RT Journal Article
T1 ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia
A1 Buendia, Izaskun
A1 Tenti, Giammarco
A1 Michalska Dziama, Patrycja
A1 Méndez-López, Iago
A1 Luengo, Enrique
A1 Satriani, Michele
A1 Padín-Nogueira, Fernando
A1 López, Manuela G.
A1 Ramos García, María Teresa
A1 García, Antonio G.
A1 Menéndez Ramos, José Carlos
A1 León Martínez, Rafael
AB During brain ischemia, oxygen and glucose deprivation induces calcium overload, extensive oxidative stress, neuroinflammation, and, finally, massive neuronal loss. In the search of a neuroprotective compound to mitigate this neuronal loss, we have designed and synthesized a new multitarget hybrid (ITH14001) directed at the reduction of calcium overload by acting on two regulators of calcium homeostasis; the mitochondrial Na+/Ca2+ exchanger (mNCX) and L-type voltage dependent calcium channels (VDCCs). This compound is a hybrid of CGP37157 (mNCX inhibitor) and nimodipine (L-type VDCCs blocker), and its pharmacological evaluation revealed a moderate ability to selectively inhibit both targets. These activities conferred concentration-dependent neuroprotection in two models of Ca2+ overload, such as toxicity induced by high K+ in the SH-SY5Y cell line (60% protection at 30 μM) and veratridine in hippocampal slices (26% protection at 10 μM). It also showed neuroprotective effect against oxidative stress, an activity related to its nitrogen radical scavenger effect and moderate induction of the Nrf2-ARE pathway. Its Nrf2 induction capability was confirmed by the increase of the expression of the antioxidant and anti-inflammatory enzyme heme-oxygenase I (3-fold increase). In addition, the multitarget profile of ITH14001 led to anti-inflammatory properties, shown by the reduction of nitrites production induced by lipopolysaccharide in glial cultures. Finally, it showed protective effect in two acute models of cerebral ischemia in hippocampal slices, excitotoxicity induced by glutamate (31% protection at 10 μM) and oxygen and glucose deprivation (76% protection at 10 μM), reducing oxidative stress and iNOS deleterious induction. In conclusion, our hybrid derivative showed improved neuroprotective properties when compared to its parent compounds CGP37157 and nimodipine.
YR 2016
FD 2016-10-12
LK https://hdl.handle.net/20.500.14352/97178
UL https://hdl.handle.net/20.500.14352/97178
LA eng
NO Instituto de Salud Carlos III
NO European Commission-ERC
NO Ministerio de Sanidad(España)
NO Miguel Servet
NO Bayer A. G.
NO Fundación FIPSE
NO Ministerio de Economía, Comercio y Empresa(España)
NO Ministerio de Economía, Cultura y Deporte(España)
NO Fundación Tatiana Pérez de Guzmán el Bueno
NO BioIberica
DS Docta Complutense
RD 23 ago 2024