Role of HSP70 in motoneuron survival after excitotoxic stress in a rat spinal cord injury model in vitro.
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.
['Shabbir|Ayisha|A|', 'Bianchetti|Elena|E|', 'Cargonja|Renato|R|', 'Petrovic|Antonela|A|', 'Mladinic|Miranda|M|', 'Pilipović|Kristina|K|', 'Nistri|Andrea|A|']
D000818:Animals D000831:Animals, Newborn D051033:Apoptosis Inducing Factor D016227:Benzoquinones D016923:Cell Death D002470:Cell Survival D002491:Central Nervous System Agents D004195:Disease Models, Animal D005260:Female D018840:HSP70 Heat-Shock Proteins D007608:Kainic Acid D047029:Lactams, Macrocyclic D008124:Locomotion D008159:Lumbar Vertebrae D008297:Male D008839:Microelectrodes D009046:Motor Neurons D011684:Purine Nucleosides D017208:Rats, Wistar D013116:Spinal Cord D013119:Spinal Cord Injuries D013904:Thoracic Vertebrae
excitotoxicity apoptosis-inducing factor caspase-independent cell death heat shock proteins spinal networks