Lithium toxicology: Effect of isotopic composition on lethality and behavior

Alexander, George J.; Lieberman, K.W.; Okamoto, Michiko; Stokes, Peter E.; Triana, E.

doi:10.1016/0091-3057(82)90238-6

Cited by 8 publications

(7 citation statements)

References 3 publications

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“…5 nitrergic, glutamatergic and GABA-ergic systems in acute lithium toxicity. Clinical signs in rats received lithium at toxic dose, were observed similar to the signs seen in mice (Alexander et al, 1982). According to the results obtained, some drugs used for the pre-treatments, intensified these signs in rats intoxicated with lithium.…”

Section: Discussionsupporting

confidence: 62%

Nitrergic, glutamatergic and gabaergic systems in lithium toxicity

et al. 2012

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-We examined the role of nitrergic, glutamatergic and gamma-aminobutyric acid (GABA)-ergic systems in the mechanism(s) underlying lithium induced acute toxicity. With this aim, lithium (18 mEq/kg, i.p.) intoxicated rats were observed for 3 hr recording their clinical signs and death. Lithium exposure at the dose used produced central nervous system (CNS) depression. Pre-treatment of N w -nitro-L-arginine methyl ester (L-NAME) a nonselective nitric oxide synthase inhibitor (10 mg/kg, i.p.), 7-nitroindazole (7-NI) a selective neuronal nitric oxide synthase inhibitor (25 mg/kg, i.p.), nitric oxide precursor L-arginine (1,000 mg/kg, i.p.) and MK-801 a noncompetitive antagonist of N-methyl-D-aspartic acid class of glutamate receptors (0.5 mg/kg, i.p.) all increased CNS depression and mortality in lithium group however, no change was seen in GABA receptor agonist GABA (1,000 mg/kg, i.p.) or D-arginine (1,000 mg/kg, i.p.) a biologically inactive enantiomer of L-arginine pre-treated rats. Glutamic acid decarboxylase (GAD) enzyme activity was measured in hippocampus, cerebral cortex and cerebellum of the different groups of animals. GAD enzyme activity reduced in cerebral cortex but not altered in hippocampus or cerebellum by lithium as compared to the control (saline) group. We conclude that an interaction with nitrergic and glutamatergic systems may have a role in the acute toxicity of lithium in rats.The inhibition of glutamate metabolism may arise from this interaction and the involvement of GABA-ergic system should be further investigated in this toxicity.

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Section: Discussionsupporting

confidence: 62%

Nitrergic, glutamatergic and gabaergic systems in lithium toxicity

et al. 2012

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“…It is of interest that 6 Li and natural Li, which contains about 93% 7 Li, showed no difference in their potency for inducing neuroprotection and neurotoxic effects. 6 Li and 7 Li have been shown to have a signi®cant difference in their NMR spectra (Riddell 1991), rate of intracellular uptake (Sherman et al 1984), lethality dose (Alexander et al 1982), and potency to inhibit inositol monophosphatase (Sherman et al 1984). 6 Li and 7 Li were found in a subsequent study, however, not to differ in the latter two properties (Parthasarathy et al 1992).…”

Section: Discussionmentioning

confidence: 94%

“…6 Li and 7 Li have been shown to have a significant difference in their NMR spectra (Riddell 1991), rate of intracellular uptake (Sherman et al . 1984), lethality dose (Alexander et al . 1982), and potency to inhibit inositol monophosphatase (Sherman et al .…”

Section: Discussionmentioning

confidence: 99%

Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation

Hashimoto

Hough

Nakazawa

et al. 2002

Journal of Neurochemistry

293

185

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The therapeutic mechanisms of lithium for treating bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults. Here, we studied neuroprotective effects of lithium against excitotoxicity in cultured cerebral cortical neurons. Glutamate-induced excitotoxicity in cortical neurons was exclusively mediated by NMDA receptors. Pre-treatment of cortical neurons with LiCl time-dependently suppressed excitotoxicity with maximal protection after 6 days of pretreatment. Signi®cant protection was observed at the therapeutic and subtherapeutic concentration of 0.2±1.6 mM LiCl with almost complete protection at 1 mM. Neuroprotection was also elicited by valproate, another major mood-stabilizer. The neuroprotective effects of lithium coincided with inhibition of NMDA receptor-mediated calcium in¯ux. Lithium pre-treatment did not alter total protein levels of NR1, NR2A and NR2B subunits of NMDA receptors. However, it did markedly reduce the level of NR2B phosphorylation at Tyr1472 and this was temporally associated with its neuroprotective effect. Because NR2B tyrosine phosphorylation has been positively correlated with NMDA receptor-mediated synaptic activity and excitotoxicity, the suppression of NR2B phosphorylation by lithium is likely to result in the inactivation of NMDA receptors and contributes to neuroprotection against excitotoxicity. This action could also be relevant to its clinical ef®cacy for bipolar patients. Keywords: bipolar disorder, excitotoxicity, lithium, neuroprotection, NMDA receptor, phosphorylation. Lithium has been one of the primary drugs used to treat bipolar mood disorder as it was introduced into psychiatry over half a century ago. The therapeutic effect of lithium requires long-term treatment, occurs at a narrow dose-range and is not immediately reversed after discontinuation of the drug. The therapeutic mechanisms of lithium are still unclear; however, some prominent molecular and cellular actions of this drug have been identi®ed. These include its ability to inhibit key intracellular signaling kinases and phosphatases such as glycogen synthase kinase-3 and inositol monophosphatase and to affect transcriptional activity and gene expression (for review see Jope 1999; Manji and Lenox 2000;Phiel and Klein 2001). However, it remains unclear as to whether these actions are related to the clinical ef®cacy of this drug, especially considering that many of these effects are acute and occur at supratherapeutic dose ranges.

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“…These results indicate that activation of Wnt/β‐catenin signaling pathway in HVFs of POP women can increase the production of collagen I. It should be noted that lithium chloride has many side effects, such as hypoactivity, intense perspiration, and diarrhea 22 . Therefore, lithium chloride should be used carefully.…”

Section: Discussionmentioning

confidence: 91%

“…It should be noted that lithium chloride has many side effects, such as hypoactivity, intense perspiration, and diarrhea. 22 Therefore, lithium chloride should be used carefully. We can reasonably speculate that in the future, we could treat or reduce the severity of POP or prevent POP by activating Wnt/β-catenin signaling pathway of fibroblasts in pelvic floor supporting tissue.…”

Section: Discussionmentioning

confidence: 99%

Effects of the decrease of β‐catenin expression on human vaginal fibroblasts of women with pelvic organ prolapse

Gong

Yang

Jin

et al. 2021

J of Obstet and Gynaecol

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Background Pelvic organ prolapse (POP) lowers the quality of life in elderly women, and there have been no studies on its role in the pathogenesis of POP. The purpose of this study is to investigate the effect of β‐catenin on proliferation and collagen anabolism in human vaginal fibroblasts (HVFs). Materials and Methods The adherence and differential adherence methods were used to culture and purify HVFs. RNA interference was applied to knockdown β‐catenin and lithium chloride was used to activate Wnt/β‐catenin signaling pathway. β‐catenin nuclear translocation was tested by immunofluorescence, and HVF proliferation was detected by performing MTT assays. Results The expression of β‐catenin, phosphorylated‐β‐catenin, phosphorylated‐glycogen synthase kinase 3β (p‐GSK3β), collagen I, matrix metalloproteinase 2 (MMP2), and tissue‐derived inhibitors of metalloproteinases 2 (TIMP2) was assessed by western blot analysis. The expression of β‐catenin and collagen I was lower in HVFs of POP group than that of control group. The proliferation rate of HVFs in POP group was lower than that in control group. Knockdown of β‐catenin decreased the cell proliferation rate and the expression of collagen I. Lithium chloride can activate the Wnt/β‐catenin signaling pathway. Conclusion β‐catenin participates in the proliferation and collagen I synthesis of HVFs. The decrease of β‐catenin expression may be closely related to the occurrence, and development of POP. LiCl can activate the Wnt/β‐catenin signaling pathway in HVFs and thus increase HVFs proliferation and collagen synthesis.

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Lithium toxicology: Effect of isotopic composition on lethality and behavior

Cited by 8 publications

References 3 publications

Nitrergic, glutamatergic and gabaergic systems in lithium toxicity

Nitrergic, glutamatergic and gabaergic systems in lithium toxicity

Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation

Effects of the decrease of β‐catenin expression on human vaginal fibroblasts of women with pelvic organ prolapse

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