title: Functionalized acridin-9-yl phenylamines protected neuronal HT22 cells from glutamate-induced cell death by reducing intracellular levels of free radical species.
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 Aryl(1)-NH-Aryl(2) 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800E Leigh Street, Richmond, VA 23298-0540, USA.
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore.
authors.forename: Tianming
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Republic of Singapore. Electronic address: phagoml@nus.edu.sg.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Go
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D000814:Aniline Compounds; D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D018698:Glutamic Acid
keywords: Acridin-9-yl phenylamines; Glutamate challenge; Mouse hippocampal cells HT22; Neuroprotection; Oxytosis; Radical quenching