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Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species |
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| Affiliation: | 1. Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800E Leigh Street, Richmond, VA 23298-0540, USA;2. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore;1. Departamento de Química Inorgánica, Universidade de Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, Galicia, Spain;2. Instituto de Investigación Biomédica – Universidade de Vigo, Departamento de Química Inorgánica, 36310, Vigo, Galicia, Spain;3. Departamento de Química Física y Centro Singular de Investigación en Química Biológica y Materiales Moleculares, Campus Vida, 15782, Santiago de Compostela, Galicia, Spain;1. Institute für Physik, Humboldt-Universität zu Berlin, Newtonstraße 15, D-12489 Berlin, Germany;2. Bogolyubov Institute for Theoretical Physics, National Academy of Sciences of Ukraine, Metrologichna str., 14-b, UA-03143 Kiev, Ukraine |
| Abstract: | The in vitro neuronal cell death model based on the HT22 mouse hippocampal cell model is a convenient means of identifying compounds that protect against oxidative glutamate toxicity which plays a role in the development of certain neurodegenerative diseases. Functionalized acridin-9-yl-phenylamines were found to protect HT22 cells from glutamate challenge at submicromolar concentrations. The Aryl1-NH-Aryl2 scaffold that is embedded in these compounds was the minimal pharmacophore for activity. Mechanistically, protection against the endogenous oxidative stress generated by glutamate did not involve up-regulation of glutathione levels but attenuation of the late stage increases in mitochondrial ROS and intracellular calcium levels. The NH residue in the pharmacophore played a crucial role in this regard as seen from the loss of neuroprotection when it was structurally modified or replaced. That the same NH was essential for radical scavenging in cell-free and cell-based systems pointed to an antioxidant basis for the neuroprotective activities of these compounds. |
| Keywords: | Acridin-9-yl phenylamines Neuroprotection Mouse hippocampal cells HT22 Glutamate challenge Oxytosis Radical quenching |
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