Novel mechanism of action for the mood stabilizer lithium

Abstract

Background Bipolar Disorder (BD) is associated with a decrease in cellular resilience. Despite the half a century old discovery of lithium's efficacy for the treatment of BD, its exact mechanisms remain elusive. Accumulating data suggest that lithium's cytoprotective properties involve the modulation of several UPR proteins, such as GRP78. Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is an endoplasmic reticulum resident protein that regulates proteostasis through directly interacting with GRP78. The purpose of this study was to determine whether lithium increases MANF expression using cellular and rodent models and, if so, to elucidate the cellular mechanisms of action. Procedure Mouse striatal neuroblasts were treated with PBS, lithium, or lithium + Activator Protein‐1 (AP‐1) inhibitor for 24–72 hours. Once cells were harvested, mRNA was extracted. In vivo experiments included, intraperitoneal injections of lithium or saline to male Sprague Dawley rats twice daily for 14 consecutive days. Following drug treatment, brain tissue was isolated, and mRNA was extracted from various regions. MANF gene expression was measured using RT‐qPCR. Results In vitro studies showed lithium‐treated cells displayed a significant increase in MANF mRNA expression compared to controls. In contrast, cells treated with lithium and AP‐1 inhibitor showed no increase in expression. Similarly, in vivo studies revealed that lithium‐treated rats compared to controls had a significant increase in MANF expression in the PFC and striatum. Conclusion Taken together, these data suggest that lithium's therapeutic mechanism involves the maintenance of ER homeostasis via increased MANF gene expression mediated by the AP‐1 transcription factor.

Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis inC. elegans

“…One of these involves treating animals with bioactive compounds such as curcumin and lithium. Recently, these two chemicals were reported to increase manf transcription in mammalian cells [27, 28]. Similar experiments in worms also showed increased manf-1 levels, albeit only modestly (SKBT, unpublished).…”

“…One of these involves treating animals with bioactive compounds such as curcumin and lithium. Recently, these two chemicals were reported to increase manf transcription in mammalian cells [27,28].…”

“…To test this hypothesis, we took different approaches to activate in vivo expression of manf-1. One of these included treating animals to bioactive compounds curcumin and lithium that, similar to studies in mammalian systems (Abu-Hijleh et al 2020), increased manf-1 levels but only modestly (Taylor and Gupta, in prep). Other approaches involved generating two different transgenic strains, one of which (hsp::manf-1) contained manf-1 cDNA under the control of a heat shock promoter and the other (manf-1p::manf-1::mCherry) carried manf-1 genomic DNA along with the endogenous promoter (see Methods).…”

The impact of quetiapine monotherapy or in combination with lithium on the thyroid function in patients with bipolar depression: A retrospective study

“…Quetiapine is an atypical antipsychotic drug that can antagonize the activity of dopamine D2 receptor and serotonin 5‐HT2A receptor, 22 while lithium is a commonly used mood stabilizer that inhibits the abnormal release of norepinephrine and dopamine 23 by maintaining the homeostasis of endoplasmic reticulum in the cerebral cortex and striatum. 24 Quetiapine can compete with thyroid hormones to bind UDP‐glucuronosyltransferase transferase, resulting in decreased thyroid hormone sensitivity. 14 Lithium could inhibit the release of thyroid hormone via alteration in tubulin polymerization as well as inhibition of the action of TSH on cyclic adenosine monophosphate, 17 thus resulting in thyroid function changes.…”