Dynamic mechanical deformation of neurons triggers an acute calcium response and cell injury involving the N-methyl-D-aspartate glutamate receptor.
A biomechanical in vitro model of traumatic brain injury was used to examine cellular response to physical insults and the underlying mechanisms that lead to cell dysfunction. A cell shearing injury device was used to deform human NTera-2 neurons at high loading rates during the investigation of mechanisms of cytosolic free calcium increases, which may be detrimental to a cell. Cytosolic free calcium rose immediately to almost three times baseline and was associated with lactate dehydrogenase release at 24 hr, indicating significant cell injury. Low loading rates did not elicit these responses. A major portion of the calcium increase and subsequent cell injury was dependent on the presence of extracellular free calcium. Blocking the N-methyl-D-aspartate glutamate receptor complex with dizocilipine maleate attenuated calcium increases by 45% in injured neurons and blocked a significant part (50%) of the lactate dehydrogenase release. In addition, pretreatment with nifedipine or riluzole also significantly reduced cytosolic free calcium but did not affect cell injury, whereas tetrodotoxin had no affect on either outcome parameter. These results suggest that the increased membrane permeability and immediate calcium influx associated with this model of mechanical injury trigger several cellular pathways, including N-methyl-D-aspartate receptor-mediated cell damage.
LaPlaca
M C
MC
Department of Bioengineering, University of Pennsylvania, Philadelphia 19104, USA. laplacam@mail.med.upenn.edu
Thibault
L E
LE
D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D002460:Cell Line; D048429:Cell Size / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000201:enzymology / Q000473:pathology* / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013314:Stress, Mechanical
D015220:Calcium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D007770:L-Lactate Dehydrogenase; D002118:Calcium