Lithium

Lithium Chloride inhibits Proteasome 26S

Several studies show that LiCl inhibits 26S:

LiCl alone, or in combination with all-trans-retinoic acid, increased cellular levels of ubiquitinated retinoic acid receptor α and markedly reduced chymotryptic-like activity of WEHI-3B D+ 20 S and 26 S proteasome enzymes. (R1)

LiCl interacts synergistically with all-trans-retinoic acid, promoting the terminal differentiation of WEHI-3B D(+) cells, a phenomenon partially due to the ability of the monovalent lithium cation to inhibit the proteasome-dependent degradation of retinoic acid receptor alpha protein. In this report, the 20S proteasome was purified from WEHI-3B D(+) cells and the effects of LiCl on chymotrypsin-like (Chtl) activity and peptidyl-glutamyl peptide hydrolyzing (PGPH) activity were determined. LiCl functions to inactivate both proteasomal activities in a time-dependent manner, without affecting non-proteasomal proteases. The half-lives for inactivation of Chtl and PGPH hydrolyzing activities were approximately 23 and 36min, respectively, at 10mM LiCl. … The findings suggest that the inactivation of Chtl and PGPH activities by LiCl occurs through a proteasomal conformational change. (R2)

However another study reports somewhat conflicting (or confusing) finding:

Lithium is also a potent inhibitor of glycogen synthase kinase-3β (GSK3β) activity, which is linked to Alzheimer’s disease (AD). In experiments with cultured HEK293T cells, we show here that GSK3β stabilizes synaptic acetylcholinesterase (AChE-S), a critical component of AD development.

Cells treated with lithium exhibited rapid proteasomal degradation of AChE-S. Furthermore treatment of the cells with MG132, an inhibitor of the 26S proteasome, prevented the destabilizing effect of lithium on AChE-S. (R3)

Prevents degradation of Retinoic Acid Receptor alpha

Lithium inhibits proteasome, which prevents RARA from degradation:

LiCl interacts synergistically with all-trans-retinoic acid, promoting the terminal differentiation of WEHI-3B D(+) cells, a phenomenon partially due to the ability of the monovalent lithium cation to inhibit the proteasome-dependent degradation of retinoic acid receptor alpha protein. (R4)

Inhibits GSK3b, stabilizes beta-catenin and upregulates PIMT

These results demonstrated regulation of PIMT expression by lithium at both the transcriptional and the translational levels. Additionally, inhibition by siRNA of GSK-3 and beta-catenin modulated the expression of the PIMT in accordance with GSK-3 pharmacological inhibition. Valproic acid, an antiepileptic drug with mood-stabilizing properties, up-regulated phospho-GSK-3beta (Ser9), beta-catenin and PIMT levels similarly to lithium. (R5)

Accumulation can cause hyperreflexia

Thus, recent advances seem to show that the benefits of lithium extend beyond just the treatment of mood. Neuroprotection against excitotoxicity or brain damage is another role of lithium.

However, in contrast, several reports have presented that a high dose of lithium could induce irreversible neurotoxicity effects.

Excessive intake or impaired excretion could result in lithium accumulation. Lithium is mainly susceptible to accumulation in bone, muscle, liver, thyroid, and kidney.

Dehydration, febrile illness, or gastrointestinal loss can lead to elevated lithium levels in serum.

Renal toxicity is more common in patients on chronic lithium therapy with nephrogenic diabetes insipidus. The neurologic effects are hyperreflexia, nystagmus, or ataxia and remain mostly reversible.

Other troubles are reversible cardiovascular effects (QT prolongation, intraventricular conduction defects), gastrointestinal effects, and endocrine effects. But, low doses of lithium are correlated with lower side-effects. (R6)