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