Lithium to augment the effects of a BACE (Beta-Secretase) Inhibitor for the prevention of Alzheimer’s Disease

James Wallace

Lithium to augment the effects of a BACE (Beta-Secretase) Inhibitor for the prevention of Alzheimer’s Disease*

*U.S. Patent Pending #US 20140271911 A1

Words of Caution

This presentation is for educational purposes only. Even very small doses of lithium may be contraindicated in some individuals taking certain medications or those with kidney conditions. As always, please work with a knowledgeable physician before beginning any type of supplement or medication protocol.

Linking Neuronal Hyperactivity with Calcium Signaling, Amyloid, Mitochondrial Dysfuntion, ER Stress, and Neurodegeneration

Increased Activity Is Paired With Calcium

Signaling and Calcium Influx

Metabolic Stress and ROS 1-3 Calcium Derangements 4,5 Increased

Synaptic Exocytosis 6,7

• Progressive Oxydative Damage

• Mitochondrial Dysfunction

• Diminished Metabolic Capacity

• ER Stress/UPR/Inflam./Misfolding

• Synaptic Dysfunction

• Excitotoxic Damage


• Interstitial Amyloid

• Amyloid Deposits

1 – Celsi F. et al., “Mitochondria, calcium and cell death: a deadly triad in neurodegeneration” Biochim. Biophys. Acta., Vol. 1787, 2009, 335-344.

2 - Calì T. et al., “Mitochondrial Ca2+ and neurodegeneration.” Cell Calcium, vol. 52, 2012, 73-85.

3 – Szydlowska K. and Tymianski M., “Calcium, ischemia and excitotoxicity” Cell Calcium, vol. 47, 2010, 122-129.

4 – Zhang H. et al., “Calcium signaling, excitability, and synaptic plasticity defects in a mouse model of Alzheimer's disease” J. Alzheimers Dis., vol. 45, 2015, 561-580.

5 – Cirrito J.R. et al., "Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.", Neuron, vol. 48, 2005, 913-922.

6 - Bero A.W. et al. “Neuronal activity regulates the regional vulnerability to amyloid-β deposition” Nat. Neurosci., vol 14, 2011, 750-766.

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://vector.me/search/up-down-arrow&ei=vCuMVIE5xqg2l7qA0Ao&psig=AFQjCNHBSTQTmgQi3tDEv4Tnwgme8KhEnQ&ust=1418558744015934






Vs.

Potentially•Increased Neuronal Activity•Increased Rates of Autophagy Mediated Extrusion of Amyoid•Increased Rates of Ca2+ Signaling•Increased Metabolic Demands•Increased ROS Generation

In Neurons Susceptible to AD…..

Pre–Alzheimer’s DiseaseMilieu

Post–Alzheimer’s DiseaseMilieu

•Reduced Neuronal Activity•Reduced Autophagy•Increased Rates of Resting Ca2+ Levels•Reduced Metabolic Functioning•Decreased # of Mitochondria•ER Stress/Inflammation•Increased Quantities of Intracellular Amyloid•Synaptic Dysfunction

MK-8931 (Verubecestat) - Phase III - Merck

AZD3293 (Lanabecestat) - Phase III - Eli Lilly/Astra Zeneca

E2609 (Elenbecestat) Phase III – Eisai

JNJ-54861911 - Phase II - Janssen

CNP520 - Phase II - Novartis

Currently, BACE Inhibitors are in Clinical Trials – others may follow

Could lithium safely and effectively augment anti-amyloid therapy in those at risk for Alzheimer’s disease?

Well-Characterized Processes Implicated in Alzheimer’s disease:

Beta-Secretase (BACE) mediated amyloidogenesis 1

N-methyl-d-aspartate receptor mediated calcium influx 2

Inositol triphosphate receptor mediated calcium influx 3

Multi-Targeted Drug Design Strategy

1 - Vassar R. et al., “Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE”, Science, vol. 286, 1999, 735-741.2 - Lipton S.A. and Rosenberg P.A., "Excitatory amino acids as a final common pathway for neurologic disorders", N. Engl. J. Med., vol. 330, 1994, 613-622.3 - Stutzmann G.E., "Calcium dysregulation, IP3 signaling, and Alzheimer's disease", Neuroscientist, vol. 11, 2005, 110-115.

As described in the Amyloid hypothesis, Alzheimer’s disease is preceded by, and in some unproven manner is initiated by, Amyloid (Aβ). 1-3 By disrupting the cleavage of Amyloid Precursor Protein (APP), beta-secretase inhibitors can potentially reduce the generation of Amyloid (Aβ) and reduce Amyloid (Aβ) deposits. 4,5

Proposed Mechanism of Action for BACE Inhibition

1 - Hardy J. and Allsop D., “Amyloid deposition as the central event in the aetiology of Alzheimer's disease”, Trends Pharmacol. Sci., vol. 12, 1991, 383-388.

2 - Karran E. et al., "The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics", Nat. Rev. Drug Discov., vol. 10, 2011, 698-712..

3 - Sperling R.A. et al., "Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease”, Alzheimers Dement., vol. 7, 2011, 280-292..

4 - Ghosh A.K. et al., “Beta-Secretase as a therapeutic target for Alzheimer's disease”, Neurotherapeutics, vol. 5, 2008, 399-408.

5 - Vassar R. et al., “Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE”, Science, vol. 286, 1999, 735-741.

A coding substitution on Amyloid Precursor Protein (APP) adjacent to the beta-secretase cleavage site is associated with protection against Alzheimer’s disease.

The A673T Substitution

Jonsson T. et al., "A mutation in APP protects against Alzheimer’s disease and age-related

cognitive decline", Nature, 2012, vol. 488, 96–99.


Increased Activity

Is Paired With Calcium


Metabolic Stress

and ROS 1,2 Calcium Derangements 3,4 Increased























Long before the onset of neurodegeneration, brain regions with higher rates of activity and metabolism in young adults - overlap regions observed to have significant quantities of amyloid depositi0n in subjects with Alzheimer’s disease - in the default mode network (DMN). 1,2

In transgenic Tg2576 mice, higher concentrations of interstitial amyloid and higher quantities of amyloid deposition have been observed in brain regions with higher rates of activity. 3

It has been proposed that neurons with increased activity rates have higher rates of synaptic vesicle release and higher rates of synaptic amyloid release resulting in increased concentrations of interstitial amyloid. 4

In Tg2576 mice, higher concentrations of interstitial amyloid have been shown to influence amyloid deposition. 3

Does regionally specific neuronal hyperactivity influence and promote regionally specific amyloid deposition?

1 - Buckner R.L. et al.,“Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity,

amyloid, and memory”, J. Neurosci., vol. 25, 2005, 7709-7717.

2 - Buckner R.L. et al., “The brain's default network: anatomy, function, and relevance to disease”, Ann. NY Acad. Sci., vol. 1124, 2008, 1-38.

3 - Bero A.W. et al., "Neuronal activity regulates the regional vulnerability to amyloid-β deposition." Nat. Neurosci., vol. 14, 2011, 750-756.

4 - Cirrito J.R. et al., "Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.", Neuron, vol. 48, 2005, 913-922.

Roselli F. and Caroni P., "From Intrinsic Firing Properties to Selective Neuronal Vulnerability in Neurodegenerative Diseases" Neuron, vol. 85, 2015, 901-

910.

Busche M.A. and Konnerth A., "Neuronal hyperactivity - A key defect in Alzheimer's disease?", Bioessays, 2015, Epub ahead of print.

Increased Neuronal Activity

Increased Interstitial Amyloid

Amyloid Deposits

Neuronal Hyperactivity (1-4)

1 - Bero A.W. et al., "Neuronal activity regulates the regional vulnerability to amyloid-β deposition." Nat. Neurosci., vol. 14, 2011, 750-756.

2 - Cirrito J.R. et al., "Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.", Neuron, vol. 48, 2005, 913-922.

3 - Roselli F. and Caroni P., "From Intrinsic Firing Properties to Selective Neuronal Vulnerability in Neurodegenerative Diseases" Neuron, vol. 85, 2015, 901-910.

4 - Busche M.A. and Konnerth A., "Neuronal hyperactivity - A key defect in Alzheimer's disease?", Bioessays, 2015, Epub ahead of print.

Higher Rates of Synaptic Vesicle and Synaptic Amyloid Exocytosis







The Default Mode Network and Amyloid

Buckner R.L. et al.,“Molecular, structural, and functional characterization of Alzheimer's disease:

evidence for a relationship between default activity, amyloid, and memory”, J. Neurosci., vol. 25,

2005, 7709-7717


Increased Activity



Metabolic Stress
























Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. (Mertens J et al.) – Nature 2015.

Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. (Stern S et al.) – Molecular Psychiatry 2017

Lithium and Neuronal Hyperactivity

‘Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.’ (Stern S et al.) – Molecular Psychiatry 2017

Lithium and Neuronal Hyperactivity

Autophagy mediated extrusion of amyloid (which has been shown to be less impaired during preclinical stages) might influence and contribute to extracellular amyloid accumulations. 1,2

Autophagy impairments (which have been shown to become significant during the later stages of Alzheimer’s disease) might influence and contribute to intracellular amyloid accumulations. 3

Role of Autophagy in Amyloid Processing-Extracellular and Intracellular Amyloid

1 - Nilsson P. et al. "Aβ secretion and plaque formation depend on autophagy", Cell Rep., vol 5, 2013, 61-69.

2 - Nilsson P., Saido T.C., "Dual roles for autophagy: degradation and secretion of Alzheimer's disease Aβ peptide", Bioessays,

vol. 36, 2014, 570-578.

3 - Nixon R.A., "Autophagy, amyloidogenesis and Alzheimer disease" J. Cell Sci., vol. 120, 2007, 4081-91.

Extracellular Amyloid has been proposed to exert toxicity on cell membranes and neurotransmitter receptors. 1,2

Intracellular Amyloid has been proposed to disrupt the intracellular milieu of neurons, contributing to organelle pathology, including mitochondrial damage, and ER Stress. 3,4

Extracellular and Intracellular Amyloid

1 - Nixon R.A., "Autophagy, amyloidogenesis and Alzheimer disease" J. Cell Sci., vol. 120, 2007, 4081-91.

2 - Nixon R.A., "Alzheimer neurodegeneration, autophagy, and Abeta secretion: the ins and outs (comment on DOI

10.1002/bies.201400002)", Bioessays, vol. 36, 2014, 547.

3 - Umeda T., "Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal

leakage, and mitochondrial dysfunction in vivo", J. Neurosci. Res., vol. 89, 2011, 1031-1042.

4 - Wirths O., "Intraneuronal Aβ accumulation and neurodegeneration: lessons from transgenic models" Life Sci., vol. 91, 2012,

1148-1152.

Feed-Forward Interactions between Intracellular Calcium and Amyloid

Ca2+ Amyloid

1 - Green K.N. and LaFerla F.M., "Linking calcium to Abeta and Alzheimer's disease", Neuron, vol. 59, 2008, 190-194.

2 - Demuro A. et al., "Calcium signaling and amyloid toxicity in Alzheimer disease", J. Biol. Chem., vol. 285, 2010, 12463-12468.3 - De Caluwé J. and Dupont G., "The progression towards Alzheimer's disease described as a bistable switch arising from the

positive loop between amyloids and Ca(2+)", J. Theor. Biol., vol. 331, 2013, 12-18.

4 - Texidó L. et al., “Amyloid β peptide oligomers directly activate NMDA receptors” Cell Calcium, vol. 49, 2011, 184-190.

5 - Jensen L.E. et al., "Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca(2+) via InsP3R-dependent and -

independent mechanisms.“, Front. Mol. Neurosci., vol. 6:36, 2013.

Abnormal Ca2+ signalingthrough plasma membrane

channels

Extracellular Amyloid

Intracellular AmyloidAbnormal Ca2+ signaling

through endoplasmic reticulum channels

Calcium Microdomains

In neurons, Ca2+ in the cytoplasm mediates both Long-Term Potentiation (LTP) and Long-Term Depression (LTD). 1

Resting intraneuronal calcium levels in the cytoplasm ~ 100 nM. 2

Increased intracellular calcium concentrations have been observed in neurons from 3xTg-AD transgenic mice. 3

Models of Alzheimer’s disease suggest that increased resting intracellular calcium levels disrupt memory consolidation. 4

Intracellular Calcium

1 - Malenka R.C. and Bear M.F., "LTP and LTD: an embarrassment of riches", Neuron, vol. 44, 2004, 5–21.

2 - Berridge M.J et al., "The versatility and universality of calcium signaling", Nat. Rev. Mol. Cell Biol., vol. 1, 2000, 11–21.

3 - Lopez J.R. et al., “Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice”, J. Neurochem., vol. 105, 2008, 262-271.

4 - Bezprozvanny I. and Hiesinger P.R., “The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration”, Mol. Neurodegener., vol. 8, 2013, 23.


Increased Activity



Metabolic Stress
























Lithium has been shown to antagonize NMDA receptors-Nonaka et al. EC50 of Li – 1.3 mEq/L, 6–7 days of Li required for maximum effect, 24 h of Li was ineffective; Hashimoto et al. EC 50 of Li – 0.4 mEq/L, At 1.0 mEq/L 5–6 days required for maximum effect, 1 h of Li was ineffective. 1,2

Lithium has been shown to inhibit Inositol Monophosphatase (IMP) and reduce Inositol Triphosphate (IP3)-In vitro experiments by Hallcher et al. (1980) and Berridge et al.(1982) have shown that lithium inhibits IMP half-maximally at 0.80 mEq/L and 1.0 mEq/L respectively. 3,4

-Lithium has been shown to dose-dependently reduce carbachol-stimulated IP3 accumulation at concentrations as low as 0.1 mEq/L, and half-maximally at 1 mEq/L. 5

Lithium has been shown to reduce intracellular calcium ion concetrationsThis effect was observed in a 7 day protocol of lithium at 1.0 mEq/L. 6

How can lithium influence calcium signaling?

Therapeutic Concentrations of Lithium 0.6 – 1.2 mEq/L (FDA)

1 - Nonaka S. et al., “Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx”, Proc. Natl. Acad. Sci. U. S. A., vol. 95, 1998, 2642-2647.

2 - Hashimoto R. et al., “Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation”, J. Neurochem., vol. 80., 2002, 589-597.

3 - Hallcher L.M. and Sherman W.R., “The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain”, J. Biol. Chem., vol. 255, 1980, 10896-10901.

4 - Berridge M.J. et al., “Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands”, Biochem. J., vol. 206, 1982, 587.

5 - Batty I. and Nahorski S.R., "Differential effects of lithium on muscarinic receptor stimulation of inositol phosphates in rat cerebral cortex slices", J. Neurochem., vol. 45, 1985, 1514-1521.

6 - Sourial-Bassillious N. et al., "Glutamate-mediated calcium signaling: a potential target for lithium action." Neuroscience. vol. 161, 2009, 1126-1134.

By antagonizing NMDA receptors, lithium can potentially reduce the stimulation of neurons and directly inhibit external calcium ion influx through NMDA receptor channels.

Lithium, NMDA Receptors, and External Calcium

Inositol Depletion Hypothesis – Berridge et al. (1989) Lithium has been shown to inhibit IMP Lithium has been shown to lower IP3 levels

Inositol Depletion Hypothesis

By lowering IP3, lithium can reduce calcium ion influx from internal ER stores through IP3 receptor channels.

IP3 and Internal Calcium Ion Stores

IP3 + NMDA - two pathways of calcium influx from internal and external stores potentially influenced by lithium

As the diagram depicts – other pathways of calcium ion influx also exist.

Lithium Lithium

NMDA Antagonism

IMP Inhibition

Lowered Intracellular Calcium Intrusion from

External Stores

Reduced IP3

Lowered Intracellular Calcium Intrusion from

ER Stores

ER Ca2+External Ca2+











Lithium BACE Inhibitor

Amyloid(BACE Inhibition)

Calcium dysregulation(NMDA Receptor Antagonism)(IMP Inhibition/IP3 lowered)

Lowered Intracellular Calcium

Reduced

Amyloid

Lithium

ER Ca2+External Ca2+ Amyloid (Aβ)











Hippocampal VolumeSubjects with bipolar disorder taking lithium (for at least 2 years) had hippocampal volumes comparable to healthy controls and larger hippocampal volumes than non-lithium treated subjects. Data suggests this effect is independent of treatment response. 1,2

Markers for Oxidative Stress – SOD and SOD/CAT ratioIn healthy subjects, a 2-4 week regimen of lithium (mean lithium 0.85 ± 0.22 mEq/L; mean duration 15.2 ± 6.1 days) was associated with decreased levels of SOD. SOD levels decreased after lithium treatment (1.19 ± 0.28 U/g) compared to baseline (2.61 ± 0.51 U/g, p=0.01); SOD/CAT ratios decreased after treatment (4.12±1.32) compared to baseline(9.72 ± 2.34, p=0.02). No significant changes in TBARS or CAT were observed.3

SOD – superoxide dysmutase; CAT – catalase; TBARS - thiobarbituric acid reactive substances

1 - Hajek T. et al., “Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response”, Psychol. Med., vol. 44, 2014, 507-517.

2 – Hajek T. et al., “Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment”, Bipolar Disord., vol. 14, 2012, 261-270.

3 - Khairova R., “Effects of lithium on oxidative stress parameters in healthy subjects”, Mol. Med. Rep., vol. 5, 2012, 680-682.

Lithium and Biomarkers

In the past decade, two observational studies, one in Brazil, and one in Denmark, have shown that subjects with bipolar disorder who are treated with lithium have a reduced prevalence of dementia. While this data suggests that continued use of lithium may reduce the risk for developing Alzheimer’s disease in asymptomatic adults, confounding factors could have affected the results. 1,2

1 - Nunes P.V. et al., "Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder", Br. J. Psychiatry, vol. 190, 2007, 359-360.

2 - Kessing L.V. et al., "Does lithium protect against dementia?", Bipolar Disord., vol. 12, 2010, 87-94.

Repositioning Lithium for the Prevention of Neurodegenerative Disease

2015 – The British Journal of Psychiatry

A recently published observational study involving over 40,000 U.S. subjects in 8 states age ≥ 50 showed that subjects with bipolar disorder who received 301–365 days of lithium had a reduced risk of developing dementia. PMID: 25614530

(hazard ratio = 0.77, 95% CI 0.60-0.99)

Gerhard T. et al.., "Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study”, Br. J. Psychiatry, 2015, 1-6, in press.

Mg+2 and Li+ have similar ionic radii and charge (Li+ has a slightly smaller ionic radius compared the Mg+2, allowing Li+ to fit into Mg+2 substrates).

Given the similarities between the two ions, Li + is implicated in cross-reacting with substrates regulated by Mg+2. 1-4

Mg+2 sensitive targets including IMP and NMDA receptor channels – and potentially, hundreds of other biological substrates regulated by Mg+2, are potential targets of lithium ions.

Mg+2 also has similar physical properties with Ca+2, – this might account for the inhibitory effects of Mg+2, and Li+, on NMDA receptor channel mediated Ca+2 influx, and might also account for the possible influence of Li+ on other calcium signaling pathways.

Lithium, Magnesium, and Calcium

1 - Birch N.J., “Letter: Lithium and magnesium-dependent enzymes. Lancet”, vol. 304, 1974, 965-966.2 - Amari L., et al., “Comparison of fluorescence, (31)P NMR, and (7)Li NMR spectroscopic methods for investigating Li(+)/Mg(2+) competition for biomolecules.” Anal. Biochem., vol. 272, 1-7. 3 - Amari L., "Competition between Li+ and Mg2+ in neuroblastoma SH-SY5Y cells: a fluorescence and 31P NMR study", Biophys. J., vol. 76, 1999, 2934-2942.4- Pasquali L. et al., "Intracellular pathways underlying the effects of lithium", Behav. Pharmacol., vol 21, 2010, 473-492.

PHYSICOCHEMICAL PROPERTIES OF SOME ALKALI AND ALKALINE EARTH

ELEMENTS *

(Li) (Mg) (Ca)

Atomic Radius 1.33 1.36 1.74

Crystal Ionic Radius 0.60 0.65 0.99

Corrected Hydrated Radius 3.40 4.65 3.21

Electronegativity 1.0 1.2 1.0

Polarizing Power 2.8 4.7 2.05

* Stern, K. H.; Amis, E. S., Chem. Rev., 1959, 59, 1.

Lithium, Magnesium, and Calcium

1. The membrane voltage-gated calcium ion channel CALHM1 has been linked to intracellular Ca+2 regulation and maintaining Ca+2 homeostasis in neurons - in response to extracellular Ca+2 concentration variations.

2. Mg+2 has been shown to influence CALMH1 gating (IC50 = 3.26 mM; Hill coefficient = 2.3), but at a lower affinity compared to Ca+2 (Ma Z et al. 2012); - according to the authors, the dose response relation for Mg+2 is similar in shape to that of Ca+2 at the same holding potential, suggesting that both cations bind to the same CALHM1 sites and regulate CALHM1 channel gating by a similar mechanism.

3. CALHM1 receptors have been shown to be similarly regulated by Ca+2 and Mg+2 (Tanis JE et al. 2013)

Calcium Homeostasis Modulator 1 (CALHM1)

Ma Z. et al., “Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates

extracellular Ca2+ regulation of neuronal excitability” Proc. Natl. Acad. Sci. U. S. A., vol. 109, 2012, E1963-1971.

Tanis J.E. et al, “CLHM-1 is a functionally conserved and conditionally toxic Ca+2 -permeable ion channel in Caenorhabditis

elegans” J. Neurosci., vol. 33, 2013, 12275-12286.

Ma Z. et al, “Calcium homeostasis modulator (CALHM) ion channels” Pflugers Arch., 2015.

Given (1) the similarity in physical properties between Li+, Mg+2, and Ca+2; and (2) the potential influence that Li+ may have on cross reacting with Mg+2 and Ca+2 binding sites; and (3) the similar influence that Mg+2 and Ca+2 may have on modulating Ca+2 influx through CALMH1 channels; then, in addition to antagonizing NMDA receptors and inhibiting IMP – Lithium might also influence CALMH1 Ca+2 gating and inhibit Ca+2 influx through CALMH1 channels at the sites on CALHM1 that have been shown to bind Mg+2 and Ca+2

This possible effect of Li+ on CALMH1 channels could have influenced the results observed by Nonaka et al. 1998 and Hashimoto et al. 2002 regarding the effect of Li+ on NMDA receptor channel mediated Ca+2 influx and excitotoxicity.

Calcium Homeostasis Modulator 1 (CALHM1)

Vincristine- In 2012, Alimoradi et al. showed that lithium at sub-therapeutic concentrations reduced neuronal pathological lesions in Sprague Dawley rats related to Vincristine treatment. 1

Paclitaxel (2011, 2012)- Lithium has been shown to reduce chemotherapy induced peripheral neuropathy related to Paclitaxel treatment. 2,3

- Dr. Barbara E. Ehrlich’s group proposed that this effect could be attributed to the effect of lithium on calcium signaling; by disrupting interactions between paclitaxel, Neuronal Calcium Sensor 1 (NCS-1), and IP3 Receptors; and in turn preserving NCS-1 levels and calcium levels. 3-5

1 - Alimoradi H. et al., Effects of lithium on peripheral neuropathy induced by vincristine in rats, Acta. Med. Iran., 2012, vol. 50:373-

379.

2 - Pourmohammadi N. et al., Lithium attenuates peripheral neuropathy induced by paclitaxel in rats, Basic Clin. Pharmacol. Toxicol.,

2012, vol. 110:231-237.

3 - Mo M. et al., Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment., FASEB J., 2012, vol. 26:4696-4709.

4 - Benbow J.H. et al., Protection of neuronal calcium sensor 1 protein in cells treated with paclitaxel, J. Biol. Chem., 2011, vol.

286:34575-34582.

5 - Benbow J.H. et al., Inhibition of paclitaxel-induced decreases in calcium signaling, J. Biol. Chem., 2012, vol. 287:37907-37916.

Lithium - Hematology/Oncology

Alzheimer's Association National Plan Milestone Workgroup - 2014

PubMed ID 25341459 - http://www.ncbi.nlm.nih.gov/pubmed/25341459


Milestone A: Convene an advisory meeting of experts from the pharmaceutical industry, government, academia, the FDA, and the nonprofit sector to advance rational drug repositioning and combination therapybased on translational bioinformatics and network pharmacology approaches and to explore opportunities for new public-private partnerships to facilitate drug rescue/repurposing and combination therapy.

Timeline: 1 yr - 2014


Milestone B: Initiate research programs for translational bioinformatics and network pharmacology to support rational drug repositioning and combination therapy from discovery through clinical development.

Timeline: 3–5 yrs - 2015–2019


Milestone C: Initiate early clinical development for at least 6 existing drugs or drug combinations for thetreatment or prevention of AD.

Timeline: 2-4 yrs - 2018–2021

Wallace J., “Calcium dysregulation, and lithium treatment to forestall Alzheimer's disease - a merging of hypotheses”, Cell Calcium, vol. 55, 2014, 175-81.

Additional Reading

James Wallace

Thank you

Health & Medicine

Lithium to augment the effects of a BACE (Beta-Secretase) Inhibitor for the prevention of Alzheimer’s Disease