Lithium:
The First Molecular Drug
Wise Young PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Piscataway, NJ
wisey@pipeline.com
Lithium: The First Molecular Drug
Overview
Bipolar disease
Bone marrow
Mechanisms
GSK3-beta
Messengers
Hematopoiesis
Granulocytosis
Lymphopenia
Immune function
Immune modulator
Leukemia
Depression
Alzheimer’s
Dementia
Taupathies
Amyloidosis
Neuroprotection
Parkinson’s
Huntington’s
Alcohol
Prion disease
ALS
BNDF
NGF
NT-3
GDNF
Antagonistic effects
Polymorphisms
Neurogenesis
LTP
Proliferation
Gabaergic effects
Neural Progenitors
Wnt/Notch
NAA levels
Gray matter
Apoptosis
Epilepsy
Dosing
Toxicity
Mutagenicity
Teratogenicity
Carcinogenicity
Organ damage
Sensitivity
Toxicity
Efficacy
Adverse interactions
Other bipolar Rx
Conclusion (I, II, III)
Young W (2009). Review of Lithium Effects on Brain and Blood. Cell Transplantation 18: 1-100.
Lithium & Bipolar Disease
Lithium has been used for over 100 years to treat
manic depression.
A Cochrane review (Burgess, et al. 2001) concluded
lithium has heterogenous but significant beneficial
effects on bipolar disorders,
a non-significant trend of benefit in unipolar disorder,
and no significant negative effects
The FDA approved lithium in 1971.
It is the first line therapy for bipolar disease.
3% of U.S. have bipolar disease and half take lithium.
Lithium & Bone Marrow
Lithium is the third element of the periodic table, in
the same family as sodium and potassium. Why it
has any effects on manic depression was not known.
Two observations suggested that lithium affects not
only brain but also bone marrow:
People who take lithium often have increased white
cell counts (granulocytosis) and reduced lymphocyte
count (lymphocytopenia).
Veterinarians observed that lithium restored white
blood cell counts and immune functions faster in
dogs that have had chemotherapy and radiation.
Lithium Mechanisms
Glycogen Synthetase Kinase
Lithium stimulates and inhibits phosphokinases and
phosphatases that converge to inhibit glycogen
synthetase kinase 3-beta (GSK3b)
GSK3b activates glycogen synthetase, the enzyme
that converts glucose to glycogen storage
GSK also phosphorylates (inhibits) nuclear factors:
WNT/beta catenin - differentiates neurons
Lef/TCF (T-cell factor)- stimulates T-cell proliferation
Nuclear factor of T-cells (NFAT) - activates T-cells and
stimulates neurons to produce neurotrophins
Lithium Messengers
Lithium inhibits:
Phosphoinositol (PI) kinase, thereby reducing PI level
G protein by blocking association and dissociation.
Guanylate cyclase, preventing cGMP accumulation.
Adenyl cyclase, doubling basal cAMP levels.
GSK3-beta, preventing phosphorylation of nuclear
factors AP-1, CREB, HSF-1, NFAT, Myc, beta-catenin,
CCAAT/enhancer binding proteins, NFkappa-B.
Lithium increase interleukin-2 levels.
Lithium stimulates Na/K pump activity.
Lithium & Hematopoiesis
Lithium increases platelet counts, neutrophil counts,
and colony-stimulating factor (CSF) levels
Lithium has been successfully used to treat
hyperthyroid and other granulocytopenia
aplastic anemia
radiation- and clozapine-induced neutropenia
childhood neutropenia
Felty’s syndrome (autoimmune rheumatoid arthritis)
The dose for these lithium effects are relatively low
(0.1 mM) compared to doses needed for depression.
Granulocytosis
Hammond & Dale (1980) used lithium to treat
canine cyclic hematopoiesis, eliminating recurrent
neutropenia and normalized other white cell counts.
Levitt, et al. (1980) showed 1 mM lithium increases
murine granulocyte production by 232%
granulocyte-monocyte progenitor cells by 125%
increased megakarycotes by 246%
Gallicho, et al (1980) showed that lithium increased
both pluripotent and committed stem cell colonies,
increasing differentiation towards granulocytosis.
Lymphopenia
Lithium inhibits T-cell production, reducing both Tcell counts and T-cell colonies grown from blood of
lithium-treated patients.
Fernandez & MacSween (1980) proposed that
lithium shifts hematopoiesis from lymphocytes to
granulocytes.
Lithium directly inhibits T-cell production by
causing thymus involution (Pere-Cruet & Darcy)
reducing OKT4 cells and OKT4/OKT8 ratios
Immune Function
Lithium boosts immune function of lymphocytes:
increases lymphocyte response to mitogens, i.e. LPS,
concavalin-A, lectin, phytohemagglutinin (PHA).
prevents histamine suppression of T-cell mitogenesis
blocks prostaglandin inhibition of IL-2 and T-cells
increases immunoglobulin (IgG, IgM) synthesis
Increases thymidine uptake by activated lymphocytes.
Lithium stops lymphocytic inhibition of granulocytes
blocks interferon-mediated arrest of granulocytosis
increases production of G-CSF from lymphocytes.
prevents activation of suppressor T-cells.
Immune Modulator
Lithium is used as an immune modulator:
an oral adjuvant for viral vaccines.
used topically for seborrheic dermatitis.
sometimes used to treat autoimmune psoriasis.
inhibits experimental allergic encephalomyelitis
Possible undesirable side effects
Lithium increases anti-thyroid antibodies but does not
induce auto-antibody production.
Lithium given with vaccines increase splenic
blastogenesis but not lymphocytic proliferation.
Lithium and Leukemia
Lithium does not affect mononuclear cells from
acute myelomonocytic leukemia and does not
stimulate leukemic myeloid colony sizes in vitro.
Lithium also does not affect neutropenia associated
with glycogen storage diseases, some drug-induced
and chemotherapy-induced neutropenia, or large
granular lymphocyte proliferation.
In no case has lithium been shown to produce
leukemia or inappropriate hematopoiesis.
Lithium & Depression
Lithium itself is not an antidepressant. The effects of
lithium on depression takes weeks to be apparent.
Lithium inhibits GSK3-beta to cause the following:
Proliferation and differentiation of neural stem cells
Increased expression of neurotrophic growth factors
Greater immune responsivity and granulocytosis
Each of the effects have multiple downstream effects.
Stem cell proliferation and growth
Increased plasticity.
Lithium & Alzheimer’s
Early studies discouraged lithium use in Alzheimer’s
Lithium accentuates extrapyramidal symptoms in
people with Alzheimer’s disease (Kelwala, et al 1984)
People with degenerative brain disease have greater
lithium neurotoxicity (Coffrey & Ross, 1985).
Much data suggest that lithium can stop dementia.
GSK3b phosphorylates tau and prevents cytoskeletal
pathology, including Abeta toxicity, of Alzheimer’s.
GSK3b reverses inhibition of Wnt/beta-catenin by
mutated presenilin (PS1) gene of familial Alzheimer’s
People with Alzheimer’s disease have high GSK3b.
Lithium & Dementia
Dunn, et al. (2005) reported that patients that take
lithium have a higher risk of dementia but the risk
paradoxically declined with longer lithium intake.
Nunex, et al. (2007) did a case-control study
comparing 66 patients that take lithium with 48 ageand disease-matched controls.
Only 3% of the patients (5%) of the lithium-treated
group developed dementia.
16 patients (33%) of the non-lithium treated group
developed dementia.
Lithium & Taupathies
Hyperphosphorylated tau is a major component of
neurofibrillary tangles in Alzheimer’s and other
neurodegenerative diseases (Planel, et al. 2001)
Lithium reverses accumulation of tau protein by
inhibiting GSK3b and other phosphokinases that
phosphorylate tau, e.g. PKA, Akt/PKB, and PK1.
induces protein phosphatase 2A (PP2A) activity to
dephosphorylate tau (Tsuji, et al. 2003)
Chronic lithium treatment reduces tau protein
accumulation in transgenic mouse models.
Lithium & Amyloidosis
Beta-amyloid (Abeta) is highly neurotoxic and
activate tau protein kinase (PK1) and GSK3b, both
which are blocked by lithium (Hoshi, et al. 2003).
Lithium reduces production of Abeta from amyloid
precursor protein (APP) by blocking GSK3a and
CDK5, which cleave APP (Sun, et al. 2002).
Lithium and valproic acid both reduce Abeta peptide
production in HEK293 cells transected to produce
APP by binding Pin1 (Akiyama, et al 2004).
Lithium Neuroprotection
Lithium protects neurons by
blocking NMDA receptor mediated calcium current
activating wnt/beta-catenin (De Ferrari, et al. 2003),
neuroprotective genes (Rowe & Chuang, 2004)
heat shock factor 1
activator protein 1
CREB protein
Bcl-2.
tolerance to oxidative stress (Schafer, et al 2004).
preventing Abeta toxicity (Wei, et al., 2000)
Many of these effects take time to occur.
Lithium & Parkinson’s Disease
GSK3b mediates 6-OHDA induced neuronal death.
Lithium and other GSK3b blockers prevent 6-OHDA
induced apoptosis (Ghen, et al. 2004).
GSK3b acts downstream of PP2A and PI-3 kinase
AKt pathways, and upstream of mitochondria
associated caspase-induced apoptosis (Lin, et al,
2007)
Lithium blocks ceramide-induced apoptosis by
inhibiting PKB and GSK3b. This effect is specific to
lithium and not valproic acid.
Lithium & Huntington’s
Huntington’s disease is a genetic condition where a
polyglutamine expansion mutation confers a toxic
gain-of-function. Autophagy clears the proteins.
Lithium induces mTOR independent autophagy by
inhibiting inositol monophosphatase, reducing
inositol and IP3 levels.
Inhibition of GSK3b also stimulates autophagy and
clearance of mutant huntingtin. Sarkar, et al. (2008)
suggested lithium+rapamycin treatment.
Lithium & Alcohol
Alcohol causes neurodegeneration in young
mammals and lithium blocks the alcohol-induced
neurodegeneration (Chakraborty, et al., 2008)
Lithium blocks alcohol-induced neurodegeneration
in 7-day mice by preventing induction of caspase-3
and dephosphorylation of Akt, GSK3b, and AMPK.
Lithium inhibited alcohol-induced accumulation of
N-acetylphosphotidylethanolamine and cholesterol
esters in the brain.
Lithium & Prion Disease
Lithium may be useful for treating prion-induced
neurodegenerative disease, e.g. subacute spongiform
encephalopathies (Ledoux, 2004, 2005)
Lithium prevents prion peptide PrP106-126 induced
cell death in neuron and neuroblastoma cultures
(Perez, et al, 2003)
Dominant negative mutants of GSK3 (which turns off
GSK3 activity) protect cells that are exposed to
PrP106-126.
Lithium & ALS
Amyotrophic lateral sclerosis (ALS) is a deadly
neurodegenerative disease that kills >80% of
patients within 5 years.
Fornai, et al. (2007) randomized 44 ALS patients to
lithium (0.4-0.8 mM serum levels) or control
treatment. After 15 months, 29% of control patients
died while all lithium-treated patients survived and
showed less motor loss than the controls.
Subsequent trials were unable to confirm these
results although the trials are well-controlled.
Lithium & BDNF
Depression reduces brain-derived neurotrophic
factor (BDNF) in brain while lithium and valproate
increases BDNF in the brain (Post, 2007)
Lithium and valproate activate promoter IV of BDNF
in neurons (Yasuda, et al. 2007) and increase BDNF
levels in the hippocampus (Frey, et al., 2007).
Lithium increases BDNF receptor (TrkB) in anterior
cingulate but not hippocampus (Mudo, et al., 1996).
Acute but not chronic lithium increases CREB
phosphorylation, a target of TrkB (Rantamaki, 2006).
Lithium & NGF
Lithium increases nerve growth factor (NGF) and
glial derived neurotrophic factor (GDNF) in the rat
hippocampus (Angelucci, et al. 2003).
Lithium increases NGF in frontal cortex (+23%),
hippocampus (+72%), amygdala (+74%), and limbic
forebrain (+47%) but not striatum, hypothalamus, or
midbrain.(Hellwig, et al. 2002).
Lithium & NT-3
Neurotrophin-3 (NT-3) stimulates axon growth and
promotes neurogenesis in forebrain and
hippocampus.
Lithium increases levels of NT-3 in serum and
hippocampus of rats, given before, during and after
amphetamine-induced mania (Walz, et al. 2007).
Valproate also increased NT-3 but only when given
before amphetamine.
Lithium and GDNF
Secreted by astrocytes, glia-derived neurotrophic
factor (GDNF) is important for maintenance and
survival of neurons.
People with major depression and bipolar disorders
have significantly lower GDNF than normal control
subjects.
Lithium increased GDNF in some brain regions of
rats with depression and schizophrenia (Angelucci,
et al. 2003, 2004) and seizures (Gao, et al. 2003).
Antagonistic Effects
Lithium increases expression of neurotrophins and
their receptors but it also antagonize some effects of
neurotrophins. For example,
Lithium antagonizes NGF-induced reorganization of
microtubules (Burstein, et al., 1985) and AP-1
binding (Unlap & Jope, 1997).
Lithium antagonizes BDNF-induced PI-3 kinase
mediated dephosphorylation of tau proteins (Elliot, et
al. 2005) and Fox03a activation (Mao, et al., 2007)
Thus, lithium has complex effects on neurotrophins.
Lithium & Polymorphisms
The therapeutic effects of lithium on patients with
depression can be predicted by BNDF
polymorphisms (Serretti & Artioli, 2003).
In 111 patients with bipolar disorder (45 male, 68
female), lithium effects associated with BDNF and
serotonin transporter (Rybakowski, et al. 2007).
These data suggest that lithium effects may be
related to both BDNF and serotonin transporter
characteristics.
Lithium & Neurogenesis
Lithium stimulated neurogenesis in vitro and in vivo.
Short-term lithium induces neurogenesis in striatal
injury sites and reduce cell proliferation in the
subventricular zone (Senatorov,et al. 2004)
Chronic lithium treatment enhances hippocampal
neurogenesis in rats. BRDU-labeled cells increase
dramatically in granular layer and >90% are neurons
(Chen, et al. 2000; Son, et al. 2003)
Lithium selectively increases neuronal differentiation
of hippocampal progenitor cells in vitro and in vivo
(Kim, et al., 2004)