Lithium as a Neuroprotectant?

Lithium is an elemental chemical found naturally as an alkali metal. The ionic form can be used to form salts which are readily available for medicinal purposes. Although the exact mechanism of action for lithium is unknown, it is believed to function by simultaneously raising serotonin levels and lowering norepinephrine levels. Lithium is used primarily as a mood stabilizer, as it has the unique ability to treat both mania and depression. Unfortunately, the downside of lithium is that it has a very narrow therapeutic window, meaning the blood levels which provide benefits are very close to the blood levels which cause side effects and toxicity. Because of the need for such close monitoring of blood levels, the medication has largely fallen out of favor except for certain diseases like bipolar disorder.

One of the curious things about lithium is its effect on the brain. Patients who have bipolar disorder and are being treated with lithium often have imaging studies of their brain as part of their routine management. Radiologists noticed that patients on lithium develop hypertrophy of their brain, meaning that their brains are denser than average. Scientists began to wonder if somehow the lithium was causing new brain cells to grow, and thought there might be an application for diseases that cause cell death in the central nervous system.

One of the more severe examples of such a disease is amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s Disease. ALS produces a progressive degeneration of the nerve cells in the central nervous system that supply the muscles of the body, leading to progressive weakness, paralysis, and eventually death. The causes of ALS are largely unknown, and there is no known cure. The average span from time of diagnosis to death is 3 to 5 years, making it a devastating disease. The only current treatment option for ALS is a medication called riluzole, which functions as a neuroprotectant meaning it delays the degenerative process. Even this medication only adds a few months of time, and slightly prolongs the time to requiring a ventilator to breathe.

Because the prognosis for ALS is so poor, many trials are underway for substances that may serve as a better neuroprotective agent. Lithium is one of the chemicals that holds a fair amount of promise. In February 2008, scientists from Italy published a study in the Proceedings of the National Academy of Sciences where they took 44 patients with ALS and divided them into two groups: one receiving riluzole, and the other receiving riluzole plus lithium. The two groups were case matched, meaning the researchers tried to make them as equal as possible in terms of severity of disease. The groups were tested for their functional level at the beginning of the trial, and then followed up 15 months later to repeat their testing. Of the patients who received riluzole, about a third of them had died, and the remainder had significant functional decline during the interim. By contrast, of the patients receiving riluzole and lithium, not a single patient had died, and the entire group had only a mild decrease in their functional level.

The results of this study were astonishing, and scientists are now hopeful that lithium may play a role in many neurodegenerative diseases. Clinical trials are already underway for the use of lithium in diseases like Parkinson’s disease, Huntington’s disease, spinal cord injury, and even Alzheimer’s dementia. If the results of the 2008 study can be reproduced and translated into additional disease states, this old medication may be able to provide millions of patients with neurodegenerative disorders with a new lease on life.

References

F. Fornai, P. Longone, L. Cafaro, O. Kastsiuchenka, M. Ferrucci, M. L. Manca, G. Lazzeri, A. Spalloni, N. Bellio, P. Lenzi, N. Modugno, G. Siciliano, C. Isidoro, L. Murri, S. Ruggieri, A. Paparelli (2008). Lithium delays progression of amyotrophic lateral sclerosis Proceedings of the National Academy of Sciences, 105 (6), 2052-2057 DOI: 10.1073/pnas.0708022105