In vitro studies of multiple impact injury to mammalian CNS neurons: prevention of perikaryal damage and death by ketamine.
We have developed an in vitro model of rapid acceleration injury (RAI) to study the effects of multiple impact (220 g/impact, 3-5 s intervals) trauma on cultures of mammalian CNS cells. Our initial investigations have shown that: (1) multiple impacts delivered tangential to the plane of growth caused neuronal death while normal impacts did not; (2) glia were not affected by tangential or normal RAI; (3) most neuronal death occurred within 15 min; (4) the threshold for neuronal death was above 440 g (cumulative); (5) neuronal death reached a maximum of 50% at cumulative accelerations greater than or equal to 1100 g; (6) somal swelling and increased nuclear prominence were often observed after tangential RAI, and the frequency of these changes increased with the cumulative acceleration; and (7) ketamine prevented neuronal death and morphological changes during tangential RAI. We hypothesize that neuronal sensitivity to multiple impact RAI depends on the density of N-methyl-D-aspartate (NMDA) complexes in the dendrosomatic membranes. We also hypothesize that the events leading to neuronal death during multiple impact injury are: (1) calcium leakage through NMDA channels causes weakening of the cytoskeleton; (2) loss of cytoskeletal integrity allows nuclear shifting during impact; and (3) nuclear pressure disrupts the plasmalemma causing a lethal influx of calcium.
Lucas
J H
JH
Center for Network Neuroscience, Department of Biological Sciences, University of North Texas, Denton 76203.
Wolf
A
A
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000293:injuries* / Q000473:pathology; D005260:Female; D007649:Ketamine / Q000494:pharmacology*; D051379:Mice; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology; D013194:Staining and Labeling
D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D002118:Calcium