Lithium protects rat cerebellar granule cells against apoptosis induced by anticonvulsants, phenytoin and carbamazepine.
We have studied the neuroprotective actions of lithium against various insults in cultured cerebellar granule cells of rats. The anticonvulsants, phenytoin and carbamazepine, have been shown to induce apoptosis of cerebellar granule cells at high concentrations. Here we found that co-presence of LiCl (1-10 mM) dose-dependently protected against phenytoin (20 microM)- and carbamazepine (100 microM)-induced neuronal apoptosis as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide metabolism, morphological inspection, chromatin condensation and DNA fragmentation. These neuroprotective effects were not prevented by inclusion of myoinositol nor mimicked by a potent inositol monophosphatase inhibitor, suggestive of a mechanism independent of inositol monophosphatase blockade. Lithium also significantly protected against apoptosis of cerebellar granule cells induced by aging of the cultures. Additionally, lithium suppressed death of cerebellar granule cells exposed to a low concentration of extracellular potassium. In contrast, it had no protective effect on cell death induced by Ca++ ionophores, a Na+ channel opener, a protein kinase inhibitor, a nitric oxide donor or H2O2. Thus, lithium has robust neuroprotective effects against apoptotic cell death induced by multiple insults with limited selectivity. These actions provide a new avenue to study the molecular and cellular mechanisms of this drug.
Nonaka
S
S
Section on Molecular Neurobiology, National Institutes of Health, Bethesda, Maryland, USA.
Katsube
N
N
Chuang
D M
DM
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002220:Carbamazepine / Q000633:toxicity*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects*; D007294:Inositol / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010672:Phenytoin / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D002220:Carbamazepine; D007294:Inositol; D010672:Phenytoin; D008094:Lithium; D019869:Phosphatidylinositol 3-Kinases; D015720:5'-Nucleotidase; D011188:Potassium