In an earlier study, we demonstrated that
PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel
neuroprotectant, provides protection against
glutamate,
staurosporine,
veratridine, or
hypoxia/
hypoglycemia toxicities in primary cortical neuronal cultures by upregulating Bcl-2 expression [R.-W. Chen, C. Yao, X.C. Lu, Z.-G. Jiang, R. Whipple, Z. Liao, H.A. Ghanbari, B. Almassian, F.C. Tortella, J.R. Dave.
PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel
neuroprotectant, elicits its function in primary neuronal cultures by upregulating Bcl-2 expression. Neuroscience 135 (2005) 191-201]. Both JNK (
c-Jun N-terminal kinase) and p38 MAP (
mitogen-activated protein) kinase activation have a direct inhibitory action on Bcl-2 by phosphorylation. In the present study, we continued to explore the mechanism of
PAN-811 neuroprotection. Our results indicate that treatment of cultured cortical neurons with
glutamate (100 microM) induces phosphorylation of both JNK and
p38 MAPK. Specifically, pretreatment of neurons with 10 microM
PAN-811 (an optimal neuroprotective concentration) for 1h, 4h, or 24h significantly suppresses
glutamate-mediated activation of both JNK and
p38 MAPK. Furthermore, the
p38 MAPK-specific inhibitor
SB203580 and the JNK-specific inhibitor
SP600125 prevented
glutamate-induced neuronal death in these primary cultures. Our results demonstrate that
glutamate-induced phosphorylation of JNK and
p38 MAPK is suppressed by
PAN-811, which might contribute to Bcl-2 upregulation and
PAN-811 neuroprotection.