Experimental data on lithium salts: From neuroprotection to multi-organ complications

Folic acid supplementation improved cognitive deficits associated with lithium administration during pregnancy in rat offspring

“…Considering that lithium is the first priority in the treatment of bipolar disorder on one hand, and severe adverse effects due to its narrow therapeutic index in addition to free protein binding that result in equal equilibrium plasma concentration between mothers and foetuses on the other hand, the present study was designed to assess the prenatal effect of lithium on neonates, and folic acid as preventive treatment at three different doses was used. Based on the results, the administration of folic acid with a high dose of lithium improved both behavioural and biochemical test results (Kakhki & Ahmadi‐Soleimani, 2022). Surprisingly, folic acid alone also improved some behavioural results, including OF and increased the level of antioxidant and interleukin‐10 as an anti‐inflammatory agent over oxidative stress and pro‐inflammatory cytokines.…”

“…After that, they were allocated into eight groups ( n = 15 rats/group), including vehicle received regular tap water; the second group received PTU (propylthiouracil, 0.05%) dissolved in drinking water as the hypothyroidism group, two other groups were treated with 15 and 30 mg/kg of lithium in the form of lithium carbonate dissolved in daily drinking water and the fifth, sixth and seventh groups were treated with lithium at dose of 30 mg/kg with three different doses of folic acid (as a protective agent) including 5, 10 and 15 mg/kg to assess its effect on the anticipated defects, and the last group received only the highest dose of folic acid (15 mg/kg) to investigate the effect of folic acid in comparison with vehicle. All doses used in the present study were considered according to previous studies (Budni et al, 2012; Canever et al, 2018; Kakhki & Ahmadi‐Soleimani, 2022; Van Deun et al, 2021).…”

“…Lithium salts have been clinically used for a long time as a mood‐stabilizing or adjunctive treatment in attenuation of recurrent major depression as well as psychotropic medication in particular for treatment of acute or recurrent phases of bipolar disorder (Kakhki & Ahmadi‐Soleimani, 2022; Machado‐Vieira et al, 2009; Sani et al, 2017). Although a great deal of new fields of lithium have been recently discovered, which are more likely mediated through the inhibition of two main signalling pathways including glycogen synthase kinase‐3 and protein kinase C, both of which are involved in neurodevelopment as well (Kirshenboim et al, 2004; Vallée et al, 2021).…”

“…In fact, there are numerous evidences associated with the neuroprotective effects of lithium via increasing neurogenesis and decreasing apoptotic process mediated by activation of endogenous neural progenitor cells, by which explore new ways for treatment of neurodegenerative or ischaemic brain diseases such as Alzheimer's, Parkinson's and Down syndrome (Ferensztajn‐Rochowiak & Rybakowski, 2016; Manji et al, 2000; Zanni et al, 2015). Despite the positive effect of lithium, there are numerous studies associated with the deleterious effect of lithium on embryos (Fornaro et al, 2020; Jacobson et al, 1992), particularly in the first trimester of pregnancy leads to disruption in cell differentiation, which results in dangerous adverse effects on vital organs including the thyroid gland, brain and cardiovascular system which are more likely attributed to the mechanism described above (Diav‐Citrin et al, 2014; Kakhki & Ahmadi‐Soleimani, 2022; Viguera et al, 2007). Indeed, these adverse effects caused by lithium depend on various factors such as prescribed dosage, concentration and usage duration, but the maturation status is addressed by numerous literature as a more important factor, which means that exposure to lithium in the early stage of embryo development can cause more defects.…”

“…Further, several clinical and animal studies have been conducted with increased congenital malformation like Ebstein's anomaly, intrauterine growth restriction and neonatal toxicity in those who take lithium in pregnancy especially first trimester (Conover, 1994; Cott & Wisner, 2003; Običan & Scialli, 2011). It is worthy to note that both positive and negative impacts of lithium are attributed to the inhibition of glycogen synthase kinase‐3 (Kakhki & Ahmadi‐Soleimani, 2022). However, according to some studies, multiple vital organ dysfunction in neonates whose mothers were exposed to lithium related to hypothyroidism caused by lithium (Silva et al, 2014).…”