title: ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia.
abstract: 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.
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendia
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: Giammarco
authors.initials: G
authors.lastname: Tenti
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa , 28006 Madrid, Spain.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Michalska
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa , 28006 Madrid, Spain.
authors.forename: Iago
authors.initials: I
authors.lastname: Méndez-López
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa , 28006 Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Luengo
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.|Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: Michele
authors.initials: M
authors.lastname: Satriani
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa , 28006 Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Padín-Nogueira
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa , 28006 Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Ramos
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa , 28006 Madrid, Spain.
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Menéndez
authors.affiliation: Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid , 28029 Madrid, Spain.|Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa , 28006 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: León
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019439:Chromaffin Cells; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009553:Nimodipine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013841:Thiazepines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000605974:7-chloro-5-(2-isopropylphenyl)-3,5-dihydro-4,1-benzothiazepin-2-(1H)-one; D001570:Benzodiazepinones; C000624283:ITH14001; D018696:Neuroprotective Agents; D013841:Thiazepines; D009553:Nimodipine; D002118:Calcium
keywords: Calcium dyshomeostasis; Nrf2 inducers; cerebral ischemia; mitochondrial NCX; multitarget drugs; voltage dependent calcium channels