Lubeluzole protects hippocampal neurons from excitotoxicity in vitro and reduces brain damage caused by ischemia.
Previously reported effects of lubeluzole, such as inhibition of glutamate release, inhibition of nitric oxide (NO) synthesis and blockage of voltage-gated Na+- and Ca2+-ion channels, suggest a neuroprotective action of this drug. Here we report about the effects of lubeluzole and its R-isomer on glutamate-induced neuronal cell death in mixed hippocampal cultures. In addition, we studied the effect of lubeluzole in focal cerebral ischemia models in mice and rats. In hippocampal cultures exposed to 500 nM glutamate for 1 h, lubeluzole (0.1-100 nM), but not the R-isomer (1-100 nM), reduced the percentage of damaged neurons from 42 +/- 8% to 18 +/- 7% (P < 0.01). In mice and rats, lubeluzole reduced ischemic brain damage, when administered immediately after middle cerebral artery occlusion. Interestingly, the protective effect (reduction of the infarct volume in rats to 77% of control; P < 0.01) was also found when the lubeluzole treatment (2.5 mg/kg) was started 3 h after ischemia. Especially this latter effect suggests that lubeluzole will be a useful drug for stroke therapy.
Culmsee
C
C
Institut für Pharmakologie und Toxikologie, Fachbereich Pharmazie, Philipps-Universität Marburg, Germany. culmsee@mailer.uni-marburg.de
Junker
V
V
Wolz
P
P
Semkova
I
I
Krieglstein
J
J
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D018846:Excitatory Amino Acids / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013844:Thiazoles / Q000627:therapeutic use*
D018846:Excitatory Amino Acids; D018696:Neuroprotective Agents; D010880:Piperidines; D013844:Thiazoles; D018698:Glutamic Acid; C097722:lubeluzole