Abstract
Background. During the last decades, data on potential cytoprotective effects of decarboxylated and deiodinated endogenous compounds – metabolites of thyroid hormones, constituting the thyronome, have been accumulated. The aim of this review is to systematize the biological effects of thyronome components in the central nervous system from the position of their possible role as potential neuroprotectants.
Material and methods. English- and Russian-language full-text articles from PubMed, Mendeley, and e-library electronic databases were selected for analysis using query «(thyroid OR thyroid hormone metabolite OR *-iodo-thyronamine OR thyronamine OR TAAR OR thyronome OR T0AM OR T1AM OR thyroacetic acid) AND (brain OR central nervous system OR CNS OR stroke OR neurodegenerat*)». The search depth amounted to 10 years.
Results. The review systematizes the most important neurotropic properties of 3-T1AM and other thyronome components, including their influence on behavioral effects, memory, pain threshold level, apoptosis, autophagy, and excitotoxic neuronal death, and describes the role of individual receptors and intracellular signal transduction pathways in the realization of these properties.
Conclusion. The components of thyronome, in particular 3-T1AM, demonstrate a wide range of potential neuroprotective properties, and for its potential use in the clinic, it is relevant to find ways to increase local concentration in the brain or permeability to the BBB, as well as the development of more effective synthetic analogues.
Authors and affiliations
D.A. Kudlay(1), D.A. Filimonov(2), V.V. Morozov(3), R.V. Ishchenko(2), A.B. Eresko4,
N.N. Trubnikova(2), M.A. Belotserkovskaya(2), I.A. Kisilenko(2), I.N. Nosova(2),
1-Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University
of the Ministry of Health of the Russian Federation (Sechenov University), Trubetskaya st., 8, build. 2, Moscow, 119991, Russian Federation;
2-Federal State Budgetary Institution “V.K. Gusak Institute of emergency and reconstructive surgery” of the Ministry of health
of the Russian Federation, Leninsky Avenue, 47, Donetsk, 283045, Russian Federation;
3-ICBFM “Institute of Chemical Biology and Fundamental Medicine” Siberian Branch of the Russian Academy of Sciences,
Ak. Lavrentieva, 8, Novosibirsk, 630090, Russian Federation;
4-International Intergovernmental Scientific Research Organization Joint Institute for Nuclear Research,
Joliot Curie St., 6, Dubna, 141980, Russian Federation
References
Zucchi R., Rutigliano G., Saponaro F. Novel thyroid hormones. Endocrine. 2019; 66 (1): 95–104. DOI: 10.1007/s12020-019-02018-4.
Homuth G., Lietzow J., Schanze N., Golchert J., Köhrle J. Endocrine, Metabolic and Pharmacological Effects of Thyronamines (TAM), Thyroacetic Acids (TA) and Thyroid Hormone Metabolites (THM) – Evidence from in vitro, Cellular, Experimental Animal and Human Studies. Exp Clin Endocrinol Diabetes. 2020; 128 (6–07): 401–13. DOI: 10.1055/a-1139-9200
Филимонов Д.А., Ересько А.Б., Ракша Е.В., Трубникова Н.Н., Ищенко Р.В., Терещенко Д.А., Кисилинко И.А., Носова И.А. Антиоксидантные эффекты синтетического аналога тиронамина при экспериментальной ишемии головного мозга. Медицина экстремальных ситуаций. 2024; 1: 64–71. DOI: 10.47183/mes.2024.003. [Filimonov D.A., Eresko A.B., Raksha E.V., Trubnikova N.N., Ishenko R.V., Tereshenko D.A., Kisilinko I.A., Nosova I.A. Antioksidantnye effekty sinteticheskogo analoga tironamina pri eksperimentalnoj ishemii golovnogo mozga. Medicina ekstremalnyh situacij. 2024; 1: 64–71. DOI:10.47183/mes.2024.003 (in Russian)]
Bandini L., Sacripanti G., Borsò M., Tartaria M., Fogliaro M.P., Giannini G., Carnicelli V., Figuccia M.E., Verlotta S., De Antoni F., Zucchi R., Ghelardoni S. Exogenous 3-Iodothyronamine (T1AM) Can Affect Phosphorylation of Proteins Involved on Signal Transduction Pathways in In Vitro Models of Brain Cell Lines, but These Effects Are Not Strengthened by Its Catabolite, 3-Iodothyroacetic Acid (TA1). Life. 2022; 12: 1352. DOI: 10.3390/life12091352
Zucchi R., Rutigliano G., Saponaro F. Novel thyroid hormones. Endocrine. 2019; 66 (1): 95–104. DOI: 10.1007/s12020-019-02018-4
Chiellini G., Bellusci L., Sabatini M., Zucchi R. Thyronamines and analogues – the route from rediscovery to translational research on thyronergic amines. Mol. Cell Endocrinol. 2017; 458: 149–55. DOI: 10.1016/j.mce.2017.01.002
Rutigliano G., Bandini L., Sestito S., Chiellini G. 3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome? Int J. Mol. Sci. 2020; 21 (6): 2005. DOI: 10.3390/ijms21062005
Kоhrle J., Biebermann H. 3-Iodothyronamine – A Thyroid Hormone Metabolite With Distinct Target Profiles and Mode of Action. Endocrine Reviews. 2019; 40 (2): 602–30. DOI: 10.1210/er.2018-00182
Zucchi R., Rutigliano G., Saponaro F. Novel thyroid hormones. Endocrine. 2019; 66 (1): 95–104. DOI: 10.1007/s12020-019-02018-4
Martin J.V., Sarkar P.K. Nongenomic roles of thyroid hormones and their derivatives in adult brain: are these compounds putative neurotransmitters? Front Endocrinol (Lausanne). 2023; 14: 1210540. DOI:10.3389/fendo.2023.1210540
Musilli C., De Siena G., Manni M.E., Logli A., Landucci E., Zucchi R., Saba A., Donzelli R., Passani M.B., Provensi G., Raimondi L. Histamine Mediates Behavioural and Metabolic Effects of 3-Iodothyroacetic Acid, an Endogenous End Product of Thyroid Hormone Metabolism: A Novel Link between Thyroid and Histamine. Br. J. Pharmacol. 2014; 171: 3476–84. DOI: 10.1111/bph.12697.
Di Leo N., Moscato S., Borso’ M., Sestito S., Polini B., Bandini L., Grillone A., Battaglini M., Saba A., Mattii L., Ciofani G., Chiellini G. Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study. Molecules. 2021; 26 (6): 1616. DOI: 10.3390/molecules26061616
Huang S., Liu L., Tang X., Xie S., Li X., Kang X., Zhu S. Research progress on the role of hormones in ischemic stroke. Front Immunol. 2022; 13: 1062977. DOI: 10.3389/fimmu.2022.1062977
Panas H.N., Lynch L.J., Vallender E.J., Xie Z., Chen G.L., Lynn S.K., Scanlan T.S., Miller G.M. Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. J. Neurosci Res. 2010; 88: 1962–9. DOI:10.1002/jnr.22367
Rutigliano G., Bertolini A., Grittani N., Frascarelli S., Carnicelli V., Ippolito C., Moscato S., Mattii L., Kusmic C., Saba A., Origlia N., Zucchi R. Effect of Combined Levothyroxine (L-T4) and 3-Iodothyronamine (T1AM) Supplementation on Memory and Adult Hippocampal Neurogenesis in a Mouse Model of Hypothyroidism. Int. J. Mol. Sci. 2023; 24: 13845. DOI:10.3390/ijms241813845
Underhill S.M., Hullihen P.D., Chen J., Fenollar-Ferrer C., Rizzo M.A., Ingram S.L., Amara S.G. Amphetamines signal through intracellular TAAR1 receptors coupled to Galpha13 and GalphaS in discrete subcellular domains. Mol. Psychiatry. 2021; 26: 1208–23. DOI: 10.1038/s41380-019-0469-2
Li ZM., Miller M., Gachkar S., Mittag J., Schriever SC., Pfluger PT., Schramm KW., De Angelis M. Determination of 3-iodothyronamine (3-T1AM) in mouse liver using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2021; 1165: 122553. DOI: 10.1016/j.jchromb.2021.122553.
Rutigliano G., Accorroni A., Zucchi R. The Case for TAAR1 as a Modulator of Central Nervous System Function. Front Pharmacol. 2018; 8: 987. DOI: 10.3389/fphar.2017.00987
Dinter J., Mühlhaus J., Jacobi SF., Wienchol CL., Cöster M., Meister J., Hoefig CS., Müller A., Köhrle J., Grüters A., Krude H., Mittag J., Schöneberg T., Kleinau G., Biebermann H. 3-iodothyronamine differentially modulates alpha-2A-adrenergic receptor-mediated signaling. J. Mol. Endocrinol. 2015; 54 (3): 205–16. DOI: 10.1530/JME-15-0003.
Braunig J., Mergler S., Jyrch S., Hoefig C.S., Rosowski M., Mittag J., Biebermann H., Khajavi N. 3-Iodothyronamine activates a set of membrane proteins in murine hypothalamic cell lines. Front Endocrinol (Lausanne). 2018; 9: 523. DOI: 10.3389/fendo.2018.00523
Rutigliano G., Zucchi R. Molecular Variants in Human Trace Amine‑Associated Receptors and Their Implications in Mental and Metabolic Disorders. Cellular and Molecular Neurobiology. 2020; 40: 239–55. DOI:10.1007/s10571-019-00743-y
Laurino A., De Siena G., Saba A., Chiellini G., Landucci E., Zucchi R., Raimondi L. In the brain of mice, 3-iodothyronamine (T1AM) is converted into 3-iodothyroacetic acid (TA1) and it is included within the signaling network connecting thyroid hormone metabolites with hisЕФЬine. Eur J. Pharmacol. 2015; 761: 130–4. DOI: 10.1016/j.ejphar.2015.04.038
Laurino A., Lucenteforte E., De Siena G., Raimondi L. The impact of scopolamine pretreatment on 3-iodothyronamine (T1AM) effects on memory and pain in mice. Horm Behav. 2017; 94: 93–6. DOI: 10.1016/j.yhbeh.2017.07.003
Bellusci L., Laurino A., Sabatini M., Sestito S., Lenzi P., Raimondi L., Rapposelli S., Biagioni F., Fornai F., Salvetti A., Rossi L., Zucchi R., Chiellini G. New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection. Front Pharmacol. 2017; 8: 905. DOI: 10.3389/fphar.2017.00905
Zhang X., Mantas I., Alvarsson A., Yoshitake T., Shariatgorji M., Pereira M., Nilsson A., Kehr J., Andrén PE., Millan MJ., Chergui K., Svenningsson P. Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or β-Phenylethylamine. Front Pharmacol. 2018; 9: 166. DOI: 10.3389/fphar.2018.00166
Lv J., Liao J., Tan W., Yang L., Shi X., Zhang H., Chen L., Wang S., Li Q. 3-Iodothyronamine Acting through an Anti-Apoptotic Mechanism Is Neuroprotective Against Spinal Cord Injury in Rats. Ann Clin Lab Sci. 2018; 48 (6): 736–42
Landucci E., Gencarelli M., Mazzantini C., Laurino A., Pellegrini-Giampietro DE., Raimondi L. N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity. Neurochem Int. 2019; 129: 104460. DOI: 10.1016/j.neuint.2019.05.004
Bellusci L., Runfola M., Carnicelli V., Sestito S., Fulceri F., Santucci F., Lenzi P., Fornai F., Rapposelli S., Origlia N., Zucchi R., Chiellini G. Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents Through the Modulation of SIRT6. Molecules. 2020; 25 (5): 1054. DOI: 10.3390/molecules25051054
Accorroni A., Rutigliano G., Sabatini M., Frascarelli S., Borsò M., Novelli E., Bandini L., Ghelardoni S., Saba A., Zucchi R., Origlia N. Exogenous 3-Iodothyronamine Rescues the Entorhinal Cortex from β-Amyloid Toxicity. Thyroid. 2020; 30 (1): 147–60. DOI: 10.1089/thy.2019.0255
Tozzi F., Rutigliano G., Borsò M., Falcicchia C., Zucchi R., Origlia N. T1AM-TAAR1 signalling protects against OGD-induced synaptic dysfunction in the entorhinal cortex. Neurobiol Dis. 2021; 151: 105271. DOI: 10.1016/j.nbd.2021.105271
Polini B., Ricardi C., Bertolini A., Carnicelli V., Rutigliano G., Saponaro F., Zucchi R., Chiellini G. T1AM/TAAR1 System Reduces Inflammatory Response and β-Amyloid Toxicity in Human Microglial HMC3 Cell Line. Int. J. Mol. Sci. 2023; 24 (14): 11569. DOI: 10.3390/ijms241411569
Sakanoue W., Yokoyama T., Hirakawa M., Maesawa S., Sato K., Saino T. 3-Iodothyronamine, a trace amine-associated receptor agonist, regulates intracellular Ca2+ increases via CaMK II through Epac2 in rat cerebral arterioles. Biomed Res. 2023; 44 (5): 219–32. DOI: 10.2220/biomedres.44.219
Kim B., Ko YH., Si J., Na J., Ortore G., Chiellini G., Kim JH. Thyroxine metabolite-derived 3-iodothyronamine (T1AM) and synthetic analogs as efficient suppressors of transthyretin amyloidosis. Comput Struct Biotechnol J. 2023; 21: 4717–28. DOI: 10.1016/j.csbj.2023.09.028
Minatohara K., Akiyoshi M., Okuno H. Role of Immediate-Early Genes in Synaptic Plasticity and Neuronal Ensembles Underlying the Memory Trace. Front Mol Neurosci. 2016; 8: 78. DOI: 10.3389/fnmol.2015.00078
Шляпина В.Л., Юртаева С.В., Рубцова М.П., Донцова О.А. На распутье: механизмы апоптоза и аутофагии в жизни и смерти клетки. Acta Naturae. 2021; 2 (49): 106–15. DOI: 10.32607/actanaturae.11208. [Shljapina V.L., Jurtaeva S.V., Rubcova M.P., Doncova O.A. Na rasput’e: mehanizmy apoptoza i autofagii v zhizni i smerti kletki. Acta Naturae. 2021; 2 (49): 106–15 (in Russian)]
Mputhia Z., Hone E., Tripathi T., Sargeant T., Martins R., Bharadwaj P. Autophagy Modulation as a Treatment of Amyloid Diseases. Molecules. 2019; 24 (18): 3372. DOI: 10.3390/molecules24183372.
Crino P.B. The mTOR signalling cascade: paving new roads to cure neurological disease. Nat Rev Neurol. 2016; 12 (7): 379–92. DOI: 10.1038/nrneurol.2016.81
Иваненко К.А., Прасолов В.С., Хабушева Э.Р. Транскрипционный фактор Sp1 в регуляции экспрессии генов, кодирующих компоненты сигнальных путей MAPK, JAK/STAT и PI3K/Akt. Молекулярная биология. 2022; 56 (5): 832–47. DOI: 10.31857/S0026898422050081. [Ivanenko K.A., Prasolov V.S., Habusheva Je.R. Transkripcionnyj faktor Sp1 v reguljacii jekspressii genov, kodirujushhih komponenty signal’nyh putej MAPK, JAK/STAT i PI3K/Akt. Molekuljarnaja biologija. 2022; 56 (5): 832–47 (in Russian)]
Deleyto-Seldas N., Efeyan A. The mTOR–Autophagy Axis and the Control of Metabolism. Front Cell Dev Biol. 2021; 9: 655731. DOI: 10.3389/fcell.2021.655731
Shao J., Yang X., Liu T., Zhang T., Xie Q.R., Xia W. Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage. Protein Cell. 2016; 7: 281–90. DOI: 10.1007/s13238-016-0257-6
Zhou H., Mo L., Huang N., Zou C., Li C., Lin M., Zhang B., Wei B., Li P., Si X., Chen J., Li W., Liu X., Hu B. 3-iodothyronamine inhibits apoptosis induced by myocardial ischemia reperfusion via the Akt/FoxO1 signaling pathway. Ann Transl Med.
2022; 10 (4): 168. DOI: 10.21037/atm-21-7041
Verma M., Lizama B.N., Chu C.T. Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration. Transl Neurodegener. 2022; 11 (1): 3. DOI: 10.1186/s40035-021-00278-7. PMID: 35078537; PMCID: PMC8788129.
Docherty A., Emelifeonwu J., Andrews PJD. Hypothermia after traumatic brain injury. JAMA. 2018; 320 (21): 2204–6. DOI: 10.1001/jama.2018.17121
Huang S., Liu L., Tang X., Xie S., Li X., Kang X., Zhu S. Research progress on the role of hormones in ischemic stroke. Front Immunol. 2022; 13: 1062977. DOI: 10.3389/fimmu.2022.1062977.
Han Y., Han Z., Huang X., Li S., Jin G., Feng J., Wu D., Liu H. An injectable refrigerated hydrogel for inducing local hypothermia and neuroprotection against traumatic brain injury in mice. J. Nanobiotechnology. 2024; 22 (1): 251. DOI: 10.1186/s12951-024-02454-z