title: PBT2 inhibits glutamate-induced excitotoxicity in neurons through metal-mediated preconditioning.
abstract: Excitotoxicity is the pathological process by which neuronal death occurs as a result of excessive stimulation of receptors at the excitatory synapse such as the NMDA receptor (NMDAR). Excitotoxicity has been implicated in the acute neurological damage from ischemia and traumatic brain injury and in the chronic neurodegeneration in Alzheimer's disease (AD) and Huntington's disease (HD). As a result NMDAR antagonists have become an attractive therapeutic strategy for the potential treatment of multiple neurodegenerative diseases. However NMDAR signaling is dichotomous in nature, with excessive increases in neuronal intracellular calcium through excessive NMDAR activity being lethal but moderate increases to intracellular calcium levels during normal synaptic function providing neuroprotection. Subsequently indiscriminant inhibition of this receptor is best avoided as was concluded from previous clinical trials of NMDAR antagonists. We show that the metal chaperone, PBT2, currently in clinical trials for HD, is able to protect against glutamate-induced excitotoxicity mediated through NMDARs. This was achieved by PBT2 inducing Zn(2+)-dependent increases in intracellular Ca(2+) levels resulting in preconditioning of neurons and inhibition of Ca(2+)-induced neurotoxic signaling cascade involving calpain-activated cleavage of calcineurin. Our study demonstrates that modulating intracellular Ca(2+) levels by a zinc ionophore is a valid therapeutic strategy to protect against the effects of excitotoxicity thought to underlie both acute and chronic neurodegenerative diseases.
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: jot@unimelb.edu.au.
authors.forename: Timothy
authors.initials: T
authors.lastname: Johanssen
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia; Centre for Neural Engineering and Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Nuttawat
authors.initials: N
authors.lastname: Suphantarida
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia; School of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Xiang M
authors.initials: XM
authors.lastname: Liu
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia; Centre for Neural Engineering and Department of Electrical and Electronic Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia; Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia; Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: kbarnham@unimelb.edu.au.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D007464:Clioquinol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D018698:Glutamic Acid / Q000633:toxicity*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008559:Memantine / Q000008:administration & dosage; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D013997:Time Factors
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008670:Metals; C531955:PBT2 compound; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D007464:Clioquinol; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D008559:Memantine
keywords: Alzheimer's disease (AD); Calcium flux; Excitotoxicity; Huntington's disease (HD); Zinc