The outcome for gait recovery from paralysis due to spinal lesion remains uncertain even when damage is limited. One critical factor is the survival of motoneurons, which are very vulnerable cells. To clarify the early pathophysiological mechanisms of spinal damage, an in vitro injury model of the rat spinal cord caused by moderate excitotoxicity was used. With this preparation we investigated whether motoneuron survival was dependent on the expression of the neuroprotective protein HSP70. In the present study excitotoxicity evoked by kainate induced delayed (24 h) loss (35%) of motoneurons, which became pyknotic with translocation of the cell death biomarker apoptosis-inducing factor (AIF) to the nucleus. This process was concomitant with suppression of locomotor network electrical activity. Surviving cells showed strong expression of HSP70 without nuclear AIF. The HSP70 inhibitor VER155008 per se induced neurotoxicity similar to that of kainate, while the HSP90 inhibitor geldanamycin did not damage spinal tissue. Electrophysiological recording following kainate or VER155008 indicated depression of motoneuron field potentials, with decreased excitability and impaired synaptic transmission. When these two drugs were applied together, more intense neurotoxicity emerged. Our data indicate that HSP70 was one important contributor to motoneuron survival and suggest that enhancing HSP70 activity is a potential future strategy for neuroprotecting these cells. The intracellular activity of HSP70 determines whether a spinal motoneuron withstands an excitotoxic insult through prevention of the nuclear translocation of the deadly factor AIF to trigger cell death. A shows a control motoneuron equipped to bind and block the AIF nuclear translocation, whereas B shows that a pharmacological inhibitor of HSP70 prevents this protective action and leads to cell death. Exploiting the HSP70 activity may be a promising tool for neuroprotection against injury. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
|Titolo:||Role of HSP70 in motoneuron survival after excitotoxic stress in a rat spinal cord injury model in vitro|
|Autori:||Shabbir, A; Bianchetti, A; Cargonja, R; Petrovic, A; Mladinic, M; Pilipović, K; Nistri, A|
|Data di pubblicazione:||2015|
|Digital Object Identifier (DOI):||10.1111/ejn.13108|
|Appare nelle tipologie:||1.1 Journal article|
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