Pyrrolidine dithiocarbamate activates p38 MAPK and protects brain endothelial cells from apoptosis: a mechanism for the protective effect in stroke?
The antioxidant and inhibitor of nuclear factor kappaB pyrrolidine dithiocarbamate (PDTC) potently reduces infarct size in various experimental stroke models. In addition, it has been shown to have a favourable safety profile in humans. In this study, we further investigated the mechanistic actions of PDTC on cerebral microvascular endothelial cells as main components of the blood-brain barrier. We propose activation of p38 MAPK by PDTC as an additional protective mechanism. C57/BL6 mice were subjected to transient MCAO for 2 h and treated with PDTC (100 mg/kg) or vehicle i.p. before reperfusion. Infarct size was determined after 24 h. Apoptosis was induced in a cerebral microvascular endothelial cell line and the effect of pretreatment with PDTC and its dependency on p38 MAPK activity was assayed. PDTC administered 2 h after MCAO reduced infarct size by 61% (P < 0.05) and reduces the apoptotic death rate in vivo. In vitro, PDTC reduces the apoptotic death rate of bEnd.3 cells. p38 MAPK was activated by PDTC and its inhibition abrogated the protective effect of PDTC. PDTC reduces infarct size after stroke with a reasonable time window and decreases apoptotic cell death in vivo and in vitro. The attenuation of apoptotic cell death in brain microvascular endothelial cells is dependent on p38 MAPK activity.
Klinik für Neurologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. w.pfeilschifter@med.uni-frankfurt.de
Waltraud
W
Pfeilschifter
Bozena
B
Czech
Britta P
BP
Hoffmann
Marian
M
Sujak
Timo
T
Kahles
Helmuth
H
Steinmetz
Tobias
T
Neumann-Haefelin
Josef
J
Pfeilschifter
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000166:cytology*; D053148:Caspase 3 / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy*; D013859:Thiocarbamates / Q000494:pharmacology / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018696:Neuroprotective Agents; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3