Lithium is an old drug that was first used for manic depressive or bipolar disorder more than 60 years ago. Over the last decade this drug has also been considered as treatment for several neurodegenerative diseases including Huntington's disease (HD); but the problem is its high risk of toxicity, particularly for long term use. But now with the recent publication about NP03, a novel (or new) low-dose lithium reformulation showing neuroprotective benefit in the YAC128 mouse model of HD, it is back in the running as a promising potential HD therapeutic.
NP03 is a new drug from Medesis Pharma that delivers lithium in a water and oil microemulsion that allows for much lower (15X lower) therapeutic dosing. Barring future problems, this drug may be on its way to study in people.
Lithium Studies in HD mouse models
The "old" lithium salt preparations have been studied in two HD mouse models including the YAC [Chiu CT 2011], where motor, cognitive and behavioral benefit was described, though lithium did not increase life span. In study with the "new" NP03 lithium, the benefit described was impressive [Pouladi MA 2012]. Study performed at 12 months (when the untreated YAC mouse is very symptomatic), motor coordination tests showed marked improvement in the NP03 YAC, almost as good as the normal mouse control. And importantly, two measures of the of striatum, the area of brain most damaged by HD, volume and neuron counts in the NP03-treated YAC mouse were essentially the same as in the normal mouse. This means that NP03 is highly neuroprotective -- at least in the YAC mouse. Though the exact mechanism of lithium action is not known, the authors went further to show that NP03 increased levels of several pro-life chemicals (like BDNF) and decreased pro-death chemicals. A complete recent article that details the studies of lithium in models of disease with comments on mechanism (s) of action is available on Pub Med [Chiu CT 2011].
NP03 lithium is absorbed through mucous membranes. When (and if) this drug gets to people, it would be placed in the mouth and held in the cheek till absorbed, not swallowed.
Medesis Pharma: the NP03 Drug Company
This company doesn't work on new drugs but instead on ways to improve delivery of drugs. Why is this important? Great drugs won't do any good if not delivered to the right place. They use "microemulsion" technology which places the drug inside tiny water nanodroplets and lipid mixtures. Clearly this mechanism of delivery allows for excellent penetration through cell membranes of the blood-brain barrier.
This company also is working similar ways to deliver larger biomolecules to the brain. Very useful for HD is the potential method of delivering oligonucleotides for gene silencing. At present the mode of delivery for ISIS oligonucleotides is through spinal cord. A preparation that could be absorbed from the mouth would be a lot better.
Even if NP03 turns out to be a very good drug for HD people, and if everything moved on schedule through the FDA process --we are still several years away from being able to use it -- which leads us to the next issue.
Should we take Lithium now?
At least for the present this author does not recommend lithium for HD individuals if taken for neuroprotection. I would recommend it only for the HD individual who has manic depressive symptoms AND who is compliant with frequent blood test monitoring. Otherwise the risks -- usually kidney, heart, thyroid problems -- are likely greater than the benefit. Further, lithium has brain side effects including apathy, lowering of cognition, fatigue, and others, which makes it very hard to know the difference between drug side effect or disease progression.
We need to remember that there are several available drugs and supplements that are helpful in various models of Huntington's disease at dose equivalents that can't be tolerated, or are prohibitively toxic to people. Lithium in its present formulation is one of these drugs. Author's opinion? Unless there are manic depressive symptoms, it is probably better to wait for a safer lithium to be tested in clinical trials.
Chiu CT, Liu G, Leeds P, Chuang DM. Combined treatment with the mood stabilizers lithium and valproate produces multiple beneficial effects in transgenic mouse models of Huntington's disease. Neuropsychopharmacology. 2011 Nov;36(12):2406-21. doi: 10.1038/npp.2011.128. Epub 2011 Jul 27. PubMed abstract
Pouladi MA, Brillaud E, Xie Y, Conforti P, Graham RK, Ehrnhoefer DE, Franciosi S, Zhang W, Poucheret P, Compte E, Maurel JC, Zuccato C, Cattaneo E, Néri C, Hayden MR. NP03, a novel low-dose lithium formulation, is neuroprotective in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2012 Dec;48(3):282-9. doi: 10.1016/j.nbd.2012.06.026. Epub 2012 Jul 10. PubMed abstract
Chiu CT, Chuang DM. Neuroprotective action of lithium in disorders of the central nervous system. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2011 Jun;36(6):461-76. doi: 10.3969/j.issn.1672-7347.2011.06.001. PubMed abstract