Hydrogen Sulfide (H<sub>2</sub>S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture
Chronic neuroinflammation and oxidative stress play an important role in the onset and progression of neurodegenerative disorders, including Alzheimer’s disease, which can ultimately lead to neuronal damage and loss. The mechanisms of sustained neuroinflammation and the coordinated chain of events t...
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2025-07-01
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| author | Leonardo Brunetti Fabio Francavilla Mauro Niso Jakub Kosma Frydrych Ewa Trojan Igor A. Schepetkin Liliya N. Kirpotina Beata Grygier Krzysztof Łukowicz Mark T. Quinn Agnieszka Basta-Kaim Enza Lacivita Marcello Leopoldo |
| author_facet | Leonardo Brunetti Fabio Francavilla Mauro Niso Jakub Kosma Frydrych Ewa Trojan Igor A. Schepetkin Liliya N. Kirpotina Beata Grygier Krzysztof Łukowicz Mark T. Quinn Agnieszka Basta-Kaim Enza Lacivita Marcello Leopoldo |
| author_sort | Leonardo Brunetti |
| collection | DOAJ |
| description | Chronic neuroinflammation and oxidative stress play an important role in the onset and progression of neurodegenerative disorders, including Alzheimer’s disease, which can ultimately lead to neuronal damage and loss. The mechanisms of sustained neuroinflammation and the coordinated chain of events that initiate, modulate, and then lead to the resolution of inflammation are increasingly being elucidated, offering alternative approaches for treating pathologies with underlying chronic neuroinflammation. Here, we propose a new multitarget approach to address chronic neuroinflammation and oxidative stress in neurodegenerative disorders by activating the formyl peptide receptor 2 (FPR2) combined with the potentiation of hydrogen sulfide (H<sub>2</sub>S) release. FPR2 is a key player in the resolution of inflammation because it mediates the effects of several endogenous pro-resolving mediators. At the same time, H<sub>2</sub>S is an endogenous gaseous transmitter with anti-inflammatory and pro-resolving properties, and it can protect against oxidative stress. Starting from potent FPR2 agonists identified in our laboratories, we prepared hybrid compounds by embedding an H<sub>2</sub>S-donating moiety within the molecular scaffold of these FPR2 agonists. Following this approach, we identified several compounds that combined potent FPR2 agonism with the ability to release H<sub>2</sub>S. The release of H<sub>2</sub>S was assessed in buffer and intracellularly. Compounds <b>7b</b> and <b>8b</b> combined potent FPR2 agonist activity, selectivity over FPR1, and the ability to release H<sub>2</sub>S. Compounds <b>7b</b> and <b>8b</b> were next studied in murine primary microglial cells stimulated with lipopolysaccharide (LPS), a widely accepted in vitro model of neuroinflammation. Both compounds were able to counterbalance LPS-induced cytotoxicity and the release of pro-inflammatory (IL-18, IL-6) and anti-inflammatory (IL-10) cytokines induced by LPS stimulation. |
| format | Article |
| id | doaj-art-c02f1ec28e4049f6b13207c518583e63 |
| institution | DOAJ |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-07-01 |
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| series | Antioxidants |
| spelling | doaj-art-c02f1ec28e4049f6b13207c518583e632025-08-20T02:45:53ZengMDPI AGAntioxidants2076-39212025-07-0114782710.3390/antiox14070827Hydrogen Sulfide (H<sub>2</sub>S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia CultureLeonardo Brunetti0Fabio Francavilla1Mauro Niso2Jakub Kosma Frydrych3Ewa Trojan4Igor A. Schepetkin5Liliya N. Kirpotina6Beata Grygier7Krzysztof Łukowicz8Mark T. Quinn9Agnieszka Basta-Kaim10Enza Lacivita11Marcello Leopoldo12Dipartimento di Farmacia-Scienze del Farmaco, Università Degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, ItalyDipartimento di Farmacia-Scienze del Farmaco, Università Degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, ItalyDipartimento di Farmacia-Scienze del Farmaco, Università Degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, ItalyLaboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, PolandLaboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, PolandDepartment of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USADepartment of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USALaboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, PolandLaboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, PolandDepartment of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USALaboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, PolandDipartimento di Farmacia-Scienze del Farmaco, Università Degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, ItalyDipartimento di Farmacia-Scienze del Farmaco, Università Degli Studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, ItalyChronic neuroinflammation and oxidative stress play an important role in the onset and progression of neurodegenerative disorders, including Alzheimer’s disease, which can ultimately lead to neuronal damage and loss. The mechanisms of sustained neuroinflammation and the coordinated chain of events that initiate, modulate, and then lead to the resolution of inflammation are increasingly being elucidated, offering alternative approaches for treating pathologies with underlying chronic neuroinflammation. Here, we propose a new multitarget approach to address chronic neuroinflammation and oxidative stress in neurodegenerative disorders by activating the formyl peptide receptor 2 (FPR2) combined with the potentiation of hydrogen sulfide (H<sub>2</sub>S) release. FPR2 is a key player in the resolution of inflammation because it mediates the effects of several endogenous pro-resolving mediators. At the same time, H<sub>2</sub>S is an endogenous gaseous transmitter with anti-inflammatory and pro-resolving properties, and it can protect against oxidative stress. Starting from potent FPR2 agonists identified in our laboratories, we prepared hybrid compounds by embedding an H<sub>2</sub>S-donating moiety within the molecular scaffold of these FPR2 agonists. Following this approach, we identified several compounds that combined potent FPR2 agonism with the ability to release H<sub>2</sub>S. The release of H<sub>2</sub>S was assessed in buffer and intracellularly. Compounds <b>7b</b> and <b>8b</b> combined potent FPR2 agonist activity, selectivity over FPR1, and the ability to release H<sub>2</sub>S. Compounds <b>7b</b> and <b>8b</b> were next studied in murine primary microglial cells stimulated with lipopolysaccharide (LPS), a widely accepted in vitro model of neuroinflammation. Both compounds were able to counterbalance LPS-induced cytotoxicity and the release of pro-inflammatory (IL-18, IL-6) and anti-inflammatory (IL-10) cytokines induced by LPS stimulation.https://www.mdpi.com/2076-3921/14/7/827neuroinflammationhybrid compoundsantioxidantneuroprotectionanti-inflammation |
| spellingShingle | Leonardo Brunetti Fabio Francavilla Mauro Niso Jakub Kosma Frydrych Ewa Trojan Igor A. Schepetkin Liliya N. Kirpotina Beata Grygier Krzysztof Łukowicz Mark T. Quinn Agnieszka Basta-Kaim Enza Lacivita Marcello Leopoldo Hydrogen Sulfide (H<sub>2</sub>S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture Antioxidants neuroinflammation hybrid compounds antioxidant neuroprotection anti-inflammation |
| title | Hydrogen Sulfide (H<sub>2</sub>S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture |
| title_full | Hydrogen Sulfide (H<sub>2</sub>S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture |
| title_fullStr | Hydrogen Sulfide (H<sub>2</sub>S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture |
| title_full_unstemmed | Hydrogen Sulfide (H<sub>2</sub>S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture |
| title_short | Hydrogen Sulfide (H<sub>2</sub>S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture |
| title_sort | hydrogen sulfide h sub 2 sub s donating formyl peptide receptor 2 fpr2 agonists design synthesis and biological evaluation in primary mouse microglia culture |
| topic | neuroinflammation hybrid compounds antioxidant neuroprotection anti-inflammation |
| url | https://www.mdpi.com/2076-3921/14/7/827 |
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