By Dean A. Haycock
Special To BioWorld Today
It wasn't easy getting lithium on the market.
The ion first earned a reputation for high toxicity after it was tried out as a salt substitute in patients with high blood pressure. In 1949, the first hints of its usefulness for treating mania appeared.
Mania is the "high" of manic-depressive psychosis marked by extreme elation, activity and pathological excitement. Lithium's early reputation for toxicity, however, kept clinical psychiatrists from considering its use.
Only after years of effort did the Scandinavian clinical researcher Morgan Schou succeed in convincing physicians that lithium could be used safely and effectively to treat mania. Still, drug companies were not eager to market it because it could not be patented.
Pfizer Inc., of New York, and Rowell Inc., a small company in Minnesota, were the first to take the trouble. Lithium eventually was accepted as one of the most effective agents in neuropharmacology and is today the most commonly used drug for stabilizing the extreme mood swings that characterize bipolar illness. Despite years of research, exactly how lithium works has remained a mystery.
Now a new study in the March 2, 1998, issue of the Proceedings of the National Academy of Sciences (PNAS) may help to explain part of the mystery. In the paper titled "Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx," De-Maw Chuang, chief of the section of molecular neurobiology in the biological psychiatry branch at the National Institutes of Health, in Bethesda, Md., and his colleagues revealed previously unsuspected effects of lithium on cultured brain cells. The researchers showed lithium protects three different types of rat neurons from the toxic effects of glutamate.
Glutamate is an excitatory neurotransmitter that is suspected of "over-stimulating" neurons and killing them when present in excess. It has been implicated as an important cause of neuronal death in stroke. Some scientists think glutamate also may be involved in Alzheimer's, Huntington's and Parkinson's diseases.
Chuang and his coworkers found that the most complete protection from the cytotoxic effect of glutamate in rat neurons follows a week of exposure to lithium. Treatment for one day offers no protection. This observation is potentially significant since it may relate to the well-known delay in lithium's therapeutic effects.
Calcium Is A Powerful Player
Lithium, like several other treatments for mood disorders, often takes days or weeks to "kick in" and improve symptoms.
"We don't really need to have continuous presence of lithium. We can treat the neurons for six or seven days and then take away the lithium by washing the cells. We then put in glutamate and can still observe the protective effect later," Chuang said.
This neuroprotective effect can last for up to 96 hours, according to Chuang. He and his collaborators thought of examining the effects of lithium on glutamate-induced toxicity after noting that psychotropic drugs such as tricyclic antidepressants could interfere with glutamate receptor function. Chuang said the results may be the first indication of glutamate's possible involvement in manic depression.
"The ability of lithium to block glutamate excitotoxicity has shed light on the possible therapeutic mechanisms of this drug," Chuang said, "It implies that the pathogenesis of this disease may involve abnormalities in the glutamate receptor function."
There are several types of glutamate receptors. The one implicated for a role in bipolar illness is the N-methyl-D-aspartate (NMDA) receptor, which regulates calcium entry into cells.
Calcium is a powerful intracellular player. It regulates release of neurotransmitters and the activity of many crucial enzymes. The new preclinical work described in PNAS suggests lithium may relieve manic-depressive symptoms by inhibiting or normalizing the glutamate receptor function in nerve cells.
"The finding that lithium down regulates the excitotoxicity of glutamate at NMDA receptors requires further investigation. Also the idea that NMDA receptors may be a target for this mechanism of mania, [and that it is] attenuated by lithium is at this time only an inference that requires further study," said Erminio Costa, scientific director of the Psychiatric Institute at the University of Illinois, in Chicago.
Enzyme Theory Discounted
In recent years, the most popular explanation of how lithium might work attributed its effectiveness to inhibition of a key enzyme, inositol monophosphatase, in cellular metabolism.
Experiments by Chuang and his coworkers suggested this enzyme inhibition is "unlikely to participate in lithium-induced neuroprotection."
Nevertheless, how lithium regulates calcium levels via glutamate receptors is not known. It could involve inhibition of other enzymes, which in turn affect the functioning of the NMDA receptor.
Because the effective doses and the timing of lithium's effects in the animal studies are similar to those observed in the clinic, the authors suggested "that modulation of glutamate receptor hyperactivity represents at least part of the molecular mechanisms by which lithium alters brain function and exerts its clinical efficacy in the treatment for manic-depressive illness."
The research team has another paper in press describing lithium's ability to protect against cell death induced by anticonvulsant drugs such as carbamazepine. This drug is also used to treat bipolar patients who are resistant to lithium treatment.
"Lithium can overcome carbamazepine's high-dose side effect. When you put them together, you probably can use a higher dose of carbamazepine clinically," Chuang said.
The researchers now are studying lithium's potential protective effects against brain damage related to glutamate toxicity in vivo. Preliminary results are encouraging, according to Chuang.
The connection between lithium and glutamate receptors raises the possibility that lithium might be useful in the treatment of other diseases.
"We think that lithium may be an effective and safe drug for the treatment of certain forms of neurodegenerative diseases that involve over-excitation of glutamate receptors," Chuang said. *