title: A beacon of hope in stroke therapy-Blockade of pathologically activated cellular events in excitotoxic neuronal death as potential neuroprotective strategies.
abstract: Excitotoxicity, a pathological process caused by over-stimulation of ionotropic glutamate receptors, is a major cause of neuronal loss in acute and chronic neurological conditions such as ischaemic stroke, Alzheimer's and Huntington's diseases. Effective neuroprotective drugs to reduce excitotoxic neuronal loss in patients suffering from these neurological conditions are urgently needed. One avenue to achieve this goal is to clearly define the intracellular events mediating the neurotoxic signals originating from the over-stimulated glutamate receptors in neurons. In this review, we first focus on the key cellular events directing neuronal death but not involved in normal physiological processes in the neurotoxic signalling pathways. These events, referred to as pathologically activated events, are potential targets for the development of neuroprotectant therapeutics. Inhibitors blocking some of the known pathologically activated cellular events have been proven to be effective in reducing stroke-induced brain damage in animal models. Notable examples are inhibitors suppressing the ion channel activity of neurotoxic glutamate receptors and those disrupting interactions of specific cellular proteins occurring only in neurons undergoing excitotoxic cell death. Among them, Tat-NR2B9c and memantine are clinically effective in reducing brain damage caused by some acute and chronic neurological conditions. Our second focus is evaluation of the suitability of the other inhibitors for use as neuroprotective therapeutics. We also discuss the experimental approaches suitable for bridging our knowledge gap in our current understanding of the excitotoxic signalling mechanism in neurons and discovery of new pathologically activated cellular events as potential targets for neuroprotection.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Ashfaqul
authors.initials: A
authors.lastname: Hoque
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Hossain
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: S Sadia
authors.initials: SS
authors.lastname: Ameen
authors.affiliation: Bio21 Institute, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Ching-Seng
authors.initials: CS
authors.lastname: Ang
authors.affiliation: Bio21 Institute, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Williamson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia; School of Biomedical Science, University of Queensland, St. Lucia, QLD, Australia.
authors.forename: Dominic C H
authors.initials: DC
authors.lastname: Ng
authors.affiliation: ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia.
authors.forename: Anderly C
authors.initials: AC
authors.lastname: Chueh
authors.affiliation: Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, VIC 3065, Australia.
authors.forename: Carli
authors.initials: C
authors.lastname: Roulston
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: heung@unimelb.edu.au.
authors.forename: Heung-Chin
authors.initials: HC
authors.lastname: Cheng
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D006801:Humans; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy*
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; C542597:Tat-NR2B9c; D008559:Memantine
keywords: Calpain; Excitotoxicity; NMDAR; Neuron death; Stroke; nNOS