RT Journal Article
T1 Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease
A1 Michalska Dziama, Patrycja
A1 Mayo, Paloma
A1 Fernández-Mendívil, Cristina
A1 Tenti, Giammarco
A1 Duarte, Pablo
A1 Buendia, Izaskun
A1 Ramos García, María Teresa
A1 López, Manuela G.
A1 Menéndez Ramos, José Carlos
A1 León, Rafael
A1 León Martínez, Rafael
AB 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 Ca2+ 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-2H-pyrazolo[3–b]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 4g 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.
YR 2020
FD 2020-07-22
LK https://hdl.handle.net/20.500.14352/97150
UL https://hdl.handle.net/20.500.14352/97150
LA eng
NO Ministerio de Educación, Cultura y Deporte(España)
NO Universidad Autónoma de Madrid
NO Universidad Complutense de Madrid
DS Docta Complutense
RD 23 ago 2024