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ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia.
ACS Chem Neurosci. 2017 01 18; 8(1):67-81.AC

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+Show Affiliations

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.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.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.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.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.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.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.Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.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.Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27731633

Citation

Buendia, Izaskun, et al. "ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia." ACS Chemical Neuroscience, vol. 8, no. 1, 2017, pp. 67-81.
Buendia I, Tenti G, Michalska P, et al. ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia. ACS Chem Neurosci. 2017;8(1):67-81.
Buendia, I., Tenti, G., Michalska, P., Méndez-López, I., Luengo, E., Satriani, M., Padín-Nogueira, F., López, M. G., Ramos, M. T., García, A. G., Menéndez, J. C., & León, R. (2017). ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia. ACS Chemical Neuroscience, 8(1), 67-81. https://doi.org/10.1021/acschemneuro.6b00181
Buendia I, et al. ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia. ACS Chem Neurosci. 2017 01 18;8(1):67-81. PubMed PMID: 27731633.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ITH14001, a CGP37157-Nimodipine Hybrid Designed to Regulate Calcium Homeostasis and Oxidative Stress, Exerts Neuroprotection in Cerebral Ischemia. AU - Buendia,Izaskun, AU - Tenti,Giammarco, AU - Michalska,Patrycja, AU - Méndez-López,Iago, AU - Luengo,Enrique, AU - Satriani,Michele, AU - Padín-Nogueira,Fernando, AU - López,Manuela G, AU - Ramos,M Teresa, AU - García,Antonio G, AU - Menéndez,J Carlos, AU - León,Rafael, Y1 - 2016/11/22/ PY - 2016/10/13/pubmed PY - 2017/10/31/medline PY - 2016/10/13/entrez KW - Calcium dyshomeostasis KW - Nrf2 inducers KW - cerebral ischemia KW - mitochondrial NCX KW - multitarget drugs KW - voltage dependent calcium channels SP - 67 EP - 81 JF - ACS chemical neuroscience JO - ACS Chem Neurosci VL - 8 IS - 1 N2 - 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. SN - 1948-7193 UR - https://www.unboundmedicine.com/medline/citation/27731633/ITH14001_a_CGP37157_Nimodipine_Hybrid_Designed_to_Regulate_Calcium_Homeostasis_and_Oxidative_Stress_Exerts_Neuroprotection_in_Cerebral_Ischemia_ L2 - https://doi.org/10.1021/acschemneuro.6b00181 DB - PRIME DP - Unbound Medicine ER -