Skip to main content
SpringerLink
Log in

Cilostazol pretreatment prevents PTSD-related anxiety behavior through reduction of hippocampal neuroinflammation

  • Research
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Current pharmacological treatments against post-traumatic stress disorder (PTSD) lack adequate efficacy. As a result, intense research has focused on identifying other molecular pathways mediating the pathogenesis of this condition. One such pathway is neuroinflammation, which has demonstrated a role in PTSD pathogenesis by causing synaptic dysfunction, neuronal death, and functional impairment in the hippocampus. Phosphodiesterase (PDE) inhibitors (PDEIs) have emerged as promising therapeutic agents against neuroinflammation in other neurological conditions. Furthermore, PDEIs have shown some promise in animal models of PTSD. However, the current model of PTSD pathogenesis, which is based on dysregulated fear learning, implies that PDE inhibition in neurons should enhance the acquisition of fear memory from the traumatic event. As a result, we hypothesized that PDEIs may improve PTSD symptoms through inhibiting neuroinflammation rather than long-term potentiation-related mechanisms. To this end, we tested the therapeutic efficacy of cilostazol, a selective inhibitor of PDE3, on PTSD-related anxiety symptoms in the underwater trauma model of PTSD. PDE3 is expressed much more richly in microglia and astrocytes compared to neurons in the murine brain. Furthermore, we used hippocampal indolamine 2,3-dioxygenase 1 (IDO) expression and interleukin 1 beta (IL-1β) concentration as indicators of neuroinflammation. We observed that cilostazol pretreatment prevented the development of anxiety symptoms and the increase in hippocampal IDO and IL-1β following PTSD induction. As a result, PDE3 inhibition ameliorated the neuroinflammatory processes involved in the development of PTSD symptoms. Therefore, cilostazol and other PDEIs may be promising candidates for further investigation as pharmacological therapies against PTSD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

References

  • Abuelezz SA, Hendawy N (2018) Insights into the potential antidepressant mechanisms of cilostazol in chronically restraint rats: impact on the Nrf2 pathway. Behav Pharmacol 29(1):28–40

    Article  PubMed  CAS  Google Scholar 

  • Acheson DT, Gresack JE, Risbrough VB (2012) Hippocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder. Neuropharmacology 62(2):674–685

    Article  PubMed  CAS  Google Scholar 

  • Alzoubi KH, Al Subeh ZY, Khabour OF (2017) Evaluating the protective effect of etazolate on memory impairment, anxiety- and depression-like behaviors induced by post traumatic stress disorder. Brain Res Bull 135:185–192

    Article  PubMed  CAS  Google Scholar 

  • Alzoubi KH, Khabour OF, Ahmed M (2018) Pentoxifylline prevents post-traumatic stress disorder induced memory impairment. Brain Res Bull 139:263–268

    Article  PubMed  CAS  Google Scholar 

  • Alzoubi KH, Al Subeh ZY, Khabour OF (2019) Molecular targets for the interactive effect of etazolate during post-traumatic stress disorder: role of oxidative stress. BDNF and histones. Behav Brain Res 369:111930

    Article  PubMed  CAS  Google Scholar 

  • Ardi Z et al (2014) The effects of a reminder of underwater trauma on behaviour and memory-related mechanisms in the rat dentate gyrus. Int J Neuropsychopharmacol 17(4):571–580

    Article  PubMed  CAS  Google Scholar 

  • Ardi Z et al (2016) Behavioral profiling as a translational approach in an animal model of posttraumatic stress disorder. Neurobiol Dis 88:139–147

    Article  PubMed  Google Scholar 

  • Bernier LP et al (2019) Nanoscale surveillance of the brain by microglia via cAMP-regulated filopodia. Cell Rep 27(10):2895-2908.e4

    Article  PubMed  CAS  Google Scholar 

  • Birk S et al (2004) The phosphodiesterase 3 inhibitor cilostazol dilates large cerebral arteries in humans without affecting regional cerebral blood flow. J Cereb Blood Flow Metab 24(12):1352–1358

    Article  PubMed  CAS  Google Scholar 

  • Bollen E et al (2014) Improved long-term memory via enhancing cGMP-PKG signaling requires cAMP-PKA signaling. Neuropsychopharmacol 39(11):2497–2505

    Article  PubMed  CAS  Google Scholar 

  • Burm SM et al (2015) Inflammasome-induced IL-1β secretion in microglia is characterized by delayed kinetics and is only partially dependent on inflammatory caspases. J Neurosci 35(2):678–687

    Article  PubMed  PubMed Central  Google Scholar 

  • Campbell B et al (2014) Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci 8

  • Caviezel MP et al (2020) The neural mechanisms of associative memory revisited: fMRI evidence from implicit contingency learning. Front Psychiatry 10

  • Chen L et al (2021) Phosphodiesterase-2 inhibitor reverses post-traumatic stress induced fear memory deficits and behavioral changes via cAMP/cGMP pathway. Eur J Pharmacol 891:173768

    Article  PubMed  CAS  Google Scholar 

  • Cohen BE et al (2009) Posttraumatic stress disorder and health-related quality of life in patients with coronary heart disease: findings from the heart and soul study. Arch Gen Psychiatry 66(11):1214–1220

    Article  PubMed  PubMed Central  Google Scholar 

  • Delhaye S, Bardoni B (2021) Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders. Mol Psychiatry 26(9):4570–4582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dong Y et al (2020) Stress-induced NLRP3 inflammasome activation negatively regulates fear memory in mice. J Neuroinflammation 17(1):205

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dunsmoor JE, Paz R (2015) Fear generalization and anxiety: behavioral and neural mechanisms. Biol Psychiatry 78(5):336–343

    Article  PubMed  Google Scholar 

  • Elzinga BM, Bremner JD (2002) Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? J Affect Disord 70(1):1–17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gu G et al (2019) Target engagement of a phosphodiesterase 2A inhibitor affecting long-term memory in the rat. J Pharmacol Exp Ther 370(3):399–407

    Article  PubMed  CAS  Google Scholar 

  • Haskó G et al (1998) Suppression of IL-12 production by phosphodiesterase inhibition in murine endotoxemia is IL-10 independent. Eur J Immunol 28(2):468–472

    Article  PubMed  Google Scholar 

  • Hauger RL et al (2012) Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy. Neuropharmacology 62(2):705–714

    Article  PubMed  CAS  Google Scholar 

  • Hayes JP et al (2011a) Reduced hippocampal and amygdala activity predicts memory distortions for trauma reminders in combat-related PTSD. J Psychiatr Res 45(5):660–669

    Article  PubMed  Google Scholar 

  • He M et al (2018) Synaptic plasticity in PTSD and associated comorbidities: the function and mechanism for diagnostics and therapy. Curr Pharm Des 24(34):4051–4059

    Article  PubMed  CAS  Google Scholar 

  • Huang LC et al (2021) The role of cilostazol and inflammation in cognitive impairment after ischemic stroke. Am J Alzheimers Dis Other Demen 36:15333175211016184

    Article  PubMed  Google Scholar 

  • Kamthong PJ, Wu M (2001) Inhibitor of nuclear factor-kappaB induction by cAMP antagonizes interleukin-1-induced human macrophage-colony-stimulating-factor expression. Biochem J 356(Pt 2):525–530

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Karayol R et al (2021) Serotonin receptor 4 in the hippocampus modulates mood and anxiety. Mol Psychiatry 26(6):2334–2349

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Keravis T, Lugnier C (2012) Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. Br J Pharmacol 165(5):1288–1305

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kessler RC et al (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62(6):593–602

    Article  PubMed  Google Scholar 

  • Khadivi A et al (2022) Cilostazol as an adjunctive treatment in major depressive disorder: a pilot randomized, double-blind, and placebo-controlled clinical trial. Psychopharmacology 239(2):551–559

    Article  PubMed  CAS  Google Scholar 

  • Kim YK, Jeon SW (2018) Neuroinflammation and the immune-kynurenine pathway in anxiety disorders. Curr Neuropharmacol 16(5):574–582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim YR et al (2016) Anti-depressant effects of phosphodiesterase 3 inhibitor cilostazol in chronic mild stress-treated mice after ischemic stroke. Psychopharmacology 233(6):1055–1066

    Article  PubMed  CAS  Google Scholar 

  • Knott EP et al (2017) Phosphodiesterase inhibitors as a therapeutic approach to neuroprotection and repair. Int J Mol Sci 18(4):696

    Article  PubMed  PubMed Central  Google Scholar 

  • Lambert HK, McLaughlin KA (2019) Impaired hippocampus-dependent associative learning as a mechanism underlying PTSD: a meta-analysis. Neurosci Biobehav Rev 107:729–749

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee DH et al (2022) Neuroinflammation in post-traumatic stress disorder. Biomedicines 10(5)

  • Lee D-H et al (2022) Neuroinflammation in Post-Traumatic Stress Disorder. Biomedicines 10(5): 953

  • Levkovitz Y et al (2015) Early post-stressor intervention with minocycline, a second-generation tetracycline, attenuates post-traumatic stress response in an animal model of PTSD. Eur Neuropsychopharmacol 25(1):124–132

    Article  PubMed  CAS  Google Scholar 

  • Lezak KR, Missig G, Carlezon WA Jr (2017) Behavioral methods to study anxiety in rodents. Dialogues Clin Neurosci 19(2):181–191

    Article  PubMed  PubMed Central  Google Scholar 

  • Li H, Zuo J, Tang W (2018) Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol 9:1048–1048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Linnman C et al (2012) Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit. Am J Psychiatry 169(4):415–423

    Article  PubMed  PubMed Central  Google Scholar 

  • Maercker A et al (2013) Proposals for mental disorders specifically associated with stress in the International Classification of Diseases-11. The Lancet 381(9878):1683–1685

    Article  Google Scholar 

  • Mair P, Wilcox R (2020) Robust statistical methods in R using the WRS2 package. Behav Res Methods 52(2):464–488

    Article  PubMed  Google Scholar 

  • Mellon SH et al (2018) Metabolism, metabolomics, and inflammation in posttraumatic stress disorder. Biol Psychiatry 83(10):866–875

    Article  PubMed  CAS  Google Scholar 

  • Minguet S et al (2005) Adenosine and cAMP are potent inhibitors of the NF-kappa B pathway downstream of immunoreceptors. Eur J Immunol 35(1):31–41

    Article  PubMed  CAS  Google Scholar 

  • Mithaiwala MN et al (2021) Neuroinflammation and the kynurenine pathway in CNS disease: molecular mechanisms and therapeutic implications. Cells 10(6):1548

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Moore NL, Gauchan S, Genovese RF (2012) Differential severity of anxiogenic effects resulting from a brief swim or underwater trauma in adolescent male rats. Pharmacol Biochem Behav 102(2):264–268

    Article  PubMed  CAS  Google Scholar 

  • Mor A et al (2021) Role of kynurenine pathway in oxidative stress during neurodegenerative disorders. Cells 10(7):1603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Muhie S et al (2017) Molecular indicators of stress-induced neuroinflammation in a mouse model simulating features of post-traumatic stress disorder. Transl Psychiatry 7(5):e1135–e1135

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nelson MD, Tumpap AM (2017) Posttraumatic stress disorder symptom severity is associated with left hippocampal volume reduction: a meta-analytic study. CNS Spectr 22(4):363–372

    Article  PubMed  Google Scholar 

  • Nishimura K et al (2007) Cilostazol, a cAMP phosphodiesterase 3 inhibitor, in the treatment of poststroke depression. J Neuropsychiatry Clin Neurosci 19(4):471–472

    Article  PubMed  Google Scholar 

  • Oxenkrug G (2013) Serotonin-kynurenine hypothesis of depression: historical overview and recent developments. Curr Drug Targets 14(5):514–521

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pai A, Suris AM, North CS (2017) Posttraumatic stress disorder in the DSM-5: controversy, change, and conceptual considerations. Behav Sci 7(1):7. https://doi.org/10.3390/bs7010007

  • Pan X et al (2022) Inhibition of phosphodiesterase 2 ameliorates post-traumatic stress-induced alcohol intake disorder by regulating cAMP/cGMP signaling. Int J Neuropsychopharmacol

  • Park WS et al (2010) Cilostazol protects mice against endotoxin shock and attenuates LPS-induced cytokine expression in RAW 264.7 macrophages via MAPK inhibition and NF-κB inactivation: not involved in cAMP mechanisms. Int Immunopharmacol 10(9):1077–1085

  • Patel DS, Anand IS, Bhatt PA (2012a) Evaluation of antidepressant and anxiolytic activity of phosphodiesterase 3 inhibitor - cilostazol. Indian J Psychol Med 34(2):124–128

    Article  PubMed  PubMed Central  Google Scholar 

  • Pedraza L et al (2015) The dynamic nature of systems consolidation: Stress during learning as a switch guiding the rate of the hippocampal dependency and memory quality. Hippocampus 26

  • Peixoto CA, Nunes AK, Garcia-Osta A (2015) Phosphodiesterase-5 inhibitors: action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition. Mediators Inflamm 2015:940207

    Article  PubMed  PubMed Central  Google Scholar 

  • Reisman M (2016) PTSD treatment for veterans: what’s working, what’s new, and what’s Next. P t 41(10):623–634

    PubMed  PubMed Central  Google Scholar 

  • Richter-Levin G (1998) Acute and long-term behavioral correlates of underwater trauma–potential relevance to stress and post-stress syndromes. Psychiatry Res 79(1):73–83

    Article  PubMed  CAS  Google Scholar 

  • Richter-Levin G, Stork O, Schmidt MV (2019) Animal models of PTSD: a challenge to be met. Mol Psychiatry 24(8):1135–1156

    Article  PubMed  Google Scholar 

  • Ritov G, Richter-Levin G (2014) Water associated zero maze: a novel rat test for long term traumatic re-experiencing. Front Behav Neurosci 8

  • Rodríguez-Gómez JA et al (2020) Microglia: agents of the CNS pro-inflammatory response. Cells 9. https://doi.org/10.3390/cells9071717

  • Roesler R et al (2014) A phosphodiesterase 4-controlled switch between memory extinction and strengthening in the hippocampus. Front Behav Neurosci 8:91

    Article  PubMed  PubMed Central  Google Scholar 

  • Rombaut B et al (2021) PDE inhibition in distinct cell types to reclaim the balance of synaptic plasticity. Theranostics 11(5):2080–2097

    Article  PubMed  PubMed Central  Google Scholar 

  • Schepers M et al (2019) Targeting phosphodiesterases—towards a tailor-made approach in multiple sclerosis treatment. Front Immunol 10

  • Seibenhener ML, Wooten MC (2015) Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp Jove 96:e52434–e52434

    Google Scholar 

  • Shi YW et al (2019) Fear renewal activates cyclic adenosine monophosphate signaling in the dentate gyrus. Brain Behav 9(8):e01280

    Article  PubMed  PubMed Central  Google Scholar 

  • Song N, and Li T (2018) Regulation of NLRP3 inflammasome by phosphorylation. Front Immunol 9

  • Sun Y, Qu Y, Zhu J (2021) The relationship between inflammation and post-traumatic stress disorder. Front Psychiatry 12

  • Takahashi N et al (2002) Inhibition of the NF-kappaB transcriptional activity by protein kinase A. Eur J Biochem 269(18):4559–4565

    Article  PubMed  CAS  Google Scholar 

  • Tóth F, Cseh EK, Vécsei L (2021) Natural molecules and neuroprotection: kynurenic acid, pantethine and α-lipoic acid. Int J Mol Sci 22. https://doi.org/10.3390/ijms22010403

  • VanElzakker MB et al (2014) From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders. Neurobiol Learn Mem 113:3–18

    Article  PubMed  Google Scholar 

  • Verbitsky A, Dopfel D, Zhang N (2020) Rodent models of post-traumatic stress disorder: behavioral assessment. Transl Psychiatry 10(1):132

    Article  PubMed  PubMed Central  Google Scholar 

  • Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2(2):322–328

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Weber NC et al (2003) ANP inhibits TNF-alpha-induced endothelial MCP-1 expression–involvement of p38 MAPK and MKP-1. J Leukoc Biol 74(5):932–941

    Article  PubMed  CAS  Google Scholar 

  • Werner NS et al (2009) Hippocampal function during associative learning in patients with posttraumatic stress disorder. J Psychiatr Res 43(3):309–318

    Article  PubMed  Google Scholar 

  • Wu X et al (2007) Adiponectin suppresses IkappaB kinase activation induced by tumor necrosis factor-alpha or high glucose in endothelial cells: role of cAMP and AMP kinase signaling. Am J Physiol Endocrinol Metab 293(6):E1836–E1844

    Article  PubMed  CAS  Google Scholar 

  • Yanai S et al (2014) Cilostazol improves hippocampus-dependent long-term memory in mice. Psychopharmacology 231(13):2681–2693

    Article  PubMed  CAS  Google Scholar 

  • Yoneyama M et al (2015) Beneficial effect of cilostazol-mediated neuronal repair following trimethyltin-induced neuronal loss in the dentate gyrus. J Neurosci Res 93(1):56–66

    Article  PubMed  CAS  Google Scholar 

  • Zaki OS et al (2022) Cilostazol alleviates NLRP3 inflammasome–induced allodynia/hyperalgesia in murine cerebral cortex following transient ischemia: focus on TRPA1/glutamate and Akt/dopamine/BDNF/Nrf2 trajectories. Mol Neurobiol 59(12):7194–7211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran

    Mohammad Amin Sadeghi, Ehsan Nassireslami & Mohsen Chamanara

  2. Department of Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, Iran

    Mohammad Amin Sadeghi, Ehsan Nassireslami & Mohsen Chamanara

  3. Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

    Sara Hemmati, Hasan Yousefi-Manesh, Laleh Foroutani & Ahmad Reza Dehpour

  4. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Sara Hemmati, Hasan Yousefi-Manesh, Laleh Foroutani & Ahmad Reza Dehpour

  5. Trauma Research Center, AJA University of Medical Sciences, Tehran, Iran

    Mojtaba Yousefi Zoshk

  6. Department of Pediatrics, AJA University of Medical Sciences, Tehran, Iran

    Mojtaba Yousefi Zoshk

  7. Cognitive Neuroscience Center, School of Medicine, AJA University of Medical Sciences, Tehran, Iran

    Yasaman Hosseini

  8. Management and Health Economics Department, AJA University of Medical Sciences, Tehran, Iran

    Kourosh Abbasian

Authors
  1. Mohammad Amin Sadeghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sara Hemmati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hasan Yousefi-Manesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laleh Foroutani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ehsan Nassireslami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mojtaba Yousefi Zoshk
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasaman Hosseini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kourosh Abbasian
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ahmad Reza Dehpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mohsen Chamanara
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M. A. S. and S. H. conceived and designed the study. M. A. S., S. H., H. Y., and L. F. performed the model induction, behavioral, and molecular experiments. M. A. S. analyzed, visualized, and interpreted the data, and wrote the initial draft. M. A. S., E. N., M. Y. Z., Y. H., K. A., A. D., and M. C. reviewed and edited the manuscript. A. D. and M. C. supervised the project. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Mohsen Chamanara.

Ethics declarations

Ethical approval

All experiments were performed in accordance with the standards of animal care determined by the Council of Laboratory Animals of AJA University of Medical Sciences, Tehran, Iran (Approval NO. IR.AJAUMS.REC.1401.181).

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sadeghi, M.A., Hemmati, S., Yousefi-Manesh, H. et al. Cilostazol pretreatment prevents PTSD-related anxiety behavior through reduction of hippocampal neuroinflammation. Naunyn-Schmiedeberg's Arch Pharmacol 397, 133–144 (2024). https://doi.org/10.1007/s00210-023-02578-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-023-02578-3

Keywords

Search

Navigation