Excitotoxic cell death of ES derived neural lineage cells

Washington University, Saint Louis MO

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Linked publications & trials

Abstract

DESCRIPTION: (From abstract) Therapeutic approaches to traumatic spinal cord injury are currently limited. Experiments proposed in the present section, Project I, are part of a new Program Project application. This Program Project has the overall long-term goal of exploring the therapeutic potential of transplanting embryonic stem (ES) cell-derived neural lineage cells (ESNLCs) into the traumatically-injured spinal cord. The specific goal of Project I is to determine the vulnerability of ES cells to excitotoxic and oxidative insults in vitro, and to identify genetic and pharmacological approaches to blocking this vulnerability that can be used to maximize ES cell survival after transplantation. The first part of Project I will test ESNLCs with whole-cell patch clamp recordings and fura-2 dye microfluorimetry to verify that many neuronal cells express functional NMDA, AMPA/kainate, gamma-amino-butyric acid (GABA) and glycine receptors, and to determine the prevalence of Group I mGluRs. Subsequently, the main portion of the Project will test the hypothesis that ES neurons and oligodendrocytes develop vulnerability to excitotoxicity in vitro (induced either by addition of exogenous excitotoxins, or exposure to oxygen-glucose deprivation), and that this vulnerability can be attenuated using NMDA or AMPA/kainate receptor blockade, anti-oxidant, or Group I mGluR blockade approaches. It will also test the hypothesis that exposure to NT-3 will enhance ES neuronal cell vulnerability to excitotoxicity. If this is the case, effort will be directed to determining whether this neurotrophin-mediated injury enhancement is mediated by trks, and can be attenuated by anti-oxidant approaches. The results of these in vitro experiments will be exploited in the design of the in vivo experiments carried out in Projects III and IV, where rodents subjected to spinal cord contusion injury will receive ESNLC transplants.