Lithium – therapeutic tool endowed with multiple beneficiary effects caused by multiple mechanisms

Vošahlíková, Miroslava; Svoboda, Petr

doi:10.21307/ane-2017-001

Cited by 37 publications

(45 citation statements)

References 194 publications

(281 reference statements)

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“…Therefore, patients at risk for stroke with unfortunate collateral status (thus portending poor outcome) could particularly profit from a lithium treatment at low concentrations via a generally improved endothelium-dependent vessel relaxation capacity. This might be speculative, but on the other hand, the lithium-augmented cerebrovascular relaxation capacity may party explain, why continuous lithium treatment can reduce the risk for stroke (Lan et al, 2015) or may improve neurologic recovery after cortical stroke (Mohammadianinejad et al, 2014) potentially caused by various beneficiary effects on neurons (Doeppner et al, 2016; Vosahlikova and Svoboda, 2016), or platelets (Barry et al, 2003) including the direct ones on vascular and cerebrovascular endothelium (Afsharimani et al, 2007; Rahimzadeh-Rofouyi et al, 2007; Bosche et al, 2013, 2016), as presented here. Directly or secondarily impaired endothelial barrier after ischemia and hemorrhages followed by vasogenic edema formation (Stokum et al, 2016) were known to be highly relevant for clinical outcome of various types of stroke (Hacke et al, 1996; Bosche et al, 2003; Macdonald, 2014; Wijdicks et al, 2014; Urday et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Safe therapeutic concentrations of lithium are typically below 1 mol/L in these patients (Geddes and Miklowitz, 2013; Yatham et al, 2013; Mohammad and Osser, 2014). In preclinical and clinical research, lithium was recognized for robust neuroprotective effects regarding various pathologic conditions (Vo et al, 2015; Doeppner et al, 2016; Vosahlikova and Svoboda, 2016). Recent studies have also identified protective effects of lithium in cardiovascular and cerebrovascular diseases (Gold et al, 2011; Chiu and Chuang, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

et al. 2016

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Lithium at serum concentrations up to 1 mmol/L has been used in patients suffering from bipolar disorder for decades and has recently been shown to reduce the risk for ischemic stroke in these patients. The risk for stroke and thromboembolism depend not only on cerebral but also on general endothelial function and health; the entire endothelium as an organ is therefore pathophysiologically relevant. Regardless, the knowledge about the direct impact of lithium on endothelial function remains poor. We conducted an experimental study using lithium as pharmacologic pretreatment for murine, porcine and human vascular endothelium. We predominantly investigated endothelial vasorelaxation capacities in addition to human basal and dynamic (thrombin-/PAR-1 receptor agonist-impaired) barrier functioning including myosin light chain (MLC) phosphorylation (MLC-P). Low-dose therapeutic lithium concentrations (0.4 mmol/L) significantly augment the cholinergic endothelium-dependent vasorelaxation capacities of cerebral and thoracic arteries, independently of central and autonomic nerve system influences. Similar concentrations of lithium (0.2–0.4 mmol/L) significantly stabilized the dynamic thrombin-induced and PAR-1 receptor agonist-induced permeability of human endothelium, while even the basal permeability appeared to be stabilized. The lithium-attenuated dynamic permeability was mediated by a reduced endothelial MLC-P known to be followed by a lessening of endothelial cell contraction and paracellular gap formation. The well-known lithium-associated inhibition of inositol monophosphatase/glycogen synthase kinase-3-β signaling-pathways involving intracellular calcium concentrations in neurons seems to similarly occur in endothelial cells, too, but with different down-stream effects such as MLC-P reduction. This is the first study discovering low-dose lithium as a drug directly stabilizing human endothelium and ubiquitously augmenting cholinergic endothelium-mediated vasorelaxation. Our findings have translational and potentially clinical impact on cardiovascular and cerebrovascular disease associated with inflammation explaining why lithium can reduce, e.g., the risk for stroke. However, further clinical studies are warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

et al. 2016

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“…Транспорт лития через клеточные мембраны. Литий может входить в клетку несколькими способами, наиболее частый -пассивный транспорт через потенциал-зависимые (voltage-gated class) и потенциал-независимые натриевые каналы (non-voltage-gated epithelial class) [20,36,45]. Проницаемость потенциал-зависимых натриевых каналов примерно одинакова для ионов Na + и Li + [45].…”

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“…Литий может входить в клетку несколькими способами, наиболее частый -пассивный транспорт через потенциал-зависимые (voltage-gated class) и потенциал-независимые натриевые каналы (non-voltage-gated epithelial class) [20,36,45]. Проницаемость потенциал-зависимых натриевых каналов примерно одинакова для ионов Na + и Li + [45]. При этом ионный радиус негидратированного лития (0,68 Å) близок к размеру негидратированного магния (0,65 Å), что объясняет конкуренцию между этими ионами в Mg 2+ -зависимых ферментах и опосредует основные биологические эффекты лития [7,13,31,45].…”

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Lithium Salts in Experimental Oncology (Review)

2019

SSMJ

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В последние годы соли лития рассматривают как потенциальные соединения для таргетной терапии, способные замедлить рост опухоли. Имеется большое количество публикаций, свидетельствующих об эффектах лития на сигнальные пути, используемые опухолевыми клетками для роста и развития, и продемонстрировавших возможность его применения в качестве противоопухолевого агента в экспериментальной онкологии. Перспективность применения солей лития для разработки противоопухолевых препаратов связана с тем, что Li имеет две основные внутриклеточные мишени: киназу гликогенсинтазы 3β (glycogen synthase kinase 3β, GSK-3β) и инозитолмонофосфатазу (inositol monophosphatase, IMPase), ингибирование которых может индуцировать гибель раковой клетки путем апоптоза или аутофагии. Показано, что литий вызывает остановку пролиферации опухолевых клеток за счет ареста клеточного цикла в фазе G 2 /M, а также стимулирует апоптоз и влияет на развитие аутофагии в опухолевых клетках. В данном обзоре обобщены данные о транспорте лития через клеточные мембраны, охарактеризованы его основные внутриклеточные мишени и представлены результаты исследований, в которых литий применялся в экспериментальной терапии рака различной локализации с акцентом на сигнальные пути, влияющие на рост и метастазирование опухолевых клеток.

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“…In addition to those natural products, the salt ionic compound, Lithium chloride, is also known to be beneficial. It is currently used in the treatment for bipolar disorder (Vosahlikova and Svoboda, 2016) and has been shown to increase lifespan of C. elegans (McColl et al, 2008). Lithium chloride has even been correlated with longevity in humans (Zarse et al, 2011).…”

Section: Pharmacological Studies Of Agingmentioning

confidence: 99%

Optimizing Pharmacological Lifespan Extension

Chao

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Lithium – therapeutic tool endowed with multiple beneficiary effects caused by multiple mechanisms

Cited by 37 publications

References 194 publications

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

Lithium Salts in Experimental Oncology (Review)

Optimizing Pharmacological Lifespan Extension

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