PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, elicits its function in primary neuronal cultures by up-regulating Bcl-2 expression.
Neurotoxicity in primary neurons was induced using hypoxia/hypoglycemia (H/H), veratridine (10microM), staurosporine (1microM) or glutamate (100microM), which resulted in 72%, 67%, 75% and 66% neuronal injury, respectively. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (PAN-811; 10microM; Panacea Pharmaceuticals, Gaithersburg, MD) pretreatment for 24 h provided maximal neuroprotection of 89%, 42%, 47% and 89% against these toxicities, respectively. Glutamate or H/H treatment of cells increased cytosolic cytochrome c levels, which was blocked by pretreatment of cells with PAN-811. Pretreatment of neurons with PAN-811 produced a time-dependent increase in the protein level of Bcl-2, which was evident even after glutamate or H/H treatments. An up-regulation in the expression of the p53 and Bax genes was also observed following exposure to these neurotoxic insults; however, this increase was not suppressed by PAN-811 pretreatment. Functional inhibition of Bcl-2 by HA14-1 reduced the neuroprotective efficacy of PAN-811. PAN-811 treatment also abolished glutamate or H/H-mediated internucleosomal DNA fragmentation.
Chen
R-W
RW
Department of Applied Neurobiology, Division of Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA. renwu.chen@na.amedd.army.mil
Yao
C
C
Lu
X C M
XC
Jiang
Z-G
ZG
Whipple
R
R
Liao
Z
Z
Ghanbari
H A
HA
Almassian
B
B
Tortella
F C
FC
Dave
J R
JR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D019254:Genes, bcl-2 / Q000235:genetics*; D007003:Hypoglycemia / Q000473:pathology; D000860:Hypoxia / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000037:antagonists & inhibitors / Q000633:toxicity; D013882:Thiosemicarbazones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D014701:Veratridine / Q000037:antagonists & inhibitors / Q000633:toxicity
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D014701:Veratridine; D045304:Cytochromes c; D019311:Staurosporine