Neuropsychiatr Dis Treat.2017 13:275-302

A  Fully Integrated New Model for Lithium’s Mode of Action: Lithium Utilizes Hidden Cellular ‘Fail-Safe-Mechanisms’.

Dr Arthur Ernst van  Woerkom, B.A., M.A., (Cantab), M.B., B.Chir., MRCPsych. Consultant Psychiatrist, South Birmingham & Solihull Mental Health NHS Foundation Trust. Longbridge CMHT, 10 Park Way, Rubery, Birmingham, U.K. B45 9PL. Email: ernie.vanwoerkom@bsmhft.nhs.uk

 

Abstract

A new model for Lithium’s mode of therapeutic action is proposed.

Lithium’s very many pervasive protective actions provide indirect evidence for the existence of a set of low-cell [Mg++] sensitive, cell-protection systems.

To survive in conditions associated with a very low cell [Mg++], (neuronal) cells will require ‘Fail-Safe’ mechanisms, as otherwise, below a critically low intracellular [Mg++], many Mg++ requiring systems risk grinding to a halt.

This specific latent vulnerability implies the existence of specific protective responses, activated by a low-intracellular [Mg++], at times acting as a metabolic ‘alarm-signal’.

It is proposed that these fail-safe systems also help to regulate; buffer, limit and restore cell [Mg++], and as Li+ mimics a low cell [Mg++] level activating these pre-existing systems also provides Lithium’s Therapeutic effects.

 

 

Summary

Lithium exhibits a very wide range of cyto-protective effects; providing evidence for the existence of a group of ‘low-cell [Mg++] activated cell-protection-systems’.

To survive conditions with a significantly lowered-cell  [Mg++] it is proposed, (neuronal)  cells will need to utilize various ‘fail-safe-mechanisms’; as below a critically low-intracellular [Mg++] concentration, hundreds of free Mg++ requiring systems risk  grinding to a halt. This latent vulnerability suggests the existence of specific, latent protective responses- activated by a low-intracellular [Mg++], which also appears to provide a  metabolic ‘alarm-signal’. Li+ would utilize the same cellular fail-safe systems;  as Li+, acting via competition with Mg++ mimics the effects of a lowered cell free [Mg++]. The augmentation of biochemical protective mechanisms, pre-configured to become activated during the metabolic crisis accompanying a ‘dangerously’ low-cell [Mg++], incidentally provides the basis of Lithium’s mood-stabilizing properties. Special conditions of very low-intracellular [Mg++] concentrations can occur; the system appears pre-configured to optimize neuro-protection, against adverse factors occurring post traumatic brain injury (t.b.i.), following which, the cell [Mg++] paradoxically drops to an unusually low-level.

 

It is proposed that Li+ and a low-cell free [Mg++] both utilize the same survival and recovery mechanisms, including the inhibition of the Li+ sensitive, and Mg++ dependent, IMPase/IPPase, GSK-3, Fructose-1,6-Biphophatase, BPNase,  PGM, Adenylate Cyclases, and G-proteins, etc. Overall cell-protection accumulates as cell [Mg++] levels drop, and/or as [Li+] levels increase. ‘Inositol-depletion’ represents a more specialized protective sub-mechanism, in addition to Lithium potentially limiting Phospholipase C linked receptor systems Inositol-depletion may exert further effects- by simultaneously also limiting PLC- linked, TRPM7 type, PIP2 requiring, Mg++/Ca++ ion channels.  This expands existing key concepts, as Li+ induced Inositol-depletion also results in ‘Inositol-Phosphate-Enhancement’, setting up a sugar-Phosphate-Mg++/Ca++ chelation-sub-mechanism, adding metal-ion ‘buffering’- as another protective and regulatory aspect of this group of fail-safe-systems; perfectly matched to the properties and kinetics of a key family of Li+ sensitive, Mg++ dependent enzymes.

 

The uncompetitive action of Lithium on the IMPase is intrinsically selective. If, in the relevant psychiatric Disorders, Li+ is operating in cells with a below-normal cell [Mg++] level, Lithium would demonstrate greater selectivity and potency; due to these enzymes- already rate-limited by a low ambient-cell [Mg++]- being further inhibited by Li+.  Such ‘double-inhibition’ would further explain Lithium’s potency, selectivity and specificity.

 

A lowered cell free [Mg++] concentration has the full potential to exert a Lithium-like   action- an innate biochemical mechanism to underpin mental and cellular-resilience.  Fail-safe-mechanisms would become fully operational only once the cell [Mg++] level drops beneath the activation-threshold. Lithium expands the parameters of the proposed ‘low-cell [Mg++] cell-protection system’. It is proposed that the therapeutic effects of Lithium occur indirectly; as a consequence of activating a cascade of latent protective pathways; pre-configured to operate in response to a low-cell [Mg++], in the t.b.i. situation- (including perinatal head-injury)- paradoxically occurring alongside relative cell ATP depletion. Cell-protection is further activated by Li+ as Lithium so neatly mimics the appearance of a lowered intracellular [Mg++] level.

 

The proposed system utilizes PRibosePP, a key Mg++ binding and key precursor substrate; linked to NAD+; in turn linked to maintaining cell [ATP], and hence to maintaining cell  [Mg++] levels.

 

The proposed new ‘Ins-Depletion-Ins-Phosphate-Enhancement-GSK-3’, ‘Fail-Safe’ paradigm swiftly transmogrifies into a re-integration of the earlier concepts. The model provides a new context, and explains both how and why Lithium works, and why it can work so well. It provides insights into some novel mechanisms that appear to underpin Mood and related Disorders. The corresponding modes of action of Valproate and Carbamazepine are also discussed in outline.

The complex and subtle mode of regulation of free cell [Mg++] that emerges may also be relevant to metabolic disorders (which appear disproportionally prevalent along-side mood and related psychiatric disorders), and which appear to have a complex relationship with Magnesium metabolism. The central focus of the paper is on neuronal systems and mood disorders, and metabolic disorders appear to invoke additional, related mechanisms.

 

Background

There has been a longstanding hope that unraveling the mode of action of Lithium might lead to a greater understanding, and ultimately, better treatments for Mood and related Disorders.

There are two seemingly dis-connected, current partial theories of Lithium’s action.

 

The ’Inositol-depletion’ model proposed that Li+ limited (notionally) ‘excess’ signal-transduction; as with the proposal here, this was based on the specific properties of certain enzymes, as Li+ inhibits both the IMPase (Inositol-Mono-Phosphatase), and the related IPPase (Inositol Polyphosphate-1-Phosphatase).

 

The more recent Glycogen Synthase Kinase, (GSK-3) theory notes that Lithium can exert

a cascade of protective effects- by inhibiting this important kinase.  The IMPase/IPPase and the GSK-3 enzymes are Mg++ dependent. In both these systems, Li+ acts via competition with Mg++ .  The inositol reversible actions of mood stabilizers do not appears to involve GSK-3 inhibition, Inositol-1-Phosphate synthase, or inositol transporters and the inositol-depletion hypothesis is considered to remain unproven. It appears unlikely that Lithium’s many pervasive effects, e.g., on plasticity and survival can be dismissed as just coincidental.

 

The hydrated ionic radius of Mg++ is similar to that of Li+ , it has previously been suggested that competition between Li+ and Mg++ ions constitutes the ultimate (molecular) basis for the mechanism of action for Li+. Lithium can displace Mg++ from some, but not all binding sites within the (nerve) cell and Li+ acts as a competitive inhibitor of numerous Mg++ dependent factors, transporters and enzymes.

 

A hidden metabolic vulnerability: Lithium augments a cellular ‘Protection-Racket’.

 

Lithium produces a remarkable width of protective- anti-apoptotic, anti-anoxic, UPR, autophagy, cell plasticity and resilience responses.

 

It is proposed that these  protective properties  reflect the activity of a system of  ‘fail-safe-mechanisms’, evolved to protect, maintain and stabilize function,  limit cell injury,  and facilitate recovery – (in the critical event of an altered cell [ATP]), associated with a very low (brain) ionized free cell Magnesium [Mg++] level  (of the order of 0.2-0.25mmol/l)-  as unless some other factor(s) intervenes, below a certain level of low-cell free [Mg++], hundreds of [Mg++] dependent systems, (including  aspects reliant on Mg++ for structural reasons), appear at risk of collapsing or grinding to a halt.

 

The model predicts that there must exist systems that protect cells alongside a critically low-cell [Mg++] contingency- and that these form the basis of Lithium’s mode of action.

 

Magnesium has powerful anti-oxidant, anti-necrotic and anti-apoptotic effects, Mg++ is itself broadly cyto-protective; cardio- and neuro-protective- against a wide range of insults.

 

The loss of cell-protection following the challenge of a significant drop in cell free [Mg++] concentration- (even if such a decrease were not associated with the probability of occurring alongside other adverse factors), would force the need for compensatory, or specialized cell-protection.

 

It is proposed that the mood-stabilizing and the protective effects of Lithium are a consequence of Lithium and/or a low cell [Mg++], progressively activating a usually ‘dormant’ set of latent cellular ‘fail-safe’ protection/ repair systems. By displacing Mg++ ions at certain critical sites- in effect Lithium ‘imitates’, mimics a ‘ lowered intracellular [Mg++] level’.

 

The significance of Lithium’s actions needs to be re-interpreted; given the Mg++ requirements- (in the milli-molar), physiological range of key members of an important family of enzymes. The IMPase, Inositol-1-Phosphatase, acted on by Li+ belongs to a group of Magnesium-dependent, and Lithium-sensitive Phosphatases; this ‘family’ includes Inositol Polyphosphate 1-Phosphatase (IPPase), Fructose-1, 6-bisphosphatase, and  Bisphosphate Nucleotidase,  Li+ also inhibits the structurally unrelated  Phosphoglucomutase.

 

These enzymes are all sensitive to Li+, and require Mg++, in relevant concentrations.

It is proposed that these enzymes, plus GSK-3,  provides the core of these specialised ‘fail-safe’ sub-mechanisms- mobilized- as ionised free cell Magnesium [Mg++] drops below the system’s activation threshold- determined by the relevant enzymes’ kinetics, but which are incidentally further co-activated by Lithium; as it is proposed, Li+, by competing with Mg++ ‘mimics’ the effects of a ‘lowered-cell [Mg++] level’.

 

The paper discusses these individual mechanisms and the role of these various enzymes, and their apparent role after head injury.

 

Inositol-depletion and  ‘inositol-phosphate-enhancement’ (and ‘sugar-phosphate-enhancement’), emerge as cooperative, semi-independent sub-mechanisms.

 

The Fail- Safe model 

The ‘fail-safe-model’ postulates the existence of a set of pre-programmed  biochemical responses- adapted to provide protection against mechanical trauma, brain injury; involving the activation of pathways sensitive to a low-free cell [Mg++], these  appear to be ‘parasitically’ utilised by Lithium to generate its therapeutic effects. These systems would also appear to provide latent protection and resilience to cells generally; this may also be relevant to cell survival in cancer, and perhaps other states of altered cell [ATP]?

 

The Magnesium Abyss; the signaling and limiting of Traumatic Brain Injury (T.B.I.).

It has been shown by Vink et al (1,2), that in rodents, brain mean cell  [Mg ++] drops 50-60%, from 0.6 mmol/l to  0.25- 0.3 mmol/l following brain injury- the mechanism of this remains somewhat mysterious. The decline in local [Mg++] is limited to the injury zone, this reduction in the cell Mg++ concentration was thought to be a specific indicator of cell damage, in all species and in all brain damage models; cell free [Mg++] concentration dropped by 40- to 60 %. [Mg++] this drop in intracellular [Mg++] seems to be a ubiquitous feature of brain injury, whatever the cause.

 

Such a drop in the context of cell damage is highly paradoxical– as the electrochemical equilibrium potential for cellular free [Mg++] is much higher.

 

T.b.i. does not appear to need to involve any actual brain ischemia, it involves a complex, multi-facetted metabolic crisis- with a reduction of Oxidative metabolism, thought to be due to a Ca++ mediated impairment of mitochondrial respiratory function, a short lived increase in glucose utilization, low Oxygen extraction, increased lactate production, a tendency to induce secondary cytokine release etc., Mild head-injury is difficult to avoid- there is evidence it occurs even with ‘normal’ birth.

 

It is not known how intracellular [Mg++] drops so precipitously after t.b.i, what might bind an increased proportion of Mg++, under these special metabolic circumstances? As one of the main Mg++ binding agents is ATP, (and the ATP concentration is expected to drop after this type of event (see 82), and hence tend to permit an increase in ionized free cell Magnesium; the depletion of cellular ATP- by anoxia or other mechanisms, removing a large amount of ATP related – Mg++-chelation usually results in an increase in intracellular [Mg++]. Yet, paradoxically, post t.b.i., for reasons (previously) less than entirely clear, the cell [Mg++] drops to a low basal level during these critical conditions.

 

Phosphoribosyl Pyrophosphate; A key linking molecule 

Depletion of cell ATP can result in a remarkable increase in PRibosePP  in some circumstances- an 80 fold increase. PRPP synthase is subject to complex regulation, sensitive to Pi and [Mg++].  Pi appears to be one key modulator of PRPP synthase in vivo . Phosphoribosyl Pyrophosphate, is also a Mg++ chelating agent.  Its structure suggests it is a likely important further substrate for the IMPase.

 

It is postulated that the main effects of Lithium on mood are mediated by mimicking the effect of a lower cell [Mg++]- thus sending an amplified cellular ‘distress signal’- this helps compensate for any modest increase in IMPase numbers, providing overall increased cell protection, including increased Mg++ and Ca++buffering and stabilization, in the longer term- the restoration and bolstering of brain cell [Mg++] and correction of IMPase numbers, perhaps helping restore longer term cell energetics by optimizing ATP levels and the ATP-Mg++/Pi ratio. Phosphate compounds can form chelates with Mg++, and excess Mg++ ions- in proportion to Phosphate or ATP, may reduce cellular energetic efficiency, this might be relevant to weight-gain- often seen on Lithium.

 

A key concept is that Lithium may be (particularly adapted to) acting in a low [Mg++] environment- as well as being congruent with the rationale for the proposed mechanism, removes some of the apparent paradoxes; it would require less stimulation to set up, or maintain InsP enhancement/Ins-depletion. In cells with a low [Mg++], as well as a greater limitation of GSK-3, Lithium would have a  greater effect on the IMPase; it would provide additional potential chelation-buffering for both Ca++ and Mg++, trap more Pi, and further limit inositol availability, and limit signaling, (as originally proposed) via limiting PKC and DAG- and by clamping cell [Mg++] and [Ca++] also clamping TRPM7 channels, and at times potentially limiting [Pi], at times, potentially limiting ATP levels; which actions dominate would vary with the phase of the Mood Disorder.

 

The existence of a proposed ‘low- cell [Mg++]’, ’fail-safe’- ‘cell-protection-system’ helps to diffuse  the  paradoxes and  limitations of the original ‘Inositol-depletion’ model; Lithium’s actions, rather than being some unexplained coincidence- can now be understood as reflecting actions on a set of ‘low-cell [Mg++]’, t.b.i., mechanical shock and mood related, cell survival mechanisms.

 

When considering how Lithium works we should consider the effects of what happens when cell [Mg++] levels shift, which is comparable to what happens when Li+ is added- the situation, par-excellence when cell [Mg++] levels severely drop, e.g., post t.b.i.

 

In examining the consequences of the accretion of inositol-Phosphate (and/or)  other PPP- including glutathione metabolism related, sugar-Phosphate type substrates; it represents a comprehensive, more understandable model, related to cell damage- limitation. The characteristics and kinetics of the IMPase, IPPase and GSK-3 enzymes match the proposed model perfectly.

 

The central concept is that the therapeutic effects of Lithium occur indirectly, as a consequence of activating a cascade of pre-existing, fail-safe pathways:  configured to activate- in an evolutionary context, against ‘unavoidable’ perinatal- head-injury insults- as (brain) cell free [Mg++] drops; these are also activated by Li+, as Lithium mimics a lowered intracellular free [Mg++] level.

 

These pathways appear to act by multi-levelled, multifaceted  sub-mechanisms; it is proposed- including the buffering- limiting of cell Mg++ and cell Ca++, and at times- by appearing to limit [Pi], and thus at those times limiting the potential for excess [ATP] formation. Lithium would only become required if the system is perturbed beyond its normal working limits; the system would still operate in the absence of Li+.

 

Adding Li+ extends, enhances the resilience, and boosts the degree of protection that the proposed innate mood-stabilizing system can provide. The enzyme kinetics suggests that if turnover is rapid, with normal IMPase numbers, low-cell [Mg++] levels can potentially drive inositol-depletion and ‘InsPhosphate-enhancement’; particularly if there are additional IMPase (co)-substrates present.

 

The function of the proposed system is to enable the cell to survive metabolic crisis conditions- associated with an altered- particularly a significantly lowered cell [Mg++].             

Lithium treatment would reinforce pre-existing low-cell [Mg++], and t.b.i. related mechanisms- permitting highly physiological responses; further explaining the lack of effect of Li+ in normal individuals, and Lithium’s often apparent remarkable specificity and potency.

 

The system that emerges employs various sub-components:- Ins-Depletion/InsP- enhancement, Pi, PPi, depletion, the potential role of other substrates (Gal-P, Fructose-P etc.), Mg++/Ca++/metal Chelation, InsP-Mg++- ATP interactions, PPP-Gal-P, product interactions, Ca++ PKC interactions, inhibition of PIP2 requiring TRPM7 ion channels, zinc, GSK, Adenylate  Cyclase, G-protein interactions, possible effects on autophagy,  and protein folding, the potential binding of other regulatory or toxic metal ions, and indirect anti-oxidant effects, etc.

 

The proposed mechanisms explain how and also why Lithium works, and why it can work so well. The proposed ‘fail-safe-mechanisms’ provide a set of ‘pre-existing’ pathways- for low-cell [Mg++], and for Li+ action.

 

Excess IMPase numbers may undermine aspects of the mechanism determining the innate resilience to mood disorders. The key to Lithium’s mode of action is that it activates latent systems of cell-protection; configured to protect against conditions of abnormal intracellular [Mg++].

 

The existence of pre-programmed- adaptive responses to conditions associated with a low intracellular free [Mg++] may have masked the true impact of the lack of systemic Mg++; this may help explain why various forms of ‘Metabolic Disorders’ appear prevalent alongside the more common psychiatric Disorders.

 

The corresponding mode of action of the other major mood stabilizers, CBZ and Valproate, and the role of the other individual key enzymes are discussed.

 

References:

1) Vink, R, McIntosh TK, Demendiuk P, et al.  Decline in intracellular free magnesium concentration is associated with irreversible tissue injury following brain trauma. J. Biol. Chemistry. 1988; 263: 757 – 761.

2) Vink, R, Cook NL, van den Heuvel C, Magnesium in acute and chronic brain injury:  An update. Magnesium Research, 2009; 22(3): 158S-162S