Biomolecules & Therapeutics

  • 제31권2호
  • /
  • Pages.227-239
  • /
  • 2023
  • /
  • 1976-9148(pISSN)
  • /
  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

4-F-PCP, a Novel PCP Analog Ameliorates the Depressive-Like Behavior of Chronic Social Defeat Stress Mice via NMDA Receptor Antagonism

  • Darlene Mae D., Ortiz (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University) ;
  • Mikyung, Kim (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University) ;
  • Hyun Jun, Lee (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University) ;
  • Chrislean Jun, Botanas (Department of Psychiatry, University of Texas Southwestern Medical Center) ;
  • Raly James Perez, Custodio (Department of Ergonomics, Leibniz Research Centre for Working Environment and Human Factors) ;
  • Leandro, Val Sayson (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University) ;
  • Nicole, Bon Campomayor (Department of Chemistry & Life Science, Sahmyook University) ;
  • Chaeyeon, Lee (Department of Fundamental Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University) ;
  • Yong Sup, Lee (Department of Fundamental Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University) ;
  • Jae Hoon, Cheong (Institute for New Drug Development, School of Pharmacy, Jeonbuk National University) ;
  • Hee Jin, Kim (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University)
  • 투고 : 2022.12.09
  • 심사 : 2023.01.11
  • 발행 : 2023.03.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Major depressive disorder is a leading cause of disability in more than 280 million people worldwide. Monoamine-based antidepressants are currently used to treat depression, but delays in treatment effects and lack of responses are major reasons for the need to develop faster and more efficient antidepressants. Studies show that ketamine (KET), a PCP analog, produces antidepressant effects within a few hours of administration that lasts up to a week. However, the use of KET has raised concerns about side effects, as well as the risk of abuse. 4 -F-PCP analog is a novel PCP analog that is also an NMDA receptor antagonist, structurally similar to KET, and might potentially elicit similar antidepressant effects, however, there has been no study on this subject yet. Herein, we investigate whether 4-F-PCP displays antidepressant effects and explored their potential therapeutic mechanisms. 4-F-PCP at 3 and 10 mg/kg doses showed antidepressant-like effects and repeated treatments maintained its effects. Furthermore, treatment with 4-F-PCP rescued the decreased expression of proteins most likely involved in depression and synaptic plasticity. Changes in the excitatory amino acid transporters (EAAT2, EAAT3, EAAT4) were also seen following drug treatment. Lastly, we assessed the possible side effects of 4-F-PCP after long-term treatment (up to 21 days). Results show that 4-F-PCP at 3 mg/kg dose did not alter the cognitive function of mice. Overall, current findings provide significant implications for future research not only with PCP analogs but also on the next generation of different types of antidepressants.

키워드

과제정보

This study was supported by the National Research Foundation of Korea (NRF) of Korea (grant number NRF_2020M3E5D9080791). This paper was also supported by research funds from newly appointed professors of Jeonbuk National University in 2021.

참고문헌

  1. Abiero, A., Botanas, C. J., Custodio, R. J., Sayson, L. V., Kim, M., Lee, H. J., Kim, H. J., Lee, K. W., Jeong, Y., Seo, J. W., Ryu, I. S., Lee, Y. S. and Cheong, J. H. (2020) 4-MeO-PCP and 3-MeO-PCMo, new dissociative drugs, produce rewarding and reinforcing effects through activation of mesolimbic dopamine pathway and alteration of accumbal CREB, deltaFosB, and BDNF levels. Psychopharmacology (Berl.) 237, 757-772. https://doi.org/10.1007/s00213-019-05412-y
  2. Autry, A., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P. F., Kavalali, E. T. and Monteggia, L. M. (2011) NMDA receptor blockade at rest triggers rapid behavioral antidepressant responses. Nature 475, 91-95. https://doi.org/10.1038/nature10130
  3. Ballard, E. D. and Zarate, C. A., Jr. (2020) The role of dissociation in ketamine's antidepressant effects. Nat. Commun. 11, 6431.
  4. Bjorkholm, C. and Monteggia, L. M. (2016) BDNF - a key transducer of antidepressant effects. Neuropharmacology 102, 72-79. https://doi.org/10.1016/j.neuropharm.2015.10.034
  5. Blendy, J. A. (2006) The role of CREB in depression and antidepressant treatment. Biol. Psychiatry 59, 1144-1150. https://doi.org/10.1016/j.biopsych.2005.11.003
  6. Botanas, C. J., Perez Custodio, R., Kim, H. J., de la Pena, J. B., Sayson, L. V., Ortiz, D. M., Kim, M. K., Lee, H. J., Acharya, S., Kim, K. M., Lee, C. J., Ryu, J. H., Lee, Y. S. and Cheong, J. H. (2021) R (-)-methoxetamine exerts rapid and sustained antidepressant effects and fewer behavioral side effects relative to S (+)-methoxetamine. Neuropharmacology 193, 108619.
  7. Chowdhury, G. M., Zhang, J., Thomas, M., Banasr, M., Ma, X., Pittman, B., Bristow, L., Schaeffer, E., Duman, R., Rothman, D., Behar, K. and Sanacora, G. (2017) Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Mol. Psychiatry 22, 120-126. https://doi.org/10.1038/mp.2016.34
  8. Custodio, R. J. P., Kim, M., Sayson, L. V., Lee, H. J., Ortiz, D. M., Kim, B. N., Kim, H. J. and Cheong, J. H. (2021) Low striatal T3 is implicated in inattention and memory impairment in an ADHD mouse model overexpressing thyroid hormone-responsive protein. Commun. Biol. 4, 1101.
  9. Divito, C. B. and Underhill, S. M. (2014) Excitatory amino acid transporters: roles in glutamatergic neurotransmission. Neurochem. Int. 73, 172-180. https://doi.org/10.1016/j.neuint.2013.12.008
  10. Duman, R. S. and Aghajanian, G. K. (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68-72. https://doi.org/10.1126/science.1222939
  11. Gass, P. and Riva, M. A. (2007) CREB, neurogenesis, and depression. BioEssays 29, 957-961. https://doi.org/10.1002/bies.20658
  12. Gass, N., Becker, R., Reinwald, J., Cosa-Linan, A., Sack, M., WeberFahr, W., Vollmayr, B. and Sartorius, A. (2019) Differences between ketamine's short-term and long-term effects on brain circuitry in depression. Transl. Psychiatry 9, 172.
  13. Gaynes, B. N., Warden, D., Trivedi, M. H., Wisniewski, S. R., Fava, M. and Rush, A. J. (2009) What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr. Serv. 60, 1439-1445. https://doi.org/10.1176/appi.ps.60.11.1439
  14. Golden, S. A., Covington, H. E., III, Berton, O. and Russo, S. J. (2011) A standardized protocol for repeated social defeat stress in mice. Nat. Protoc. 6, 1183-1191. https://doi.org/10.1038/nprot.2011.361
  15. Gong, R., Park, C. S., Abbassi, N. R. and Tang, S. J. (2006) Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. J. Biol. Chem. 281, 18802-18815. https://doi.org/10.1074/jbc.M512524200
  16. Hillhouse, T. M., Porter, J. H. and Negus, S. S. (2014) Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats. Psychopharmacology (Berl.) 231, 2705-2716. https://doi.org/10.1007/s00213-014-3451-3
  17. Ignacio, Z. M., Reus, G. Z., Arent, C. O., Abelaira, H. M., Pitcher, M. R. and Quevedo, J. (2016) New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs. Br. J. Clin. Pharmacol. 82, 1280-1290. https://doi.org/10.1111/bcp.12845
  18. Jelen, L. A., Young, A. H. and Stone, J. M. (2021) Ketamine: a tale of two enantiomers. J. Psychopharmacol. 35, 109-123. https://doi.org/10.1177/0269881120959644
  19. Kilkenny, C., Browne, W., Cuthill, I. C., Emerson, M. and Altman, D. G. (2010) Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br. J. Pharmacol. 160, 1577-1579. https://doi.org/10.1111/j.1476-5381.2010.00872.x
  20. Kim, D. G., Gonzales, E. L., Kim, S., Kim, Y., Adil, K. J., Jeon, S. J., Cho, K. S., Kwon, K. J. and Shin, C. Y. (2019) Social interaction test in home cage as a novel and ethological measure of social behavior in mice. Exp. Neurobiol. 28, 247-260. https://doi.org/10.5607/en.2019.28.2.247
  21. Kishi, T., Yoshimura, R., Ikuta, T. and Iwata, N. (2018) Brain-derived neurotrophic factor and major depressive disorder: evidence from meta-analyses. Front. Psychiatry 8, 308.
  22. Koike, H., Iijima, M. and Chaki, S. (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav. Brain Res. 224, 107-111. https://doi.org/10.1016/j.bbr.2011.05.035
  23. Lang, U. E. and Borgwardt, S. (2013) Molecular mechanisms of depression: perspectives on new treatment strategies. Cell. Physiol. Biochem. 31, 761-777. https://doi.org/10.1159/000350094
  24. Lin, C.-L. G., Kong, Q., Cuny, G. D. and Glicksman, M. A. (2012) Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases. Future Med. Chem. 4, 1689-1700. https://doi.org/10.4155/fmc.12.122
  25. Lipton, S. A. (2004) Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx 1, 101-110. https://doi.org/10.1602/neurorx.1.1.101
  26. Liu, Y., Lin, D., Wu, B. and Zhou, W. (2016) Ketamine abuse potential and use disorder. Brain Res. Bull. 126, 68-73. https://doi.org/10.1016/j.brainresbull.2016.05.016
  27. Miranda, M., Morici, J. F., Zanoni, M. B. and Bekinschtein, P. (2019) Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front. Cell. Neurosci. 13, 363.
  28. Mitrovic, V., Patyna, W., Huting, J. and Schlepper, M. (1991) Hemodynamic and neurohumoral effects of moxonidine in patients with essential hypertension. Cardiovasc. Drugs Ther. 5, 967-972. https://doi.org/10.1007/BF00143521
  29. Murrough, J. W., Wan, L. B., Iacoviello, B., Collins, K. A., Solon, C., Glicksberg, B., Perez, A., Mathew, S. J., Charney, D., Losifescu, D. V. and Burdick, K. E. (2014) Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response. Psychopharmacology (Berl.) 231, 481-488. https://doi.org/10.1007/s00213-013-3255-x
  30. Nikayin, S., Murphy, E., Krystal, J. H. and Wilkinson, S. T. (2022) Longterm safety of ketamine and esketamine in treatment of depression. Expert Opin. Drug Saf. 21, 777-787. https://doi.org/10.1080/14740338.2022.2066651
  31. Ortiz, D. M., Custodio, R. J. P., Abiero, A., Botanas, C. J., Sayson, L. V., Kim, M., Lee, H. J., Kim, H. J., Jeong, Y., Yoon, S., Lee, Y. S. and Cheong, J. H. (2021) The dopaminergic alterations induced by 4-F-PCP and 4-Keto-PCP may enhance their drug-induced rewarding and reinforcing effects: implications for abuse. Addict. Biol. 26, e12981.
  32. Palucha-Poniewiera, A. and Pilc, A. (2016) Glutamate-based drug discovery for novel antidepressants. Expert Opin. Drug Discov. 11, 873-883. https://doi.org/10.1080/17460441.2016.1213234
  33. Papp, M. and Moryl, E. (1994) Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur. J. Pharmacol. 263, 1-7. https://doi.org/10.1016/0014-2999(94)90516-9
  34. Pochwat, B., Rafalo-Ulinska, A., Domin, H., Misztak, P., Nowak, G. and Szewczyk, B. (2017) Involvement of extracellular signal-regulated kinase (ERK) in the short and long-lasting antidepressant-like activity of NMDA receptor antagonists (zinc and Ro 25-6981) in the forced swim test in rats. Neuropharmacology 125, 333-342. https://doi.org/10.1016/j.neuropharm.2017.08.006
  35. Polis, A. J., Fitzgerald, P. J., Hale, P. J. and Watson, B. O. (2019) Rodent ketamine depression-related research: finding patterns in a literature of variability. Behav. Brain Res. 376, 112153.
  36. Puran, A. C., Holstege, C. P., Jamison, K. P. and Wiegand, T. J. (2014) Phencyclidine. In Encyclopedia of Toxicology, pp. 868-870.
  37. Elsevier. Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., McGrath, P. J., Rosenbaum, J. F., Sackeim, H. A., Kupfer, D. J., Luther, J. and Fava, M. (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry 163, 1905-1917. https://doi.org/10.1176/appi.ajp.163.11.1905
  38. Sanacora, G., Zarate, C. A., Krystal, J. H. and Manji, H. K. (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat. Rev. Drug Discov. 7, 426-437. https://doi.org/10.1038/nrd2462
  39. Sayson, L. V., Botanas, C. J., Custodio, R. J. P., Abiero, A., Kim, M., Lee, H. J., Kim, H. J., Yoo, S. Y., Lee, K. W., Ryu, H. W., Acharya, S., Kim, K. M., Lee, Y. S. and Cheong, J. H. (2019) The novel methoxetamine analogs N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK) elicit rapid antidepressant effects via activation of AMPA and 5-HT2 receptors. Psychopharmacology (Berl.) 236, 2201-2210. https://doi.org/10.1007/s00213-019-05219-x
  40. Wang, Q. and Dwivedi, Y. (2021) Advances in novel molecular targets for antidepressants. Prog. Neuropsychopharmacol. Biol. Psychiatry 104, 110041.
  41. World Health Organization (2021) Suicide Worldwide in 2019: Global Health Estimates. Retrieved from: https://www.who.int/publications/i/item/9789240026643/.
  42. Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., Dossou, K. S., Fang, Y., Huang, X. P., Mayo, C. L., Wainer, I. W., Albuquerque, E. X., Thompson, S. M., Thomas, C. J., Zarate, C. A., Jr. and Gould, T. D. (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481-486. https://doi.org/10.1038/nature17998
  43. Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S. and Manji, H. K. (2006) A randomized trial of an N-Methyl-D-aspartate antagonist in treatmentresistant major depression. Arch. Gen. Psychiatry 63, 856-864. https://doi.org/10.1001/archpsyc.63.8.856