The chelating and antioxidant effects of pyrrolidine dithiocarbamate (PDTC) have been investigated extensively for preventing cell death induced by different insults. However, the toxic effects of PDTC have been studied only recently and fewer studies on the toxic effects on astrocytes have been reported. In our study, we demonstrated that both PDTC and Cu2+ alone were rated as only weakly toxic in inducing cell death in cortical astrocytes with IC50 of 300 μM and 180 μM, respectively. However, PDTC and Cu2+ in the complex form markedly potentiated with each other by about 1,000-fold with IC50 of 0.3 μM PDTC plus 10 μM Cu2+. Other metals at concentrations of 3-10 μM (VO45+, Cr6+, Mn2+, Fe2+, Co2, Ni2+, Zn2+, Pb2+, Bi2+, Ba2+, UO2+, Cs+, SeO42-, La3+) had no such potentiating effects on PDTC. Changes in morphology (nuclear condensation), apoptotic body formation, and hypodiploidity of DNA suggested that the PDTC-Cu2+ complex induced cell death through an apoptotic process. Further studies showed that the PDTC-Cu2+ complex decreased mitochondrial membrane potential, increased hydrogen peroxide production, and depleted GSH contents. After the increased oxidative stress, PDTC-Cu2+ complex differentially activated JNKs, ERK, p38 and caspase 3, which caused PARP degradation in a time-dependent manner. All these effects were consistent with the increased cellular Cu contents. The nonpermeable copper-specific chelator bathocuproine disulfonate (BCPS), but not the permeable Cu2+ chelator neocuproine, abolished all the observed effects. Antioxidants (N-acetylcysteine [NAC], vitamin C), catalase, and Cu2+-binding proteins (albumin, hemoglobin, and higher serum) reduced the cytotoxic effects of PDTC-Cu2+ complex. We concluded that the death signaling pathway of PDTC-Cu2+ complex was mediated by oxidative stress and subsequent JNK activation. These findings imply that PDTC, a widely used pesticide and medicine that is capable of penetrating the blood-brain barrier, may cause neurotoxicity through astrocyte dysfunction. (C) 2000 Wiley-Liss, Inc.
|Number of pages||13|
|Publication status||Published - 2000|
- MAP kinase
- Oxidative stress
ASJC Scopus subject areas