[Show abstract][Hide abstract] ABSTRACT: We investigated the effects of an Na(+)/H(+) exchanger inhibitor, sabiporide, on excitotoxicity in cultured neuronal cells and in vivo. Sabiporide attenuated glutamate- or NMDA (N-methyl-d-aspartic acid)-induced neuronal cell death. Sabiporide also reduced glutamate or NMDA-induced increase in [Ca(2+)](i). In in vivo brain ischemia model, sabiporide produced protective effects, decreasing the infarct size and edema volume. Our results suggest that sabiporide elicits neuroprotective effect both in vitro and in vivo.
[Show abstract][Hide abstract] ABSTRACT: We investigated the role of individual protein kinase C (PKC) isoforms during kainate toxicity in cortical neurons. Treatment with 50 microM kainate induced isoform-specific activation of PKC-delta according to the translocation from the soluble to the particulate fraction, while it caused remarkable decreases in PKC alpha, beta, epsilon and zeta in both fractions. Kainate-induced neuronal death was significantly increased by pharmacological inhibition of PKC-delta with rottlerin, suggesting a protective role of PKC-delta against kainate toxicity. A PKC activator phorbol 12-myristate 13-acetate remarkably attenuated the kainate-induced neuronal death. Although phorbol 12-myristate 13-acetate activates PKC-epsilon and PKC-delta, the protective effect of phorbol 12-myristate 13-acetate was almost completely abolished by rottlerin, but not by epsilonV1-2. These results suggest that activation of PKC-delta attenuates the kainate-induced cell death of cortical neurons.
[Show abstract][Hide abstract] ABSTRACT: In this study, we investigated whether carbofuran, a commonly used carbamate pesticide, and N-nitrosocarbofuran (NOCF), the N-nitroso metabolite of carbofuran, have cytotoxicity in mouse brain microvascular endothelial cells (bEnd.3). Results from the MTT assay in bEnd.3 cells showed that NOCF but not carbofuran caused a remarkable decrease in cell viability. The cell death induced by NOCF appeared to involve apoptosis, based on our results from annexin V staining and electron microscopy. To investigate the mechanism of the NOCF-induced cell death, we examined the effects of selective inhibitors for MAP kinase pathways, PD98059 (for MEK/ERK), SB202190 (for p38 MAP kinase), and SP600125 (for JNK), on the NOCF-induced cell death. The NOCF-induced cell death was significantly reduced by PD98059, but not by SB202190 or SP600125. NOCF increased ERK phosphorylation as early as 15 min after the treatment and this increase was maintained for 2 h. In summary, our results suggest that NOCF can induce apoptotic cell death, at least in part, through the ERK pathway in brain microvascular endothelial cells.
No preview · Article · Jan 2004 · Journal of Pharmacological Sciences