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Sex-Related and Brain Regional Differences of URB597 Effects on Modulation of MAPK/PI3K Signaling in Chronically Stressed Rats

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Abstract

Gender differences exist in depression incidence and antidepressant efficacy. In addition to the neurotransmission theory of depression, inflammation and disrupted signaling pathways play crucial roles in the pathophysiology of depression. Endocannabinoids offer a novel approach to treat inflammatory and emotional disorders like depression. URB597, a FAAH inhibitor, reduces endocannabinoids breakdown. In this study, URB597 effects were investigated on the pro-inflammatory cytokine interleukin-1β (IL-1β), nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3), and mitogen-activated protein kinase (MAPK)/ phosphatidylinositol 3-hydroxy kinase/ protein kinase B (PI3K) signaling in the hippocampus and the medial prefrontal cortex (mPFC) of male and female rats subjected to chronic unpredictable stress (CUS). The results show that CUS induces depression-like behaviors, and the URB597 exhibited antidepressant-like effects inboth sexes. URB597 reduced the CUS-induced NLRP3 and IL-1β increase in the hippocampus and mPFC of both sexes. URB597 increased the reduced pERK1/2 levels in the mPFC of both sexes and hippocampus of CUS males. URB597 also prevented the increase in p38 phosphorylation after chronic stress in the mPFC of both sexes and in the hippocampus of the females. The CUS suppressed the downstream Akt phosphorylation in the mPFC and hippocampi of both sexes. URB597 produced an up-regulation of the pAkt in the hippocampus of the CUS animals but did not affect the pAkt in the mPFC. These data demonstrated a sexual dimorphism in the neural cell signaling, and in the effects of endocannabinoids, and indicated these dimorphisms are region-specific.

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Data Availability

The datasets generated and analyzed in the study are available from the corresponding author on areasonable request.

References

  1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE et al (2003) The epidemiology of major depressive disorder: results from the National Comorbidity Survey replication (NCS-R). JAMA 289(23):3095–3105

    Article  PubMed  Google Scholar 

  2. Kokras N, Dalla C (2017) Preclinical sex differences in depression and antidepressant response: implications for clinical research. J Neurosci Res 95(1–2):731–736

    Article  CAS  PubMed  Google Scholar 

  3. Sramek JJ, Murphy MF, Cutler NR (2022) Sex differences in the psychopharmacological treatment of depression. Dialogues Clin Neurosci 18(4):447-457

  4. Pitychoutis M, Zisaki P, Dalla A, Papadopoulou-Daifoti C (2010) Pharmacogenetic insights into depression and antidepressant response: does sex matter? Curr Pharm Des 16(20):2214–2223

    Article  CAS  PubMed  Google Scholar 

  5. Price RB, Duman R (2020) Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry 25(3):530–543

    Article  PubMed  Google Scholar 

  6. Grygiel-Górniak B, Limphaibool N, Puszczewicz M (2019) Cytokine secretion and the risk of depression development in patients with connective tissue diseases. J Neuropsychiatry Clin Neurosci 73(6):302–316

    Google Scholar 

  7. Pan Y, Chen X-Y, Zhang Q-Y, Kong L-D (2014) Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats. Brain Behav Immun 41:90–100

    Article  CAS  PubMed  Google Scholar 

  8. Kaufmann FN, Costa AP, Ghisleni G, Diaz AP, Rodrigues ALS, Peluffo H, Kaster MP (2017) NLRP3 inflammasome-driven pathways in depression: clinical and preclinical findings. Brain Behav Immun 64:367–383

    Article  CAS  PubMed  Google Scholar 

  9. Xue J, Li H, Deng X, Ma Z, Fu Q, Ma S (2015) L-Menthone confers antidepressant-like effects in an unpredictable chronic mild stress mouse model via NLRP3 inflammasome-mediated inflammatory cytokines and central neurotransmitters. Pharmacol Biochem Behav 134:42–48

    Article  CAS  PubMed  Google Scholar 

  10. Wang JQ, Mao L (2019) The ERK pathway: molecular mechanisms and treatment of depression. Mol Neurobiol 56:6197–6205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim EK, Choi E-J (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta (BBA)-Mol Basis Dis 1802(4):396–405

    Article  CAS  Google Scholar 

  12. Li Y-H, Fu H-L, Tian M-L, Wang Y-Q, Chen W, Cai L-L, Zhou X-H, Yuan H-B (2016) Neuron-derived FGF10 ameliorates cerebral ischemia injury via inhibiting NF-κB-dependent neuroinflammation and activating PI3K/Akt survival signaling pathway in mice. Sci Rep 6(1):19869

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  13. Peltier J, O’Neill A, Schaffer DV (2007) PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol 67(10):1348–1361

    Article  CAS  PubMed  Google Scholar 

  14. Ives A, Nomura J, Martinon F, Roger T, LeRoy D, Miner JN, Simon G, Busso N et al (2015) Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation. Nat Commun 6(1):6555

    Article  CAS  PubMed  ADS  Google Scholar 

  15. Kitagishi Y, Kobayashi M, Kikuta K, Matsuda S (2012) Roles of PI3K/AKT/GSK3/mTOR pathway in cell signaling of mental illnesses. Depress Res Treat 2012:752563

  16. Losenkov IS, Vyalova NM, Simutkin GG, Bokhan NA, Ivanova SA (2016) An association of AKT1 gene polymorphism with antidepressant treatment response. World J Biol Psychiatry 17(3):239–242

    Article  PubMed  Google Scholar 

  17. Silveira KM, Wegener G, Joca SR (2021) Targeting 2-arachidonoylglycerol signalling in the neurobiology and treatment of depression. Basic Clin Pharmacol Toxicol 129(1):3–14

    Article  CAS  PubMed  Google Scholar 

  18. Fowler CJ (2015) The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs—A practical view. Eur Neuropsychopharmacol 25(6):749–762

    Article  CAS  PubMed  Google Scholar 

  19. Morris G, Walder K, Kloiber S, Amminger P, Berk M, Bortolasci CC, Maes M, Puri BK et al (2021) The endocannabinoidome in neuropsychiatry: Opportunities and potential risks. Pharmacol Res 170:105729

    Article  CAS  PubMed  Google Scholar 

  20. Worley NB, Hill MN, Christianson JP (2018) Prefrontal endocannabinoids, stress controllability and resilience: a hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 85:180–188

    Article  CAS  PubMed  Google Scholar 

  21. Segev A, Korem N, Mizrachi Zer-Aviv T, Abush H, Lange R, Sauber G, Hillard CJ, Akirav I (2018) Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity. Neuropsychopharmacology 43(10):2017–2027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP et al (2006) Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev 12(1):21–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Alteba S, Zer-Aviv TM, Tenenhaus A, David GB, Adelman J, Hillard CJ, Doron R, Akirav I (2020) Antidepressant-like effects of URB597 and JZL184 in male and female rats exposed to early life stress. Eur Neuropsychopharmacol 39:70–86

    Article  CAS  PubMed  Google Scholar 

  24. Jankovic M, Spasojevic N, Ferizovic H, Stefanovic B, Dronjak S (2020) Inhibition of the fatty acid amide hydrolase changes behaviors and brain catecholamines in a sex-specific manner in rats exposed to chronic unpredictable stress. Physiol Behav 227:113174

    Article  CAS  PubMed  Google Scholar 

  25. Jankovic M, Spasojevic N, Ferizovic H, Stefanovic B, Dronjak S (2022) Sex specific effects of the fatty acid amide hydrolase inhibitor URB597 on memory and brain β2-adrenergic and D1-dopamine receptors. Neurosci Lett 768:136363

    Article  CAS  PubMed  Google Scholar 

  26. Bortolato M, Mangieri RA, Fu J, Kim JH, Arguello O, Duranti A, Tontini A, Mor M et al (2007) Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol Psychiatry 62(10):1103–1110

    Article  CAS  PubMed  Google Scholar 

  27. Papp M (2012) Models of affective illness: chronic mild stress in the rat. Curr Protocols Pharmacol 57(1):5 (1-5.9. 11)

    Article  Google Scholar 

  28. Willner P, Muscat R, Papp M (1992) Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehavioral Reviews 16(4):525–534

    Article  CAS  Google Scholar 

  29. Dalla C, Pitychoutis PM, Kokras N, Papadopoulou-Daifoti Z (2011) Sex differences in response to stress and expression of depressive-like behaviours in the rat. Biological basis of sex differences in psychopharmacology, 97–118

  30. Karisetty BC, Joshi PC, Kumar A, Chakravarty S (2017) Sex differences in the effect of chronic mild stress on mouse prefrontal cortical BDNF levels: a role of major ovarian hormones. Neuroscience 356:89–101

    Article  CAS  PubMed  Google Scholar 

  31. Xing Y, He J, Hou J, Lin F, Tian J, Kurihara H (2013) Gender differences in CMS and the effects of antidepressant venlafaxine in rats. Neurochem Int 63(6):570–575

    Article  CAS  PubMed  Google Scholar 

  32. Feng X, Zhao Y, Yang T, Song M, Wang C, Yao Y, Fan H (2019) Glucocorticoid-driven NLRP3 inflammasome activation in hippocampal microglia mediates chronic stress-induced depressive-like behaviors. Front Mol Neurosci 12:210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jo E-K, Kim JK, Shin D-M, Sasakawa C (2016) Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol 13(2):148–159

    Article  CAS  PubMed  Google Scholar 

  34. Su W-J, Zhang Y, Chen Y, Gong H, Lian Y-J, Peng W, Liu Y-Z, Wang Y-X et al (2017) NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model. Behav Brain Res 322:1–8

    Article  CAS  PubMed  Google Scholar 

  35. Iwata M, Ota KT, Duman RS (2013) The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun 31:105–114

    Article  CAS  PubMed  Google Scholar 

  36. Mikkelsen K, Stojanovska L, Prakash M, Apostolopoulos V (2017) The effects of vitamin B on the immune/cytokine network and their involvement in depression. Maturitas 96:58–71

    Article  CAS  PubMed  Google Scholar 

  37. Li B, Chen M, Guo L, Yun Y, Li G, Sang N (2017) Endocannabinoid 2-arachidonoylglycerol protects inflammatory insults from sulfur dioxide inhalation via cannabinoid receptors in the brain. J Environ Sci 51:265–274

    Article  CAS  Google Scholar 

  38. Gong W, Zhang S, Zong Y, Halim M, Ren Z, Wang Y, Ma Y, Li B, Ma L, Zhou G (2019) Involvement of the microglial NLRP3 inflammasome in the anti-inflammatory effect of the antidepressant clomipramine. J Affect Disord 254:15–25

    Article  CAS  PubMed  Google Scholar 

  39. Park H-J, Shim H-S, An K, Starkweather A, Kim KS, Shim I (2015) IL-4 inhibits IL-1β-induced depressive-like behavior and central neurotransmitter alterations. Mediators Inflamm 2015:941413

  40. Benito C, Núñez E, Tolón RM, Carrier EJ, Rábano A, Hillard CJ, Romero J (2003) Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J Neurosci 23(35):11136–11141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Qi X, Lin W, Li J, Pan Y, Wang W (2006) The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress. Behav Brain Res 175(2):233–240

    Article  CAS  PubMed  Google Scholar 

  42. Iio W, Matsukawa N, Tsukahara T, Kohari D, Toyoda A (2011) Effects of chronic social defeat stress on MAP kinase cascade. Neurosci Lett 504(3):281–284

    Article  CAS  PubMed  Google Scholar 

  43. Yoon D-H, Yoon S, Kim D, Kim H, Baik J-H (2015) Regulation of dopamine D2 receptor-mediated extracellular signal-regulated kinase signaling and spine formation by GABAA receptors in hippocampal neurons. Neurosci Lett 586:24–30

    Article  CAS  PubMed  Google Scholar 

  44. Haroon E, Raison CL, Miller AH (2012) Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37(1):137–162

    Article  CAS  PubMed  Google Scholar 

  45. Zhu C-B, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett WA (2010) Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 35(13):2510–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Martín-Hernández D, Caso JR, Javier Meana J, Callado LF, Madrigal JL, García-Bueno B, Leza JC (2018) Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants. J Neuroinflamm 15:1–12

    Article  Google Scholar 

  47. Xu B, Lian S, Guo J-R, Wang J-F, Zhang L-P, Li S-Z, Yang H-M (2019) Activation of the MAPK signaling pathway induces upregulation of pro-apoptotic proteins in the hippocampi of cold stressed adolescent mice. Neurosci Lett 699:97–102

    Article  CAS  PubMed  Google Scholar 

  48. Mitic M, Lukic I, Bozovic N, Djordjevic J, Adzic M (2015) Fluoxetine signature on hippocampal MAPK signalling in sex-dependent manner. J Mol Neurosci 55:335–346

    Article  CAS  PubMed  Google Scholar 

  49. García-Fuster M, Díez-Alarcia R, Ferrer-Alcón M, La Harpe R, Meana J, García-Sevilla J (2014) FADD adaptor and PEA-15/ERK1/2 partners in major depression and schizophrenia postmortem brains: basal contents and effects of psychotropic treatments. Neuroscience 277:541–551

    Article  PubMed  Google Scholar 

  50. Wang S, Zhang H, Geng B, Xie Q, Li W, Deng Y, Shi W, Pan Y, Kang X, Wang J (2018) 2-arachidonyl glycerol modulates astrocytic glutamine synthetase via p38 and ERK1/2 pathways. J Neuroinflamm 15(1):1–10

    Article  Google Scholar 

  51. Yu JS, Cui W (2016) Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 143(17):3050–3060

    Article  CAS  PubMed  Google Scholar 

  52. Mundi PS, Sachdev J, McCourt C, Kalinsky K (2016) AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol 82(4):943–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zeni ALB, Zomkowski ADE, Maraschin M, Rodrigues ALS, Tasca CI (2012) Involvement of PKA, CaMKII, PKC, MAPK/ERK and PI3K in the acute antidepressant-like effect of ferulic acid in the tail suspension test. Pharmacol Biochem Behav 103(2):181–186

    Article  CAS  PubMed  Google Scholar 

  54. Cunha MP, Budni J, Ludka FK, Pazini FL, Rosa JM, Oliveira Á, Lopes MW, Tasca CI et al (2016) Involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. Mol Neurobiol 53:2954–2968

    Article  CAS  PubMed  Google Scholar 

  55. Li T, Liu H, Wang X, Xie Y, Bai X, Wu L, Wang Z, Liu D (2016) Resveratrol exerts antidepressant properties in the chronic unpredictable mild stress model through the regulation of oxidative stress and mTOR pathway in the rat hippocampus and prefrontal cortex. Behav Brain Res 302:191–199

    Article  PubMed  Google Scholar 

  56. Palumbo S, Paterson C, Yang F, Hood VL, Law AJ (2021) PKBβ/AKT2 deficiency impacts brain mTOR signaling, prefrontal cortical physiology, hippocampal plasticity and select murine behaviors. Mol Psychiatry 26(2):411–428

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Marija Jovicic and Ana Korntner for proof-reading the manuscript.

Funding

This work was supported by the Ministry for Science and Technological Development of the Republic of Serbia (451-03-47/2023-01/200017).

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Authors and Affiliations

  1. Department of Molecular Biology and Endocrinology, Institute of Nuclear Sciences “Vinca”, National Institute of thе Republic of Serbia, University of Belgrade, P.O.B. 522 − 090, 11000, Belgrade, Serbia

    Milica Jankovic, Natasa Spasojevic, Harisa Ferizovic, Bojana Stefanovic, Kristina Virijevic & Sladjana Dronjak

  2. Institute of Mental Health, University of Belgrade, Belgrade, Serbia

    Milica Vezmar

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  1. Milica Jankovic
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  2. Natasa Spasojevic
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Contributions

Milica Jankovic performed experimental procedures and wrote the first draft of the manuscript. Harisa Ferizovic performed experimental procedures and behavioral tests. Natasa Spasojevic undertook the statistical analysis and wrote the protocol for the study. Bojana Stefanovic and Kristina Virijevic participated in the experimental work. Milica Vezmar analyzed available literature. Sladjana Dronjak designed the study, managed literature analysis and wrote the final manuscript draft. All authors contributed to and have approved the final manuscript.

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Correspondence to Sladjana Dronjak.

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All experimental procedures were approved by Ethical committee for work with laboratory animals of Institute Nuclear Sciences “Vinca”, University of Belgrade and Ministry of Agriculture and Environmental Protection based on directive European commission 2010/63/EU, authority for Veterinary permission No. 323-07-00704/2017-05 and 323-07-02772/2019-09, and done in a way which minimizes pain and discomfort.

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Jankovic, M., Spasojevic, N., Ferizovic, H. et al. Sex-Related and Brain Regional Differences of URB597 Effects on Modulation of MAPK/PI3K Signaling in Chronically Stressed Rats. Mol Neurobiol 61, 1495–1506 (2024). https://doi.org/10.1007/s12035-023-03649-5

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