Heterocyclic thioureylenes protect from calcium-dependent neuronal cell death.
Calcium-dependent cell death occurs in neurodegenerative diseases and ischemic or traumatic brain injury. We analyzed whether thioureylenes can act in a neuroprotective manner by pharmacological suppression of calcium-dependent pathological pathways. In human neuroblastoma (SK-N-SH) cells, thioureylenes (thiopental, carbimazole) inhibited the calcium-dependent neuronal protein phosphatase (PP)-2B, the activation of the proapoptotic transcription factor nuclear factor of activated T-cells, BAD-induced initiation of caspase-3, and poly-(ADP-ribose)-polymerase cleavage. Caspase-3-independent cell death was attenuated by carbimazole and the protein kinase C (PKC) delta inhibitor rottlerin by a PP-2B-independent mechanism. Neuroprotective effects were mediated by the redox-active sulfur of thioureylenes. Furthermore, we observed that the route of calcium mobilization was differentially linked to caspase-dependent or independent cell death and that BAD dephosphorylation did not necessarily induce intrinsic caspase activation. In addition, a new 30- to 35-kDa caspase-3 fragment with an unknown function was identified. In organotypic hippocampal slice cultures, thioureylenes inhibited caspase-3 activation or reduced N-methyl-d-aspartate and kainic acid receptor-mediated cell death that was independent of caspase-3. Because prolonged inhibition of caspase-3 resulted in caspase-independent cellular damage, different types of cell death must be taken under therapeutic consideration. Here we show that thioureylenes in combination with PKCdelta inhibitors might represent a promising therapeutic approach to attenuate neuronal damage.
Humar
Matjaz
M
Department of Anesthesiology and Critical Care Medicine, Center for Clinical Research, University Hospital Freiburg, Freiburg, Germany. humar@ana1.ukl.uni-freiburg.de
Graetz
Christine
C
Roesslein
Martin
M
Goebel
Ulrich
U
Geiger
Klaus K
KK
Heimrich
Bernd
B
Pannen
Benedikt H J
BH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D013889:Thiouracil / Q000031:analogs & derivatives / Q000494:pharmacology*
D006571:Heterocyclic Compounds; D013889:Thiouracil; D002118:Calcium