Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets
Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. In search for potential efficient treatments for these pathologies, that are still consid...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/21/7424 |
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| author | Filippo Basagni Maria Luisa Di Paolo Giorgio Cozza Lisa Dalla Via Francesca Fagiani Cristina Lanni Michela Rosini Anna Minarini |
| author_facet | Filippo Basagni Maria Luisa Di Paolo Giorgio Cozza Lisa Dalla Via Francesca Fagiani Cristina Lanni Michela Rosini Anna Minarini |
| author_sort | Filippo Basagni |
| collection | DOAJ |
| description | Oxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes’ transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative <b>2</b> emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders. |
| first_indexed | 2024-03-11T11:24:14Z |
| format | Article |
| id | doaj.art-52fb8f16b20044489c72598e7b1fc8ea |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T11:24:14Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-52fb8f16b20044489c72598e7b1fc8ea2023-11-10T15:08:57ZengMDPI AGMolecules1420-30492023-11-012821742410.3390/molecules28217424Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected TargetsFilippo Basagni0Maria Luisa Di Paolo1Giorgio Cozza2Lisa Dalla Via3Francesca Fagiani4Cristina Lanni5Michela Rosini6Anna Minarini7Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, ItalyDepartment of Molecular Medicine, University of Padova, Via G. Colombo 3, 35131 Padova, ItalyDepartment of Molecular Medicine, University of Padova, Via G. Colombo 3, 35131 Padova, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, ItalyDepartment of Drug Sciences (Pharmacology Section), University of Pavia, V.le Taramelli 14, 27100 Pavia, ItalyDepartment of Drug Sciences (Pharmacology Section), University of Pavia, V.le Taramelli 14, 27100 Pavia, ItalyDepartment of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, ItalyDepartment of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, ItalyOxidative stress and neuroinflammation play a pivotal role in triggering the neurodegenerative pathological cascades which characterize neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. In search for potential efficient treatments for these pathologies, that are still considered unmet medical needs, we started from the promising properties of the antidiabetic drug pioglitazone, which has been repositioned as an MAO-B inhibitor, characterized by promising neuroprotective properties. Herein, with the aim to broaden its neuroprotective profile, we tried to enrich pioglitazone with direct and indirect antioxidant properties by hanging polyphenolic and electrophilic features that are able to trigger Nrf2 pathway and the resulting cytoprotective genes’ transcription, as well as serve as radical scavengers. After a preliminary screening on MAO-B inhibitory properties, caffeic acid derivative <b>2</b> emerged as the best inhibitor for potency and selectivity over MAO-A, characterized by a reversible mechanism of inhibition. Furthermore, the same compound proved to activate Nrf2 pathway by potently increasing Nrf2 nuclear translocation and strongly reducing ROS content, both in physiological and stressed conditions. Although further biological investigations are required to fully clarify its neuroprotective properties, we were able to endow the pioglitazone scaffold with potent antioxidant properties, representing the starting point for potential future pioglitazone-based therapeutics for neurodegenerative disorders.https://www.mdpi.com/1420-3049/28/21/7424pioglitazoneMAO-BNrf2electrophilecinnamic acidoxidative stress |
| spellingShingle | Filippo Basagni Maria Luisa Di Paolo Giorgio Cozza Lisa Dalla Via Francesca Fagiani Cristina Lanni Michela Rosini Anna Minarini Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets Molecules pioglitazone MAO-B Nrf2 electrophile cinnamic acid oxidative stress |
| title | Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets |
| title_full | Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets |
| title_fullStr | Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets |
| title_full_unstemmed | Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets |
| title_short | Double Attack to Oxidative Stress in Neurodegenerative Disorders: MAO-B and Nrf2 as Elected Targets |
| title_sort | double attack to oxidative stress in neurodegenerative disorders mao b and nrf2 as elected targets |
| topic | pioglitazone MAO-B Nrf2 electrophile cinnamic acid oxidative stress |
| url | https://www.mdpi.com/1420-3049/28/21/7424 |
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