New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection
3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide r...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2017-12-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00905/full |
| _version_ | 1811270707027378176 |
|---|---|
| author | Lorenza Bellusci Annunziatina Laurino Martina Sabatini Simona Sestito Paola Lenzi Laura Raimondi Simona Rapposelli Francesca Biagioni Francesco Fornai Francesco Fornai Alessandra Salvetti Leonardo Rossi Riccardo Zucchi Grazia Chiellini |
| author_facet | Lorenza Bellusci Annunziatina Laurino Martina Sabatini Simona Sestito Paola Lenzi Laura Raimondi Simona Rapposelli Francesca Biagioni Francesco Fornai Francesco Fornai Alessandra Salvetti Leonardo Rossi Riccardo Zucchi Grazia Chiellini |
| author_sort | Lorenza Bellusci |
| collection | DOAJ |
| description | 3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide range of neuropsychiatric and metabolic disorders. To assess potential neuroprotection by TAAR1 agonists, in the present work, we initially investigated whether T1AM and its corresponding 3-methylbiaryl-methane analog SG-2 can improve learning and memory when systemically administered to mice at submicromolar doses, and whether these effects are modified under conditions of MAO inhibition by clorgyline. Our results revealed that when i.p. injected to mice, both T1AM and SG-2 produced memory-enhancing and hyperalgesic effects, while increasing ERK1/2 phosphorylation and expression of transcription factor c-fos. Notably, both compounds appeared to rely on the action of ubiquitous enzymes MAO to produce the corresponding oxidative metabolites that were then able to activate the histaminergic system. Since autophagy is key for neuronal plasticity, in a second line of experiments we explored whether T1AM and synthetic TAAR1 agonists SG1 and SG2 were able to induce autophagy in human glioblastoma cell lines (U-87MG). After treatment of U-87MG cells with 1 μM T1AM, SG-1, SG-2 transmission electron microscopy (TEM) and immunofluorescence (IF) showed a significant time-dependent increase of autophagy vacuoles and microtubule-associated protein 1 light chain 3 (LC3). Consistently, Western blot analysis revealed a significant increase of the LC3II/LC3I ratio, with T1AM and SG-1 being the most effective agents. A decreased level of the p62 protein was also observed after treatment with T1AM and SG-1, which confirms the efficacy of these compounds as autophagy inducers in U-87MG cells. In the process to dissect which pathway induces ATG, the effects of these compounds were evaluated on the PI3K-AKT-mTOR pathway. We found that 1 μM T1AM, SG-1 and SG-2 decreased pAKT/AKT ratio at 0.5 and 4 h after treatment, suggesting that autophagy is induced by inhibiting mTOR phosphorylation by PI3K-AKT-mTOR pathway. In conclusion, our study shows that T1AM and thyronamine-like derivatives SG-1 and SG-2 might represent valuable tools to therapeutically intervene with neurological disorders. |
| first_indexed | 2024-04-12T22:06:51Z |
| format | Article |
| id | doaj.art-d26e7d117bc347ed9e8d1a3b21b50b18 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T22:06:51Z |
| publishDate | 2017-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d26e7d117bc347ed9e8d1a3b21b50b182022-12-22T03:14:55ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-12-01810.3389/fphar.2017.00905314283New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in NeuroprotectionLorenza Bellusci0Annunziatina Laurino1Martina Sabatini2Simona Sestito3Paola Lenzi4Laura Raimondi5Simona Rapposelli6Francesca Biagioni7Francesco Fornai8Francesco Fornai9Alessandra Salvetti10Leonardo Rossi11Riccardo Zucchi12Grazia Chiellini13Laboratory of Biochemistry, Department of Pathology, University of Pisa, Pisa, ItalySection of Pharmacology and Toxicology, Department of Psychology, Neurology, Drug Sciences, Health of the Child, Pharmacology, University of Florence, Florence, ItalyLaboratory of Biochemistry, Department of Pathology, University of Pisa, Pisa, ItalyLaboratory of Medicinal Chemistry, Department of Pharmacy, University of Pisa, Pisa, ItalyUnit of Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalySection of Pharmacology and Toxicology, Department of Psychology, Neurology, Drug Sciences, Health of the Child, Pharmacology, University of Florence, Florence, ItalyLaboratory of Medicinal Chemistry, Department of Pharmacy, University of Pisa, Pisa, ItalyIRCCS Neuromed, Pozzilli, ItalyUnit of Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, ItalyIRCCS Neuromed, Pozzilli, ItalyUnit of Experimental Biology and Genetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ItalyUnit of Experimental Biology and Genetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ItalyLaboratory of Biochemistry, Department of Pathology, University of Pisa, Pisa, ItalyLaboratory of Biochemistry, Department of Pathology, University of Pisa, Pisa, Italy3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide range of neuropsychiatric and metabolic disorders. To assess potential neuroprotection by TAAR1 agonists, in the present work, we initially investigated whether T1AM and its corresponding 3-methylbiaryl-methane analog SG-2 can improve learning and memory when systemically administered to mice at submicromolar doses, and whether these effects are modified under conditions of MAO inhibition by clorgyline. Our results revealed that when i.p. injected to mice, both T1AM and SG-2 produced memory-enhancing and hyperalgesic effects, while increasing ERK1/2 phosphorylation and expression of transcription factor c-fos. Notably, both compounds appeared to rely on the action of ubiquitous enzymes MAO to produce the corresponding oxidative metabolites that were then able to activate the histaminergic system. Since autophagy is key for neuronal plasticity, in a second line of experiments we explored whether T1AM and synthetic TAAR1 agonists SG1 and SG2 were able to induce autophagy in human glioblastoma cell lines (U-87MG). After treatment of U-87MG cells with 1 μM T1AM, SG-1, SG-2 transmission electron microscopy (TEM) and immunofluorescence (IF) showed a significant time-dependent increase of autophagy vacuoles and microtubule-associated protein 1 light chain 3 (LC3). Consistently, Western blot analysis revealed a significant increase of the LC3II/LC3I ratio, with T1AM and SG-1 being the most effective agents. A decreased level of the p62 protein was also observed after treatment with T1AM and SG-1, which confirms the efficacy of these compounds as autophagy inducers in U-87MG cells. In the process to dissect which pathway induces ATG, the effects of these compounds were evaluated on the PI3K-AKT-mTOR pathway. We found that 1 μM T1AM, SG-1 and SG-2 decreased pAKT/AKT ratio at 0.5 and 4 h after treatment, suggesting that autophagy is induced by inhibiting mTOR phosphorylation by PI3K-AKT-mTOR pathway. In conclusion, our study shows that T1AM and thyronamine-like derivatives SG-1 and SG-2 might represent valuable tools to therapeutically intervene with neurological disorders.http://journal.frontiersin.org/article/10.3389/fphar.2017.00905/fullthyronaminestrace amine-associated receptorslearningmemoryneuroprotectionautophagy |
| spellingShingle | Lorenza Bellusci Annunziatina Laurino Martina Sabatini Simona Sestito Paola Lenzi Laura Raimondi Simona Rapposelli Francesca Biagioni Francesco Fornai Francesco Fornai Alessandra Salvetti Leonardo Rossi Riccardo Zucchi Grazia Chiellini New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection Frontiers in Pharmacology thyronamines trace amine-associated receptors learning memory neuroprotection autophagy |
| title | New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection |
| title_full | New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection |
| title_fullStr | New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection |
| title_full_unstemmed | New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection |
| title_short | New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection |
| title_sort | new insights into the potential roles of 3 iodothyronamine t1am and newly developed thyronamine like taar1 agonists in neuroprotection |
| topic | thyronamines trace amine-associated receptors learning memory neuroprotection autophagy |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2017.00905/full |
| work_keys_str_mv | AT lorenzabellusci newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT annunziatinalaurino newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT martinasabatini newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT simonasestito newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT paolalenzi newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT lauraraimondi newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT simonarapposelli newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT francescabiagioni newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT francescofornai newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT francescofornai newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT alessandrasalvetti newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT leonardorossi newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT riccardozucchi newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection AT graziachiellini newinsightsintothepotentialrolesof3iodothyronaminet1amandnewlydevelopedthyronamineliketaar1agonistsinneuroprotection |