PAN-811 provides neuroprotection against glutamate toxicity by suppressing activation of JNK and p38 MAPK.
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.
Chen
Ren-Wu
RW
Department of Applied Neurobiology, Division of Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910, United States.
Lu
X-C May
XC
Yao
Changping
C
Liao
Zhilin
Z
Jiang
Zhi-Gang
ZG
Wei
Hans
H
Ghanbari
Hossein A
HA
Tortella
Frank C
FC
Dave
Jitendra R
JR
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics; D018698:Glutamic Acid / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts; D013844:Thiazoles; D013882:Thiosemicarbazones / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000873:Anthracenes; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C432165:pyrazolanthrone; D018698:Glutamic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C022616:thiazolyl blue