Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease
Alzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its charact...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-07-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/9/8/650 |
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| author | Patrycja Michalska Paloma Mayo Cristina Fernández-Mendívil Giammarco Tenti Pablo Duarte Izaskun Buendia María Teresa Ramos Manuela G. López J. Carlos Menéndez Rafael León |
| author_facet | Patrycja Michalska Paloma Mayo Cristina Fernández-Mendívil Giammarco Tenti Pablo Duarte Izaskun Buendia María Teresa Ramos Manuela G. López J. Carlos Menéndez Rafael León |
| author_sort | Patrycja Michalska |
| collection | DOAJ |
| description | Alzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein. Hyperphosphorylation of tau protein is related to the over-activity of GSK-3β, a kinase that participates in several pathological mechanisms including neuroinflammation. Neuronal loss is also related to cytosolic Ca<sup>2+</sup> homeostasis dysregulation that triggers apoptosis and free radicals production, contributing to oxidative damage and, finally, neuronal death. Under these premises, we have obtained a new family of 4,7-dihydro-2<i>H</i>-pyrazolo[3–<i>b</i>]pyridines as multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3β and to block L-type voltage dependent calcium channels. Novel derivatives have also demonstrated an interesting neuroprotective profile on in vitro models of neurodegeneration. Finally, compound <b>4g</b> revokes cellular death induced by tau hyperphosphorylation in hippocampal slices by blocking reactive oxygen species (ROS) production. In conclusion, the multitarget profile exhibited by these compounds is a novel therapeutic strategy of potential interest in the search of novel treatments for Alzheimer’s disease. |
| first_indexed | 2024-03-10T18:16:49Z |
| format | Article |
| id | doaj.art-4b4837fca2e441d5af6c869f948b013e |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T18:16:49Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-4b4837fca2e441d5af6c869f948b013e2023-11-20T07:37:37ZengMDPI AGAntioxidants2076-39212020-07-019865010.3390/antiox9080650Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s DiseasePatrycja Michalska0Paloma Mayo1Cristina Fernández-Mendívil2Giammarco Tenti3Pablo Duarte4Izaskun Buendia5María Teresa Ramos6Manuela G. López7J. Carlos Menéndez8Rafael León9Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, SpainInstituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, SpainInstituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, SpainUnidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, SpainInstituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, SpainInstituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, SpainUnidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, SpainInstituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, SpainUnidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, SpainInstituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, SpainAlzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein. Hyperphosphorylation of tau protein is related to the over-activity of GSK-3β, a kinase that participates in several pathological mechanisms including neuroinflammation. Neuronal loss is also related to cytosolic Ca<sup>2+</sup> homeostasis dysregulation that triggers apoptosis and free radicals production, contributing to oxidative damage and, finally, neuronal death. Under these premises, we have obtained a new family of 4,7-dihydro-2<i>H</i>-pyrazolo[3–<i>b</i>]pyridines as multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3β and to block L-type voltage dependent calcium channels. Novel derivatives have also demonstrated an interesting neuroprotective profile on in vitro models of neurodegeneration. Finally, compound <b>4g</b> revokes cellular death induced by tau hyperphosphorylation in hippocampal slices by blocking reactive oxygen species (ROS) production. In conclusion, the multitarget profile exhibited by these compounds is a novel therapeutic strategy of potential interest in the search of novel treatments for Alzheimer’s disease.https://www.mdpi.com/2076-3921/9/8/650Alzheimer’s diseasemultitarget drugs4,7-dihydro-2<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridines GSK-3β inhibitorsvoltage gated calcium channels antagonistsanti-inflammatory drugsneuroprotection |
| spellingShingle | Patrycja Michalska Paloma Mayo Cristina Fernández-Mendívil Giammarco Tenti Pablo Duarte Izaskun Buendia María Teresa Ramos Manuela G. López J. Carlos Menéndez Rafael León Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease Antioxidants Alzheimer’s disease multitarget drugs 4,7-dihydro-2<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridines GSK-3β inhibitors voltage gated calcium channels antagonists anti-inflammatory drugs neuroprotection |
| title | Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease |
| title_full | Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease |
| title_fullStr | Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease |
| title_full_unstemmed | Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease |
| title_short | Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease |
| title_sort | antioxidant anti inflammatory and neuroprotective profiles of novel 1 4 dihydropyridine derivatives for the treatment of alzheimer s disease |
| topic | Alzheimer’s disease multitarget drugs 4,7-dihydro-2<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridines GSK-3β inhibitors voltage gated calcium channels antagonists anti-inflammatory drugs neuroprotection |
| url | https://www.mdpi.com/2076-3921/9/8/650 |
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