TY - JOUR AU - Büki, András AU - Siman, R AU - Trojanowski, JQ AU - Povlishock, JT TI - The role of calpain-mediated spectrin proteolysis in traumatically induced axonal injury. JF - JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY J2 - J NEUROPATH EXP NEUR VL - 58 PY - 1999 IS - 4 SP - 365 EP - 375 PG - 11 SN - 0022-3069 DO - 10.1097/00005072-199904000-00007 UR - https://m2.mtmt.hu/api/publication/1250912 ID - 1250912 N1 - Export Date: 27 January 2024; CODEN: JNENA AB - In animals and man, traumatic brain injury (TBI) results in axonal injury (AI) that contributes to morbidity and mortality. Such injured axons show progressive change leading to axonal disconnection. Although several theories implicate calcium in the pathogenesis of AI, experimental studies have failed to confirm its pivotal role. To explore the contribution of Ca2+-induced proteolysis to axonal injury, this study was undertaken in an animal model of TBI employing antibodies targeting both calpain-mediated spectrin proteolysis (CMSP) and focal neurofilament compaction (NFC), a marker of intra-axonal cytoskeletal perturbation, at 15-120 minutes (min) postinjury. Light microscopy (LM) revealed that TBI consistently evoked focal, intra-axonal CMSP that was spatially and temporally correlated with NFC. These changes were seen at 15 min postinjury with significantly increasing number of axons demonstrating CMSP immunoreactivity over time postinjury. Electron microscopy (EM) demonstrated that at 15 min postinjury CMSP was confined primarily to the subaxolemmal network. With increasing survival (30-120 min) CMSP filled the axoplasm proper. These findings provide the first direct evidence for focal CMSP in the pathogenesis of generalized/diffuse AI. Importantly, they also reveal an initial subaxolemmal involvement prior to induction of a more widespread axoplasmic change indicating a spatial-temporal compartmentalization of the calcium-induced proteolytic process that may be amenable to rapid therapeutic intervention. LA - English DB - MTMT ER - TY - JOUR AU - Okonkwo, DO AU - Büki, András AU - Siman, R AU - Povlishock, JT TI - Cyclosporin a limits calcium-induced axonal damage following traumatic brain injury. JF - NEUROREPORT J2 - NEUROREPORT VL - 10 PY - 1999 IS - 2 SP - 353 EP - 358 PG - 6 SN - 0959-4965 DO - 10.1097/00001756-199902050-00026 UR - https://m2.mtmt.hu/api/publication/1250932 ID - 1250932 N1 - Export Date: 27 January 2024; CODEN: NERPE AB - In traumatic axonal injury, Ca2+ influx across a focally damaged axolemma precipitates local mitochondrial failure, degradation of the subaxolemmal spectrin network and compaction of neurofilaments, which collectively contribute to axonal failure. In previous studies, cyclosporin A pretreatment preserved mitochondrial integrity and attenuated axonal failure following trauma. Here we investigate whether this CsA-linked protection was related to the concomitant blunting of intra-axonal, Ca2+-induced cytoskeletal changes in traumatic axonal injury, assessed with antibodies targeting spectrin proteolysis and neurofilament compaction. CsA pretreatment dramatically reduced Ca2+-induced cytoskeletal damage following injury; CsA-treated rats, compared with vehicle-treated rats, displayed a 70% decrease in immunoreactive/damaged profiles. We suggest that CsA-mediated preservation of mitochondrial integrity enables the restoration of ionic and metabolic homeostasis thereby short-circuiting Ca2+-induced proteolysis in injured axons. LA - English DB - MTMT ER - TY - JOUR AU - Gamberucci, A AU - Innocenti, B AU - Fulceri, R AU - Bánhegyi, Gábor AU - Giunti, R AU - Pozzan, T AU - Benedetti, A TI - Modulation of Ca2+ influx dependent on store depletion by intracellular adenine-guanine nucleotide levels JF - JOURNAL OF BIOLOGICAL CHEMISTRY J2 - J BIOL CHEM VL - 269 PY - 1994 IS - 38 SP - 23597 EP - 23602 PG - 6 SN - 0021-9258 UR - https://m2.mtmt.hu/api/publication/1446457 ID - 1446457 AB - The effects of a number of metabolic inhibitors on the influx of Ca2+ activated by stimulation of receptors coupled to inositol 1,4,5- trisphosphate generation or by depletion of intracellular Ca2+ stores with thapsigargin were investigated in four different cell types: Ehrlich ascites tumor cells, Jurkat and HeLa cell lines, and rat hepatocytes. Independently of their chemical structure and site of inhibition, all of these metabolic poisons markedly inhibited Ca2+ influx without significantly affecting Ca2+ release. This inhibition was not due to membrane potential depolarization or to alteration in cytosolic pH but appeared correlated to a drop in the cellular concentration of ATP. The decreases in cellular [ATP] were paralleled by decreases in [GTP] and by increases in [ADP] and [GDP]. The reduction in ATP level necessary to drastically reduce Ca2+ influx was quite small, e.g. a 50% inhibition for a 5% reduction in [ATP], thus within the range of fluctuation presumably occurring under physiological conditions. We suggest that changes in the adenine or guanine nucleotide concentrations may represent an important modulatory mechanism of Ca2+ influx activated by store depletion. LA - English DB - MTMT ER -