Lowenstein DH, Chan PH, Miles MFThe stress protein response in cultured neurons: Characterization and evidence for a protective role in excitotoxicity. Neuron 7:1053-1060
Department of Neurology, University of California, San Francisco 94143. Neuron
(Impact Factor: 15.05).
01/1992; 7(6):1053-60. DOI: 10.1016/0896-6273(91)90349-5
We used purified cultures of cerebellar granule cells to investigate the possible protective role of stress proteins in an in vitro model of excitotoxicity. Initial experiments used one- and two-dimensional polyacrylamide gel electrophoresis to confirm the induction of typical stress protein size classes by heat shock, sodium arsenite, and the calcium ionophore A23187. Immunoblot analysis and immunocytochemistry verified the expression of the highly inducible 72 kd heat shock protein (HSP72). Granule cell cultures exposed to glutamate showed evidence of cellular injury that was prevented by the noncompetitive NMDA antagonist MK-801, yet glutamate did not induce a detectable stress protein response. Nonetheless, preinduction of heat shock proteins was associated with protection from toxic concentrations of glutamate. These results imply that the HSP72 expression observed in in vivo models of excitotoxicity may not be directly related to the effects of excitatory amino acids. However, the ability of stress protein induction to protect against injury from glutamate may offer a novel approach toward ameliorating damage from excitotoxins.
Available from: Aristidis Kritis
- "In rat brain, GRP75 was up regulated in situ during focal ischemic episode (Massa et al. 1995). Global ischemia as well as traumatic brain injury has also been shown to up regulate other members of the GRP family such as GRP94 and GRP78 (Lowenstein et al. 1991). GRP94 has been implicated in neuronal protection from ischemia/reperfusion damage (Bando et al. 2003), and GRP78 has been found to be induced during ischemic preconditioning (Hayashi et al. 2003). "
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ABSTRACT: Hypoxia is the lack of sufficient oxygenation of tissue, imposing severe stress upon cells. It is a major feature of many pathological conditions such as stroke, traumatic brain injury, cerebral hemorrhage, perinatal asphyxia and can lead to cell death due to energy depletion and increased free radical generation. The present study investigates the effect of hypoxia on the unfolded protein response of the cell (UPR), utilizing a 16-h oxygen-glucose deprivation protocol (OGD) in a PC12 cell line model. Expression of glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94), key players of the UPR, was studied along with the expression of glucose-regulated protein 75 (GRP75), heat shock cognate 70 (HSC70), and glyceraldehyde 3-phosphate dehydrogenase, all with respect to the cell death mechanism(s). Cells subjected to OGD displayed upregulation of GRP78 and GRP94 and concurrent downregulation of GRP75. These findings were accompanied with minimal apoptotic cell death and induction of autophagy. The above observation warrants further investigation to elucidate whether autophagy acts as a pro-survival mechanism that upon severe and prolonged hypoxia acts as a concerted cell response leading to cell death. In our OGD model, hypoxia modulates UPR and induces autophagy.
Available from: Junji Yodoi
- "Tissue concentrations of nonspecific free radical scavengers (e.g. total glutathione (GSH), ascorbic acid, c~-tocopherol, and ubiquinone) decrease significantly during partial ischemia or reperfusion after total ischemia . In contrast, stress proteins involved in responses to oxidative stress and cellular defense mechanisms have been shown to be induced by cerebral ischemia and play an important role in neuroprotection   . In a previous experiment, we demonstrated that A D F / T R X was induced in glial cells of the gerbil brain during reperfusion after transient global ischemia . "
Available from: Boris Sabirzhanov
- "Although various in vitro studies have analyzed HSP70 neuronal functions, the interpretation and generality of the results has often been obscured by the multitude of the neuronal cell types and injury conditions employed. In both primary neuronal cell cultures and neuronal cell lines, prior exposure to mild heat or ischemic stress results in protection against later exposure to either toxic conditions (heat, ischemia, or excitotoxins) (Amin et al. 1995; Lowenstein et al. 1991; Rordorf et al. 1991) or apoptotic stimuli (trophic factor withdrawal) (Mailhos et al. 1993, 1994; Wagstaff et al. 1999). The neuroprotective effects appear to be correlated with elevated expression of HSPs, including HSP70, but studies designed to directly link single HSPs over-expression to neuroprotection have provided conflicting "
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ABSTRACT: HSP70 is a member of the family of heat-shock proteins that are known to be up-regulated in neurons following injury and/or stress. HSP70 over-expression has been linked to neuroprotection in multiple models, including neurodegenerative disorders. In contrast, less is known about the neuroprotective effects of HSP70 in neuronal apoptosis and with regard to modulation of programmed cell death (PCD) mechanisms in neurons. We examined the effects of HSP70 over-expression by transfection with HSP70-expression plasmids in primary cortical neurons and the SH-SY5Y neuronal cell line using four independent models of apoptosis: etoposide, staurosporine, C2-ceramide, and β-Amyloid. In these apoptotic models, neurons transfected with the HSP70 construct showed significantly reduced induction of nuclear apoptotic markers and/or cell death. Furthermore, we demonstrated that HSP70 binds and potentially inactivates Apoptotic protease-activating factor 1, as well as apoptosis-inducing factor, key molecules involved in development of caspase-dependent and caspase-independent PCD, respectively. Markers of caspase-dependent PCD, including active caspase-3, caspase-9, and cleaved PARP were attenuated in neurons over-expressing HSP70. These data indicate that HSP70 protects against neuronal apoptosis and suggest that these effects reflect, at least in part, to inhibition of both caspase-dependent and caspase-independent PCD pathways.
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