Lithium

www.perpetualcommotion.com
"Give with a free hand, but give only your own."
-- J.R.R. Tolkien The Children of Hurin
- Lithium -

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Observations:

Lithium at 50: have the neuroprotective effects of this unique cation
been overlooked?
Biological Psychiatry. 1999 Oct 1;46(7):929-40. PMID: 10509176 [PubMed]

Manji HK, Moore GJ, Chen G.

Department of Psychiatry and Behavioral Neurosciences,
Wayne State University School of Medicine, Detroit, Michigan 48201, USA.

"Recent advances in cellular and molecular biology have resulted in the identification of two novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithium treatment has been demonstrated to markedly increase the levels of the major neuroprotective protein, bcl-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bcl-2 are also observed in cells of human neuronal origin, and are observed in rat frontal cortex at lithium levels as low as approximately 0.3 mmol/L. Bcl-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bcl-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase kinase 3 beta (GSK-3 beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the neurodegeneration observed in Alzheimer's disease). Consistent with the increases in bcl-2 levels and inhibition of GSK-3 beta, lithium has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long term beneficial effects in the treatment of mood disorders via underappreciated neuroprotective effects. To date, lithium remains the only medication demonstrated to markedly increase bcl-2 levels in several brain areas; in the absence of other adequate treatments, the potential efficacy of lithium in the long term treatment of certain neurodegenerative disorders may be warranted."

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo
Proceedings of the National Academy of Sciences of the United States
of America
PNAS | May 10, 2005 | vol. 102 | no. 19 | 6990-6995

"Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically."
http://www.pnas.org/cgi/content/abstract/102/19/6990?ck=nck

Lithium delays progression of amyotrophic lateral sclerosis.

"ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human
patients affected by ALS."
http://www.pnas.org/cgi/reprint/105/6/2052

"Hercule Poirot, Agatha Christie's famous fictional detective, had an amusing quirk in his incessant concern for his "little grey cells." I thought of Hercule several years ago when I saw the following headline in an issue of the Lancet: "Lithium-induced increase in human brain grey matter."

"That may not sound like an earth-shattering piece of news, but it actually was quite a major discovery. To that point, medical experts believed that once our brains matured, it was all downhill from then on. Decades of autopsies, x-rays, and, more recently, brain scans have repeatedly shown that brains shrink measurably with aging. But according to their report in the Lancet, Wayne State University (Detroit) researchers found that lithium has the ability to both protect and renew brain cells.1 Eight of 10 individuals who took lithium showed an average 3 percent increase in brain grey matter in just four weeks.

"Lithium may help to generate entirely new cells too: Another group of researchers recently reported that lithium also enhances nerve cell DNA replication.2 DNA replication is a first step in the formation of a new cell of any type.

"The Wayne State study used high-dose lithium, but I'm certainly not using that amount myself, nor do I recommend it. Prescription quantities of lithium just aren't necessary for "everyday" brain cell protection and re-growth. Studies done years ago have shown that very low amounts of lithium can also measurably influence brain function for the better."

Lithium fights crime and some of your most nagging health concerns

"Turns out it's not only the strict use of the death penalty lowering crime rates in some areas of Texas. And while I'm sure "Dubya" would be quick to take credit, it's not stricter laws or changes in sentencing guidelines either. Using 10 years of data accumulated from 27 Texas counties, researchers found that the incidence of homicide, rape, burglary, and suicide, as well as other crimes and drug use, were significantly lower in counties whose drinking water supplies contained 70-170 micrograms of lithium per liter than those with little or no lithium in their water.

"The researchers wrote: "These results suggest that lithium at low dosage levels has a generally beneficial effect on human behavior...increasing the human lithium intakes by supplementation, or the lithiation [adding lithium] of drinking water is suggested as a possible means of crime, suicide, and drug-dependency reduction at the individual and community level."

"And that's not to mention all of the lithium health benefits we went over in Part 1: It may be useful in treating Alzheimer's disease, senile dementia, and possibly Parkinson's disease. Lithium not only protects brain cells against normal wear and tear, but also offers additional protection against a whole variety of toxic molecules, including patent medications. It can also promote brain cell regeneration and increase brain cell mass. In essence, the research suggests that lithium is a brain anti-aging nutrient.

"All of these results are every bit as good as (if not better than) the data that led to dumping toxic waste (fluoride) into so many public water supplies. So why haven't public health and safety "authorities" been pushing for further intensive research on water-borne lithium and criminal behavior?"
http://www.tahoma-clinic.com/lithium2.shtml

Rescuing Fruit Flies from Alzheimer's Disease

ScienceDaily (July 16, 2010) — Investigators have found that fruit fly (Drosophila melanogaster) males -- in which the activity of an Alzheimer's disease protein is reduced by 50 percent -- show impairments in learning and memory as they age. What's more, the researchers were able to prevent the age-related deficits by treating the flies with drugs such as lithium, or by genetic manipulations that reduced nerve-cell signaling. The research team -- Thomas A. Jongens, Ph.D., associate professor of Genetics at the University of Pennsylvania School of Medicine; Sean M. J. McBride M.D, Ph.D. and Thomas McDonald M.D., at the Albert Einstein College of Medicine; and Catherine Choi M.D., Ph.D. at Drexel University College of Medicine -- worked with the familial form of Alzheimer's disease (FAD), an aggressive form of the disease that is caused by mutations in one of the two copies of the presenilin (PS) or amyloid precursor protein (APP) genes. Studies in animal models have previously shown that the FAD-linked PS mutations lead to less presenilin (psn) protein activity. Their findings are published in the Journal of Neuroscience. "The results from our study suggest a new route to explore for the treatment of familial Alzheimer's disease and possibly the more common sporadic forms of Alzheimer's disease," notes Jongens. "They also reveal that proper presenilin activity levels are required to maintain normal cognitive capabilities during aging."...
http://www.sciencedaily.com/releases/2010/07/100715172014.htm

Fountain of Youth from the Tap? Environmental Lithium Uptake Promotes Longevity, Scientists Demonstrate in Worms

ScienceDaily (Feb. 18, 2011) — A regular uptake of the trace element lithium can considerably promote longevity. This is the result of a new study by scientists of Friedrich Schiller University Jena...
http://www.sciencedaily.com/releases/2011/02/110218111709.htm

Lithium Profoundly Prevents Brain Damage Associated With Parkinson's Disease, Mouse Study Suggests

ScienceDaily (June 24, 2011) — Lithium profoundly prevents the aggregation of toxic proteins and cell loss associated with Parkinson's disease (PD) in a mouse model of the condition. Preclinical research is now underway at the Buck Institute for Research on Aging to determine correct dosages for a drug that continues to be the gold standard for the treatment of bipolar disorder. The Buck is currently working toward initiating a Phase IIa clinical studies of lithium in humans in conjunction with standard PD drug therapy...
http://www.sciencedaily.com/releases/2011/06/110624080329.htm

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References:

Lithium
Here is another take on the use of lithium:

I suggest reading the whole article, but here is an excerpt...

Taking (grey) matters into your own hands

"Hercule Poirot, Agatha Christie's famous fictional detective, had an amusing quirk in his incessant concern for his "little grey cells." I thought of Hercule several years ago when I saw the following headline in an issue of the Lancet: "Lithium-induced increase in human brain grey matter."

"That may not sound like an earth-shattering piece of news, but it actually was quite a major discovery. To that point, medical experts believed that once our brains matured, it was all downhill from then on. Decades of autopsies, x-rays, and, more recently, brain scans have repeatedly shown that brains shrink measurably with aging. But according to their report in the Lancet, Wayne State University (Detroit) researchers found that lithium has the ability to both protect and renew brain cells.1 Eight of 10 individuals who took lithium showed an average 3 percent increase in brain grey matter in just four weeks.

"Lithium may help to generate entirely new cells too: Another group of researchers recently reported that lithium also enhances nerve cell DNA replication.2 DNA replication is a first step in the formation of a new cell of any type.

"The Wayne State study used high-dose lithium, but I'm certainly not using that amount myself, nor do I recommend it. Prescription quantities of lithium just aren't necessary for "everyday" brain cell protection and re-growth. Studies done years ago have shown that very low amounts of lithium can also measurably influence brain function for the better."
http://www.tahoma-clinic.com/lithium1.shtml

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo
Proceedings of the National Academy of Sciences of the United States
of America
PNAS | May 10, 2005 | vol. 102 | no. 19 | 6990-6995

"Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are
involved in tauopathy progression and that kinase inhibitors may be effective therapeutically."
http://www.pnas.org/cgi/content/abstract/102/19/6990?ck=nck

Lithium delays progression of amyotrophic lateral sclerosis.
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2052-7. Epub 2008 Feb 4

"ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS."
http://www.pnas.org/cgi/reprint/105/6/2052

Lithium at 50: have the neuroprotective effects of this unique cation been overlooked?
Biological Psychiatry. 1999 Oct 1;46(7):929-40. PMID: 10509176 [PubMed]

Manji HK, Moore GJ, Chen G.

Department of Psychiatry and Behavioral Neurosciences,
Wayne State University School of Medicine, Detroit, Michigan 48201, USA.

"Recent advances in cellular and molecular biology have resulted in the identification of two novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithium treatment has been demonstrated to markedly increase the levels of the major neuroprotective protein, bcl-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bcl-2 are also observed in cells of human neuronal origin, and are observed in rat frontal cortex at lithium levels as low as approximately 0.3 mmol/L. Bcl-2 is widely regarded as a major neuroprotective protein, and genetic strategies that increase bcl-2 levels have demonstrated not only robust protection of neurons against diverse insults, but have also demonstrated an increase the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase kinase 3 beta (GSK-3 beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the neurodegeneration observed in Alzheimer's disease). Consistent with the increases in bcl-2 levels and inhibition of GSK-3 beta, lithium has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long term beneficial effects in the treatment of mood disorders via underappreciated neuroprotective effects. To date, lithium remains the only medication demonstrated to markedly increase bcl-2 levels in several brain areas; in the absence of other adequate treatments, the potential efficacy of lithium in the long term treatment of certain neurodegenerative disorders may be warranted."

Rescuing Fruit Flies from Alzheimer's Disease

ScienceDaily (July 16, 2010)

Investigators have found that fruit fly (Drosophila melanogaster) males -- in which the activity of an Alzheimer's disease protein is reduced by 50 percent -- show impairments in learning and memory as they age. What's more, the researchers were able to prevent the age-related deficits by treating the flies with drugs such as lithium, or by genetic manipulations that reduced nerve-cell signaling. The research team -- Thomas A. Jongens, Ph.D., associate professor of Genetics at the University of Pennsylvania School of Medicine; Sean M. J. McBride M.D, Ph.D. and Thomas McDonald M.D., at the Albert Einstein College of Medicine; and Catherine Choi M.D., Ph.D. at Drexel University College of Medicine -- worked with the familial form of Alzheimer's disease (FAD), an aggressive form of the disease that is caused by mutations in one of the two copies of the presenilin (PS) or amyloid precursor protein (APP) genes. Studies in animal models have previously shown that the FAD-linked PS mutations lead to less presenilin (psn) protein activity. Their findings are published in the Journal of Neuroscience...
http://www.sciencedaily.com/releases/2010/07/100715172014.htm

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