The selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole reverses depressive-like behavior induced by acute restraint stress in mice: modulation of oxido-nitrosative stress and inflammatory pathway
- 88 Downloads
Rationale and objectives
Stress-induced alterations in oxidative and inflammatory parameters have been implicated in the pathophysiology of mood disorders. Based on the antioxidant and anti-inflammatory properties of the selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI), we assessed its ability to reverse depression-like behavioral alterations, neuroinflammation, and oxidative imbalance induced by acute restraint stress.
Mice submitted to restraint for 240 min received CMI (1 or 10 mg/kg, orally) 10 min after the end of the stress induction. Behavioral and biochemical tests were carried out after further 30 min.
Restraint-induced depression-like behavior in the tail suspension test (TST), splash test, and new object exploration test was reversed by CMI. None of the treatments evoked locomotor alteration. In addition, CMI abrogated restraint-induced increases in plasma levels of corticosterone and in markers of oxidative stress and impaired superoxide dismutase and catalase activity in the prefrontal cortex (PFC) and hippocampus (HC). CMI also blocked stress-induced downregulation of mRNA levels of glucocorticoid receptor and brain-derived neurotrophic factor and upregulation of nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis alpha, indoelamine-2,3-dioxygenase, and glycogen synthase kinase 3 beta in PFC and HC.
These preclinical results indicate that administration of selenium-containing compounds might help to treat depression associated with inflammation and oxidative stress.
KeywordsAntidepressant Selenium Acute restraint stress Oxidative stress Neuroinflammation
The authors are grateful to UFPel and especially to the Biotechnology Graduate Program (UFPel) for providing support to carry out this work. CNPq is also acknowledged for the fellowship to LS, EL, FS, TC, and CWN.
AMC and MD performed the experiments and the analysis of data and wrote the manuscript. SRB, DAL, and MS performed the experiments. AMC, MD, and LS designed the project. NBP and EJL synthesized the compound CMI. TC, FKS, LS, and CWN supervised the experiments. RD revised the scientific content of the manuscript and provided valuable intellectual insights. All authors critically reviewed the content and approved the final version for publication.
Role of funding source
This study received financial support and scholarships from the Brazilian agencies CNPq, CAPES, and FAPERGS (PRONEM 16/2551-0000240-1, PqG 17/2551-00011046-9, and FAPERGS/CAPES 04/2018 - DOCFIX 18/2551-0000511-8).
Compliance with ethical standards
The studies were performed in accordance with protocols approved by the Committee on the Care and Use of Experimental Animal Resources at the Federal University of Pelotas, Brazil (4034-2017).
Conflict of interest
The authors declare they have no conflict of interest.
- Ai H, Shi XF, Hu XP, Fang WQ, Zhang B, Lu W (2017) Acute stress regulates phosphorylation of N-methyl-d-aspartate receptor GluN2B at S1284 in hippocampus. Neuroscience 351:24–35. https://doi.org/10.1016/j.neuroscience.2017.03.029 CrossRefPubMedGoogle Scholar
- Birmann PT, Sousa FSS, de Oliveira DH, Domingues M, Vieira BM, Lenardão EJ, Savegnago L (2018) 3-(4-Chlorophenylselanyl)-1-methyl-1H-indole, a new selenium compound elicits an antinociceptive and anti-inflammatory effect in mice. Eur J Pharmacol 827:71–79. https://doi.org/10.1016/j.ejphar.2018.03.005 CrossRefPubMedGoogle Scholar
- Casaril AM, Domingues M, Fronza MG, Vieira B, Begnini K, Lenardão EJ, Seixas FK, Collares T, Nogueica C, Savegnago L (2017a) Antidepressant-like effect of a new selenium-containing compound is accompanied by a reduction of neuroinflammation and oxidative stress in lipopolysaccharide-challenged mice. J PsychoneuropharmacolGoogle Scholar
- Casaril AM, Ignasiak MT, Chuang CY, Vieira B, Padilha NB, Carroll L, Lenardão EJ, Savegnago L, Davies MJ (2017b) Selenium-containing indolyl compounds: kinetics of reaction with inflammation-associated oxidants and protective effect against oxidation of extracellular matrix proteins. Free Radic Biol Med 113:395–405. https://doi.org/10.1016/j.freeradbiomed.2017.10.344 CrossRefPubMedGoogle Scholar
- Casaril AM, Martinez DM, Ricordi VG, Alves D, Lenardão EJ, Schultze E, Collares T, Seixas FK, Savegnago (2015) Evaluation of the toxicity of α-(phenylselanyl) acetophenone in mice. Regul Toxicol Pharmacol 73:868–874. doi: https://doi.org/10.1016/j.yrtph.2015.10.004
- Chen H-JC, Spiers JG, Sernia C, Lavidis NA (2016) Acute restraint stress induces specific changes in nitric oxide production and inflammatory markers in the rat hippocampus and striatum. Free Radic Biol Med 90:219–229. https://doi.org/10.1016/j.freeradbiomed.2015.11.023 CrossRefPubMedGoogle Scholar
- Dobarro M, Orejana L, Aguirre N, Ramírez MJ (2013) Propranolol reduces cognitive deficits, amyloid β levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration. Int J Neuropsychopharmacol 16:1351–1360. https://doi.org/10.1017/S1461145712001393 CrossRefPubMedGoogle Scholar
- Domingues M, Casaril AM, Birmann PT, de Lourenço DA, Vieira BM, Begnini K, Seixas FK, Collares T, Lenardão EJ, Savegnago L (2018) Selanylimidazopyridine prevents lipopolysaccharide-induced depressive-like behavior in mice by targeting neurotrophins and inflammatory/oxidative mediators. Front Neurosci 12:486. https://doi.org/10.3389/fnins.2018.00486 CrossRefPubMedPubMedCentralGoogle Scholar
- Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229. https://doi.org/10.1016/j.neuroscience.2013.04.060 CrossRefPubMedPubMedCentralGoogle Scholar
- Freitas AE, Bettio LEB, Neis VB, Santos DB, Ribeiro CM, Rosa PB, Farina M, Rodrigues AL (2014) Agmatine abolishes restraint stress-induced depressive-like behavior and hippocampal antioxidant imbalance in mice. Prog Neuro-Psychopharmacol Biol Psychiatry 50:143–150. https://doi.org/10.1016/j.pnpbp.2013.12.012 CrossRefGoogle Scholar
- Freitas AE, Machado DG, Budni J, Neis VB, Balen GO, Lopes MW, de SLF, Dalfre AL, Leal RB, Rodrigues AL (2013) Fluoxetine modulates hippocampal cell signaling pathways implicated in neuroplasticity in olfactory bulbectomized mice. Behav Brain Res 237:176–184. https://doi.org/10.1016/j.bbr.2012.09.035 CrossRefPubMedGoogle Scholar
- Gandin V, Khalkar P, Braude J, Fernandes AP (2018) Organic selenium compounds as potential chemotherapeutic agents for improved cancer treatment. Free Radic Biol Med 127:80–97. https://doi.org/10.1016/j.freeradbiomed.2018.05.001 CrossRefPubMedGoogle Scholar
- Gárate I, García-Bueno B, Madrigal JL, Caso JR, Alou L, Gómez-Lus ML, Leza JC (2014) Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflammation 11:8. https://doi.org/10.1186/1742-2094-11-8 CrossRefPubMedPubMedCentralGoogle Scholar
- Halliwell B (2007) Biochemistry of oxidative stress: Figure 1. Biochem Soc Trans 35:1147–1150. doi: https://doi.org/10.1042/BST0351147
- Jevtić G, Nikolić T, Mirčić A, Stojković T, Velimirović M, Trajković V, Marković I, Trbovich AM, Radonjić NV, Petronijević N (2016) Mitochondrial impairment, apoptosis and autophagy in a rat brain as immediate and long-term effects of perinatal phencyclidine treatment — influence of restraint stress. Progr Neuro-Psychopharmacol Biol Psychiatry. 66:87–96Google Scholar
- Justice NJ, Huang L, Tian JB, Cole A, Pruski M, Hunt AJ Jr, Flores R, Zhu MX, Arenkiel BR, Zheng H (2015) Posttraumatic stress disorder-like induction elevates β-amyloid levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses. J Neurosci 35:2612–1623. https://doi.org/10.1523/jneurosci.3333-14.2015 CrossRefPubMedPubMedCentralGoogle Scholar
- Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116. https://doi.org/10.1146/annurev.pharmtox.46.120604.141046 CrossRefPubMedGoogle Scholar
- Kil J, Lobarinas E, Spankovich C, Griffiths SK, Antonelli PJ, Lynch ED, Le Prell CG (2017) Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 390:969–979. https://doi.org/10.1016/S0140-6736(17)31791-9 CrossRefPubMedGoogle Scholar
- Kotan VO, Sarandol E, Kirhan E, Ozkaya G, Kirli S (2011) Effects of long-term antidepressant treatment on oxidative status in major depressive disorder: a 24-week follow-up study. Prog Neuro-Psychopharmacol Biol Psychiatry 35:1284–1290. https://doi.org/10.1016/j.pnpbp.2011.03.021 CrossRefGoogle Scholar
- Ledo JH, Azevedo EP, Beckman D, Ribeiro FC, Santos LE, Razolli DS, Kincheski GC, Melo HM, Bellio M, Teixeira AL, Velloso LZ, Foguel D, De Felice FG, Ferreira ST (2016) Cross talk between brain innate immunity and serotonin signaling underlies depressive-like behavior induced by Alzheimer’s amyloid-β oligomers in mice. J Neurosci 36:12106–12116. https://doi.org/10.1523/JNEUROSCI.1269-16.2016 CrossRefPubMedGoogle Scholar
- Lima-Junior DS, Costa DL, Carregaro V, Cunha LD, Silva ALN, Mineo TWP, Gutierrez FR, Bellio M, Bortoluci KR, Flavell RA, Bozza MT, Silva JS, Zamboni DS (2013) Inflammasome-derived IL-1β production induces nitric oxide–mediated resistance to Leishmania. Nat Med 19:909–915. https://doi.org/10.1038/nm.3221 CrossRefPubMedGoogle Scholar
- Loetchutinat C, Kothan S, Dechsupa S, Meesungnoen J, Jay-Gerin JP, Mankhetkorn S (2005) Spectrofluorometric determination of intracellular levels of reactive oxygen species in drug-sensitive and drug-resistant cancer cells using the 2′,7′-dichlorofluorescein diacetate assay. Radiat Phys Chem 72:323–331. https://doi.org/10.1016/J.RADPHYSCHEM.2004.06.011 CrossRefGoogle Scholar
- Lowes DA, Almawash AM, Webster NR, Reid VL, Galley HF (2011) Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis. Br J Anesthesia 107:193–201. https://doi.org/10.1093/bja/aer149 CrossRefGoogle Scholar
- Lowry OH, Rosebrough NJ, Farr AL, RandalL RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
- Lukic I, Mitic M, Djordjevic J, Tatalovic N, Bozovic N, Soldalovic I, Mihaljevic M, Pavlovic Z, Radojcic MB, Maric NP, Adzic M (2014) Lymphocyte levels of redox-sensitive transcription factors and antioxidative enzymes as indicators of pro-oxidative state in depressive patients. Neuropsychobiology 70:1–9. https://doi.org/10.1159/000362841 CrossRefPubMedGoogle Scholar
- MacDowell K, Caso J, Martín-Hernández D, Madrigal JL, Leza JC, García-Bueno B (2015) Paliperidone prevents brain Toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress. Int J Neuropsychopharmacol 18. https://doi.org/10.1093/ijnp/pyu070
- Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuro-Psychopharmacol Biol Psychiatry 35:676–692. https://doi.org/10.1016/j.pnpbp.2010.05.004 CrossRefGoogle Scholar
- Masaki C, Sharpley AL, Cooper CM, Godlewska BR, Singh N, Vasudevan SR, Harmer CJ, Churchill CG, Sharp T, Rogers RS, Cowen PJ (2016) Effects of the potential lithium-mimetic, ebselen, on impulsivity and emotional processing. Psychopharmacology 233:2655–2661. https://doi.org/10.1007/s00213-016-4319-5 CrossRefPubMedPubMedCentralGoogle Scholar
- Pesarico AP, Stangherlin EC, Mantovani AC, Zeni G, Nogueira CW (2015) 7-Fluoro-1,3-diphenylisoquinoline-1-amine abolishes depressive-like behavior and prefrontal cortical oxidative damage induced by acute restraint stress in mice. Physiol Behav 149:294–302. https://doi.org/10.1016/j.physbeh.2015.06.018 CrossRefPubMedGoogle Scholar
- Pinto Brod LM, Fronza MG, Vargas JP, Ludtke DS, Luchese C, Wilhelm EA, Savegnago L (2016) Involvement of monoaminergic system in the antidepressant-like effect of (octylseleno)-xylofuranoside in the mouse tail suspension test. Prog Neuro-Psychopharmacol Biol Psychiatry 65:201–207. https://doi.org/10.1016/j.pnpbp.2015.10.008 CrossRefGoogle Scholar
- Rosa JM, Pazini FL, Cunha MP, Colla ARS, Manosso LM, Mancini G, Souza ACG, de Bem AF, Prediger RS, Rodrigues ALS (2018) Antidepressant effects of creatine on amyloid β 1–40-treated mice: the role of GSK-3β/Nrf 2 pathway. Prog Neuro-Psychopharmacol Biol Psychiatry doi: https://doi.org/10.1016/j.pnpbp.2018.05.001, 86, 270, 278
- Schiavone S, Sorce S, Dubois-Dauphin M, Jaquet V, Colaianna M, Zotti M, Cuomo V, Trabace L, Krause K-H (2009) Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry 66:384–392. https://doi.org/10.1016/j.biopsych.2009.04.033 CrossRefPubMedGoogle Scholar
- Singh N, Sharpley AL, Emir UE, Masaki C, Herzallah MM, Gluck MA, Sharp T, Harmer CJ, Vasudeven SR, Cowen PJ, Churchill GC (2016) Effect of the putative lithium mimetic ebselen on brain myo-inositol, sleep and emotional processing in humans. Neuropsychopharmacology 41:1768–1778. https://doi.org/10.1038/npp.2015.343 CrossRefPubMedGoogle Scholar
- Sudati JH, Nogara PA, Saraiva RA, Wagner C, Alberto EE, Braga AL, Fachinetto R, Piquini PC, Rocha JBT (2018) Diselenoamino acid derivatives as GPx mimics and as substrates of TrxR: in vitro and in silico studies. Org Biomol Chem 16:3777–3787. https://doi.org/10.1039/c8ob00451j CrossRefPubMedGoogle Scholar
- Thakare VN, Dhakane VD, Patel BM (2016) Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus. Pharmacol Reports 68:1020–1027. https://doi.org/10.1016/j.pharep.2016.06.002 CrossRefGoogle Scholar