and meta-analysis. Lancet 379(9817):721–728

    Article  CAS  PubMed  Google Scholar 

  8. Leucht S et al (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382(9896):951–962

    Article  CAS  PubMed  Google Scholar 

  9. Solmi M et al (2020) Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects. World Psychiatry 19(2):214–232

    Article  PubMed  PubMed Central  Google Scholar 

  10. Baghdadi M et al (2018) Interleukin-34, a comprehensive review. J Leukoc Biol 104(5):931–951

    Article  CAS  PubMed  Google Scholar 

  11. Nugent AC et al (2020) The effect of ketamine on electrophysiological connectivity in major depressive disorder. Front Psychiatry 11:519

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ruberto VL, Jha MK, Murrough JW (2020) Pharmacological Treatments for Patients with Treatment-Resistant Depression. Pharmaceuticals (Basel) 13(6):116

  13. Jha MK, Rush AJ, Trivedi MH (2018) When discontinuing SSRI antidepressants is a challenge: management tips. Am J Psychiatry 175(12):1176–1184

    Article  PubMed  Google Scholar 

  14. Warner CH et al (2006) Antidepressant discontinuation syndrome. Am Fam Physician 74(3):449–456

    PubMed  Google Scholar 

  15. Andrade C (2019) Oral ketamine for depression, 1: Pharmacologic Considerations and Clinical Evidence. J Clin Psychiatry 80(2):19f12820

  16. Acevedo-Diaz EE et al (2020) Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression. J Affect Disord 263:568–575

    Article  CAS  PubMed  Google Scholar 

  17. Tham JCW et al (2022) Repeated subcutaneous racemic ketamine in treatment-resistant depression: case series. Int Clin Psychopharmacol 37(5):206–214

    Article  PubMed  Google Scholar 

  18. Diazgranados N et al (2010) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67(8):793–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Williams NR et al (2019) Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Mol Psychiatry 24(12):1779–1786

    Article  CAS  PubMed  Google Scholar 

  20. Anderson IM et al (2017) Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trial. Lancet Psychiatry 4(5):365–377

    Article  PubMed  PubMed Central  Google Scholar 

  21. Basso L et al (2020) Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients. J Psychiatr Res 123:1–8

    Article  PubMed  Google Scholar 

  22. Ionescu DF et al (2019) Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: a randomized, double blind, placebo controlled trial. J Affect Disord 243:516–524

    Article  CAS  PubMed  Google Scholar 

  23. Fernie G et al (2018) Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial - CORRIGENDUM. Br J Psychiatry 212(5):323

    Article  PubMed  PubMed Central  Google Scholar 

  24. Carspecken CW et al (2018) Ketamine anesthesia does not improve depression scores in electroconvulsive therapy: a randomized clinical trial. J Neurosurg Anesthesiol 30(4):305–313

    Article  PubMed  Google Scholar 

  25. Zhang M et al (2018) A randomized clinical trial of adjunctive ketamine anesthesia in electro-convulsive therapy for depression. J Affect Disord 227:372–378

    Article  CAS  PubMed  Google Scholar 

  26. Jafarinia M et al (2016) Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: a double-blind, randomized, controlled trial. J Affect Disord 204:1–8

    Article  CAS  PubMed  Google Scholar 

  27. George D et al (2017) Pilot randomized controlled trial of titrated subcutaneous ketamine in older patients with treatment-resistant depression. Am J Geriatr Psychiatry 25(11):1199–1209

    Article  PubMed  Google Scholar 

  28. Daly EJ et al (2018) Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiat 75(2):139–148

    Article  Google Scholar 

  29. Harihar C, Dasari P, Srinivas JS (2013) Intramuscular ketamine in acute depression: a report on two cases. Indian J Psychiatry 55(2):186–8

    Article  PubMed  PubMed Central  Google Scholar 

  30. Arabzadeh S et al (2018) Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial. J Affect Disord 235:236–241

    Article  CAS  PubMed  Google Scholar 

  31. Christensen MC, Schmidt S, Grande I (2022) Effectiveness of vortioxetine in patients with major depressive disorder comorbid with generalized anxiety disorder: results of the RECONNECT study. J Psychopharmacol 36(5):566–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fitzgerald PJ, Yen JY, Watson BO (2019) Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test. PLoS ONE 14(4):e0215554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang T et al (2022) Esketamine alleviates postoperative depression-like behavior through anti-inflammatory actions in mouse prefrontal cortex. J Affect Disord 307:97–107

    Article  CAS  PubMed  Google Scholar 

  34. Zarcone D, Corbetta S (2017) Shared mechanisms of epilepsy, migraine and affective disorders. Neurol Sci 38(Suppl 1):73–76

    Article  PubMed  Google Scholar 

  35. Banerjee S et al (2021) Immunoprotective potential of Ayurvedic herb Kalmegh (Andrographis paniculata) against respiratory viral infections - LC-MS/MS and network pharmacology analysis. Phytochem Anal 32(4):629–639

    Article  CAS  PubMed  Google Scholar 

  36. Peng GJ et al (2015) Research on the pathological mechanism and drug treatment mechanism of depression. Curr Neuropharmacol 13(4):514–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Redler S et al (2017) Variants in CPLX1 in two families with autosomal-recessive severe infantile myoclonic epilepsy and ID. Eur J Hum Genet 25(7):889–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hajibabaie F et al (2023) A cocktail of polyherbal bioactive compounds and regular mobility training as senolytic approaches in age-dependent Alzheimer’s: the in silico analysis, lifestyle intervention in old age. J Mol Neurosci 73(2–3):171–184

    Article  CAS  PubMed  Google Scholar 

  39. Abedpoor N et al (2022) Cross brain-gut analysis highlighted hub genes and LncRNA networks differentially modified during leucine consumption and endurance exercise in mice with depression-like behaviors. Mol Neurobiol 59(7):4106–4123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zarcone D, Corbetta S (2017) Shared mechanisms of epilepsy, migraine and affective disorders. Neurol Sci 38:73–76

    Article  PubMed  Google Scholar 

  41. Sanna MD et al (2018) Antidepressant-like actions by silencing of neuronal ELAV-like RNA-binding proteins HuB and HuC in a model of depression in male mice. Neuropharmacology 135:444–454

    Article  CAS  PubMed  Google Scholar 

  42. Shmukler BE, Rivera A, Nishimura K et al (2022) Erythroid-specific inactivation of Slc12a6/Kcc3 by EpoR promoter-driven Cre expression reduces K-Cl cotransport activity in mouse erythrocytes. Physiol Re 10(5):e15186

    CAS  Google Scholar 

  43. Kato T (2007) Molecular genetics of bipolar disorder and depression. Psychiatry Clin Neurosci 61(1):3–19

    Article  CAS  PubMed  Google Scholar 

  44. Nguyen HD, Kim MS (2022) The protective effects of curcumin on depression: genes, transcription factors, and microRNAs involved. J Affect Disord 319:526–537

    Article  CAS  PubMed  Google Scholar 

  45. Gao Z et al (2023) Repurposing ketamine to treat cocaine use disorder: integration of artificial intelligence-based prediction, expert evaluation, clinical corroboration and mechanism of action analyses [published online ahead of print. Addiction. https://doi.org/10.1111/add.16168.

  46. Rivero G et al (2013) Brain RGS4 and RGS10 protein expression in schizophrenia and depression. Eff Drug Treat Psychopharmacol 226(1):177–188

    Article  CAS  Google Scholar 

  47. Agarwal A et al (2022) Prion protein biology through the lens of liquid-liquid phase separation. J Mol Biol 434(1):167368

    Article  CAS  PubMed  Google Scholar 

  48. Salaria S et al (2022) Protein biofortification in lentils (Lens culinaris Medik.) toward human health. Front Plant Sci 13:869713

    Article  PubMed  PubMed Central  Google Scholar 

  49. Gao L et al (2022) A possible connection between reactive oxygen species and the unfolded protein response in lens development: from insight to foresight. Front Cell Dev Biol 10:820949

    Article  PubMed  PubMed Central  Google Scholar 

  50. Farooq M et al (2012) GluA2 AMPA glutamate receptor subunit exhibits codon 607 Q/R RNA editing in the lens. Biochem Biophys Res Commun 418(2):273–277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xu HB et al (2012) Comparative proteomic analysis of plasma from major depressive patients: identification of proteins associated with lipid metabolism and immunoregulation. Int J Neuropsychopharmacol 15(10):1413–1425

    Article  CAS  PubMed  Google Scholar 

  52. Liu L et al (2016) The identification of metabolic disturbances in the prefrontal cortex of the chronic restraint stress rat model of depression. Behav Brain Res 305:148–156

    Article  CAS  PubMed  Google Scholar 

  53. Shell AL et al (2022) Associations between affective factors and high-frequency heart rate variability in primary care patients with depression. J Psychosom Res 161:110992

    Article  PubMed  Google Scholar 

  54. Liu X et al (2022) Mitochondrial-endoplasmic reticulum communication-mediated oxidative stress and autophagy. Biomed Res Int 2022:6459585

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zundel CG et al (2022) Air pollution, depressive and anxiety disorders, and brain effects: a systematic review. Neurotoxicology 93:272–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang Y et al (2021) The GABAB receptor mediates neuroprotection by coupling to G13. Sci Signal 14(705):eaaz4112

    Article  CAS  PubMed  Google Scholar 

  57. Wiera G et al (2022) Integrins bidirectionally regulate the efficacy of inhibitory synaptic transmission and control GABAergic plasticity. J Neurosci 42(30):5830–5842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ma K et al (2019) Identification of key genes, pathways, and miRNA/mRNA regulatory networks of CUMS-induced depression in nucleus accumbens by integrated bioinformatics analysis. Neuropsychiatr Dis Treat. 15:685–700

    Article  PubMed  PubMed Central  Google Scholar 

  59. Zhu Z et al (2020) Effects of p38 MAPK signaling pathway on cognitive function and recovery of neuronal function after hypoxic-ischemic brain injury in newborn rats. J Clin Neurosci 78:365–370

    Article  CAS  PubMed  Google Scholar 

  60. Su WJ et al (2017) NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model. Behav Brain Res 322(Pt A):1–8

    Article  CAS  PubMed  Google Scholar 

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Funding

This study is supported by the Natural Scicence Foundation of Shenzhen University General Hospital (SUGH2020QD015), the Shenzhen Natural Science Fund (the Stable Support Plan Program 20200826225552001), the Shenzhen Health Elite Talent Project, No.2021XKQ193, and the Talent Development Foundation of The First Dongguan Affiliated Hospital of Guangdong Medical University.

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Authors and Affiliations

  1. Department of Surgery, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, 523000, Guangdong Province, China

    Chaohui Zhen, Biao Zheng, Rui Liang & Zhen Tan

  2. Department of Neurosurgery, Shenzhen Children’s Hospital, Shenzhen City, 518026, Guangdong Province, China

    Chong Wang

  3. Shenzhen Ruijian Biotechnology Co., Ltd, Shenzhen City, 518057, Guangdong Province, China

    Yanjun Ma & Jianxi Liu

  4. Health Management Center, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen City, 518055, Guangdong Province, China

    Yuli Pang, Feiyue Cai & Zhen Tan

  5. General Practice Alliance, Shenzhen City, Guangdong Province, China

    Feiyue Cai, Jiali Meng, Yuefei He & Zhen Tan

  6. Department of General Practice, Shenzhen University General Hospital, Shenzhen University, Shenzhen City, 518055, Guangdong Province, China

    Jiali Meng & Yuefei He

  7. Department of Otorhinolaryngology Head and Neck Surgery, Shenzhen Children’s Hospital, Shenzhen City, 518026, Guangdong Province, China

    Ping Xiao

  8. Zhuhai Pengkun Biomedicine Technology Co. Ltd, Zhuhai City, 519000, Guangdong Province, China

    Xi Mei

  9. State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen City, 518055, Guangdong Province, China

    Shupeng Li

  10. College of Textiles and Clothing, Yancheng Institute of Technology, Yancheng City, 224051, Jiangsu Province, China

    Guanzheng Wu

  11. Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Korea

    Guangzhen Jin

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  1. Chaohui Zhen
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  2. Chong Wang
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Contributions

Chaohui Zhen, Chong Wang, and Yanjun Ma designed the research study. Yuli Pang, Feiyue Cai, Jiali Meng, and Biao Zheng performed the research. Yuefei He, Ping Xiao, Jianxi Liu, and Rui Liang provided help and advice. Xi Mei, Shupeng Li, Guanzheng Wu, and Guangzhen Jin analyzed the data. Chaohui Zhen, Chong Wang, Yanjun Ma, and Zhen Tan wrote the manuscript. Biao Zheng, Rui Liang, and Zhen Tan reviewed and edited the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Biao Zheng, Rui Liang or Zhen Tan.

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Ethical Approval

All animal experiments were complied with the ARRIVE guidelines and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The experiments were approved by the Institutional Animal Care and Use Committee of Shenzhen Children’s Hospital.

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Zhen, C., Wang, C., Ma, Y. et al. Mechanism of Antidepressant Action of (2R,6R)-6-Hydroxynorketamine (HNK) and Its Compounds: Insights from Proteomic Analysis. Mol Neurobiol 61, 465–475 (2024). https://doi.org/10.1007/s12035-023-03555-w

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