Administration Of LiCl Research Articles

The contributory role of GSK3β in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway.

Atherosclerosis is closely related to endothelial dysfunction and hypertension. GSK3β is a critical regulator in atherosclerosis. This study was carried out to investigate the effects of GSK3β on hypertension exacerbating atherosclerosis in vitro and in vivo. L-NAME + HFD-ApoE-/- mice were used for this study for 12 weeks, and their endothelial dysfunction and inflammation were analyzed. Oil red O and H&E staining revealed that treatment with LiCl, an inhibitor of GSK3β, reduced atherosclerotic lesions and lipid accumulation. The levels of lipid homeostasis and oxidation stress were attenuated following LiCl administration. LiCl-treated ApoE-/- mice showed lowered blood pressure. LiCl also suppressed the expressions of Drp1, Bax, ICAM1, VCAM1 and TNF-α compared to HFD + L-NAME induced mice and oxLDL + L-NAME-treated Human aorta endothelial cell line(HAECs). LiCl treatment increased the expressions of MFN2 and Bcl2. Mitotracker-red, MitoSOX and JC-1 staining indicated that LiCl treatment reduced mitochondrial division and ROS production, increased mitochondrial ΔΨm compared to oxLDL + L-NAME-treated HAECs. The expression of OMA1 was decreased by LiCl treatment, while PGC1α expression was increased. In HAECs, we found that OMA1 knockdown increased mitochondrial function and the expression of PGC1α. We also demonstrated LiCl increased OMA1 ubiquitination compared with the Control group, thus decreased OMA1 expression. Furthermore, siOMA1 antagonized the increased protein expressions of ICAM1, VCAM1, TNF-α, Bax and Drp1, decreased the protein expressions of Bcl2 and MFN2 by siPGC1α. Taken together, we demonstrated that GSK3β could play a contributory role in hypertension exacerbating atherosclerosis by regulating the OMA1/PGC1α pathway and inhibiting mitochondrial function.

Chronic Lithium Treatment Alters NMDA and AMPA Receptor Synaptic Availability and Dendritic Spine Organization in the Rat Hippocampus.

The mechanisms underlying the action of lithium (LiCl) in bipolar disorder (BD) are still far from being completely understood. Previous evidence has revealed that BD is characterized by glutamate hyperexcitability, suggesting that LiCl may act, at least partially, by toning down glutamatergic signaling abnormalities. In this study, taking advantage of western blot and confocal microscopy, we used a combination of integrative molecular and morphological approaches in rats exposed to repeated administration of LiCl at a therapeutic dose (between 0.6 and 1.2 mmol/l) and sacrificed at two different time points, i.e., 24 hours and 7 days after the last exposure. We report that repeated LiCl treatment activates multiple, parallel, but also converging forms of compensatory neuroplasticity related to glutamatergic signaling. More specifically, LiCl promoted a wave of neuroplasticity in the hippocampus, involving the synaptic recruitment of GluN2A-containing NMDA receptors, GluA1-containing AMPA receptors, and the neurotrophin BDNF that are indicative of a more plastic spine. The latter is evidenced by morphological analyses showing changes in dendritic spine morphology, such as increased length and head diameter of such spines. These changes may counteract the potentially negative extra-synaptic movements of GluN2B-containing NMDA receptors as well as the increase in the formation of GluA2-lacking Ca2+-permeable AMPA receptors. Our findings highlight a previously unknown cohesive picture of the glutamatergic implications of LiCl action that persist long after the end of its administration, revealing for the first time a profound and persistent reorganization of the glutamatergic postsynaptic density receptor composition and structure.

Effects of an ethanol-paired conditioned stimulus on responding for ethanol suppressed by a conditioned-taste-aversion

Ethanol-Paired Conditioned Stimuli (CS) can increase ethanol-responding either in extinction or occurring at low rates late in a session. To examine the generality of CS-induced increases in ethanol-responding, we examined whether a CS could increase responding suppressed by Conditioned-Taste-Aversion (CTA), which presumably suppresses responding by changing ethanol's valence from positive to negative. Rats were trained to respond for ethanol under a Random Interval (RI) schedule. We then removed the lever and paired Random-Time ethanol deliveries with illumination of a stimulus light (i.e., CS) for 10 sessions. Results were compared with a Truly Random Control group, in which the light and ethanol deliveries occurred independently. In a subsequent experiment, rats were treated similarly, except the light served as a discriminative stimulus, as the lever was extended and ethanol deliveries were available under a RI during light presentations. After this training, the lever was returned and rats again responded for ethanol. Subsequently, sessions were followed by LiCl administration. When responding reached low levels, LiCl administration stopped and the light was occasionally illuminated during the session. Responding during the light presentation was compared to responding during the period preceding light presentation. Responding partially recovered across 10 sessions and was greater during light presentations than in the period before it in all three groups. Increases were not reliably different between the groups, indicating that explanations for these increases such as CS-induced increases in motivation or approach toward the light are unlikely to be correct. The most likely explanation for these light-induced increases is that during sessions in which the light had been presented previously, LiCl had never been presented and thus, the light had come to signal that ethanol was safe to drink.

Effects of different doses of lithium on the central nervous system in the rat valproic acid model of autism

Epidemiological studies have shown that low doses of lithium in the environment can have beneficial effects on mental health. Autism spectrum disorder, a neurodevelopmental disorder in which patients exhibit abnormal behaviors, pharmacological interventions usually relied on a range of psychotropic medications. However, such medications often produce severe side effects or are ineffective in symptoms. Finding alternative ways to improve abnormal behaviors in individuals with autism are warranted, in which case lithium may be a relatively safe and effective medication. Lithium salt therapy is used to treat a variety of neuropsychiatric disorders and has neuroprotective effects. In this study, we investigated the effects of different doses of lithium on neurobehavioural disorders using the rat model of autism established by valproic acid (VPA) injection. Lithium was observed to have an ameliorative effect on the social cognitive, social memory and anxiety levels in the rat model of autism. Immunofluorescence staining showed that subchronic LiCl administration (1.0 mmol/kg) significantly reduced the number of Iba-1 positive cells in the CA1 region of the hippocampus in VPA group and brought it close to the levels of control group. Significantly lower levels of the pro-inflammatory marker IL-6 were observed in the hippocampus and serum after lithium treatment. In addition, the lithium treatment increased the levels of H3K9 acetylation in the hippocampus of VPA-exposed rats. The results showed a defensive effect of environment-related lithium exposure doses on neurobehavioural deficits in the rat valproic acid model of autism, suggesting that it may be a potential drug for the treatment of autism.

Oral administration of lithium chloride ameliorate spinal cord injury-induced hyperalgesia in male rats

BackgroundNumerous studies have described the neuroprotective effect of lithium in spinal cord injury in addition to its ameliorative impact on pain sensation. In the present study, we aim to examine the efficacy of 85 mg/kg as well as 50 mg/kg dosage of the lithium chloride (LiCl) through oral consumption in spinal cord injured rats and their effect on gene expression of three candidate genes, corresponding to the hyper-sensitization. MethodsAdult Wistar (male) rats were divided into four experimental groups: control; oral administration of LiCl with 85 mg/kg and 50 mg/kg dosage; and 10 % sucrose receiver as the vehicle. BBB and heat plantar tests were performed weekly throughout four weeks to evaluate motor improvement and neuropathic pain amelioration, i.e., the alleviation in hyperalgesia. Then, the expression pattern of Kcnd2, ERK and Gria2 genes were assessed. ResultsThe BBB results demonstrated that LiCl with both dosages does not allow remarkable improvement in motor function during four weeks of treatment. The heat plantar tests show substantial recovery in LiCl treated groups versus vehicle and control after four weeks of evaluation. According to Real-time PCR, Kcnd2 and Gria2 were up-regulated in the presence of lithium in a dose-dependent manner while ERK expression was not differed remarkably. ConclusionOur results suggested that LiCl allows hyperalgesia palliation, however, did not reinforce persistent motor improvement. Also, oral lithium consumption with 50 mg/kg concentration, entails considerable restoration in gene expression level of Kcnd2 and Gria2.

Effect of Sirtuin-1 and Wnt/β-Catenin Signaling Pathway in Rat Model of Spinal Cord Injury.

Sirtuin-1 (SIRT1) has anti-inflammatory and antioxidant effects and has been reported to be involved in spinal cord injury (SCI). Wnt/β-catenin signal has been shown to play a critical role in the pathogenesis of chronic diseases, and it participated in the recovery of nerve function after SCI. However, the specific link between them in SCI is unclear. In addition, targeting posttraumatic astrocyte apoptosis is crucial for improving neural degeneration and locomotor function. Therefore, in this article, we studied the relationship of β-catenin and SIRT1 using in the SCI rat model and primary astrocyte treated with hydrogen peroxide (H2O2) or lithium chloride (LiCl). Results showed that after SCI, SCI area and motor function recover over time, and β-catenin is gradually increased to the seventh day and then in turn decreases until 4 weeks, positively correlated with cell apoptosis. The expression of SIRT1 and downstream FOXO4 gradually increased, and β-catenin is negatively correlated with SIRT1 expression. Moreover, treatment with H2O2 in primary cultured astrocyte significantly increased β-catenin and Caspase-3 expression, while decreased SIRT1 and Forkhead box O- (FOXO-) 4. The immunofluorescence results are consistent with this. Administration of LiCl further aggravates the above results. These findings suggest that SIRT1 is negatively correlated with β-catenin in SCI, which promotes the apoptosis of motor neuron cells, which may be related to the participation of FOXO4.

Lithium reduces orthodontically induced root resorption by suppressing cell death, hyalinization, and odontoclast formation in rats.

To examine whether lithium suppresses orthodontically induced root resorption (OIRR) via two mechanisms (prevention of hyalinization in periodontal tissue and suppression of odontoclasts) and to investigate the changes in the periodontal tissue and alveolar bone, focusing on the appearance of cell death, hyalinization, and odontoclasts. The maxillary first molars of 10-week-old male Wistar rats were moved mesially by a closed-coil spring for 14 days. Lithium chloride (LiCl; 0.64 mM/kg) or saline (control) was administered intraperitoneally daily. Tooth movements were measured using micro-computed tomography. Appearances of cell death, hyalinization, and odontoclasts were evaluated by histological analysis. OIRR observed on day 14 in the control group was suppressed strongly by LiCl administration. Apoptotic cells observed on day 1 in the compression area were gradually diminished on days 2 and 3 and transformed to hyalinization tissue in the control group. LiCl administration remarkably suppressed this cell death and subsequent hyalinization. Also, the appearance of odontoclasts in the compression area observed on day 7 was significantly suppressed by LiCl administration. Accordingly, these degenerative processes to OIRR were suppressed substantially by LiCl treatment. Lithium reduces OIRR through the suppression of periodontal ligament cell death, hyalinization, and odontoclast formation.

Citronellal alleviates doxorubicin-induced cardiotoxicity by suppressing oxidative stress and apoptosis via Na+ /H+ exchanger-1 inhibition.

The medical usage of Doxorubicin (DOX) as a chemotherapeutic agent is restricted owing to its cardiotoxic properties. This study was designed to explore the effect and underlying mechanisms of Citronellal (CT) on DOX-related cardiotoxicity in rats. Rats were divided into six groups: control, DOX, CT, Lithium chloride (LiCl) (a Na+/H+exchanger-1 [NHE1] activator), DOX + CT, and DOX + CT + LiCl. To induce cardiotoxicity, a cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats. CT (150 mg/kg) and LiCl (1 mg/kg) were given daily by oral gavage for 6 weeks. CT improved cardiac functional parameters and attenuated the cardiac pathological changes induced by DOX. Further study indicated that CT administration regulated the levels of oxidative stress and apoptosis-related factors and in myocardial tissues, reducing cell per-oxidative damage and apoptosis. Besides this, CT attenuated DOX-induced NHE1 upregulation, and the preventive effects of CT against DOX-induced cardiotoxicity were abrogated by the concurrent administration of LiCl. These results demonstrate that CT could ameliorate DOX-induced cardiotoxicity by inhibiting the NHE1-mediated oxidative stress, apoptosis in rats.

Lithium dilution cardiac output measurements in isoflurane-anaesthetised goats: Jugular versus cephalic lithium chloride administration

The administration of lithium chloride (LiCl) for cardiac output (CO) measurement via a peripheral instead of a central vein has been described previously as a valid alternative route in pigs and dogs. The aim of the study was to compare CO measurements after administration of LiCl using two peripheral veins, cephalic or jugular, in goats. Ten adult, female, experimental goats undergoing bilateral stifle arthrotomy were recruited for the study. Paired CO measurements were taken two minutes apart during stable conditions in isoflurane-anaesthetised goats. Forty-two paired CO measurements were taken in total, and the median (range) of paired CO measurement per goat were 4.5 (3–6). The mean (SD) CO using the cephalic and jugular vein for injection of LiCl was 5.28 (1.29) L min−1 and 5.20 (1.24) L min−1 respectively. The Bland-Altman analysis showed an acceptable agreement with a mean bias of 1.33% with limits of agreement (LoA) of −18.43 to 21.09%. The percentage of error was 25%. The four-quadrant plot analysis showed a poor agreement (71%) between the two routes. The polar plot showed a poor trending ability. An 86% inclusion rate (18/21 points) was reached with a ± 35° radial sector size. The findings revealed that the agreement between the two routes is not as precise as the authors expected, however the results are comparable with studies published previously.

Maternal LiCl exposure disrupts thyroid-cerebral axis in neonatal albino rats.

This work aimed to elucidate whether maternal lithium chloride (LiCl) exposure disturbs the thyroid-cerebral axis in neonatal albino rats. 50 mg of LiCl/kg b.wt. is orally given for pregnant Wistar rats from gestational day (GD) 1 to lactation day (LD) 28. The maternal administration of LiCl induced follicular dilatation and degeneration, hyperplasia, lumen obliteration and colloid vacuolation in the maternal and neonatal thyroid gland at postnatal days (PNDs) 14, 21 and 28. Neuronal degeneration (spongiform), gliosis, nuclear pyknosis, perivascular oedema, and meningeal hyperaemia were observed in the neonatal cerebral cortex of the maternal LiCl-treated group at examined PNDs. This disturbance appears to depend on intensification in the neonatal cerebral malondialdehyde (MDA), nitric oxide (NO), and hydrogen peroxide (H2 O2 ) levels, and attenuation in the glutathione (GSH), total thiol (t-SH), catalase (CAT), and superoxide dismutase (SOD) levels. In the neonatal cerebrum, the fold change in the relative mRNA expression of deiodinases (DII and DIII) increased significantly at PNDs 21 and 14, respectively, in the maternal LiCl-treated group. These data suggest that maternal LiCl may perturb the thyroid-cerebrum axis generating neonatal neurodevelopmental disorder.

Maintenance of conditioned place avoidance induced by gastric malaise requires NMDA activity within the ventral hippocampus.

It has been reported that during chemotherapy treatment, some patients can experience nausea before pharmacological administration, suggesting that contextual stimuli are associated with the nauseating effects. There are attempts to reproduce with animal models the conditions under which this phenomenon is observed to provide a useful paradigm for studying contextual aversion learning and the brain structures involved. This manuscript assessed the hippocampus involvement in acquiring and maintaining long-term conditioned place avoidance (CPA) induced by a gastric malaise-inducing agent, LiCl. Our results demonstrate that a reliable induction of CPA is possible after one acquisition trial. However, CPA establishment requires a 20-min confinement in the compartment associated with LiCl administration. Interestingly, both hippocampal regions seem to be necessary for CPA establishment; nonetheless, inactivation of the ventral hippocampus results in a reversion of avoidance and turns it into preference. Moreover, we demonstrate that activation of dorsal/ventral hippocampal NMDA receptors after CS–US association is required for long-term CPA memory maintenance.

Floralozone protects endothelial function in atherosclerosis by ameliorating NHE1.

Endothelial dysfunction is the pathological basis of atherosclerosis. Incomplete understanding of endothelial dysfunction etiology has impeded drug development for this devastating disease despite the currently available therapies. Floralozone, an aroma flavor, specifically exists in rabbit ear grass. Recently, floralozone has been demonstrated to inhibit atherosclerosis, but the underlying mechanisms are undefined. The present study was undertaken to explore whether floralozone pharmacologically targets endothelial dysfunction and therefore exerts therapeutic effects on atherosclerosis. The Na+/H+ exchanger 1 (NHE1), a channel protein, plays a vital role in atherosclerosis. Whether NHE1 is involved in the therapeutic effects of floralozone on endothelial dysfunction has yet to be further answered. By performing oil red staining and hematoxylin-eosin staining, vascular functional study, and oxidative stress monitoring, we found that floralozone not only reduced the size of carotid atherosclerotic plaque but also prevented endothelial dysfunction in atherosclerotic rats. NHE1 expression was upregulated in the inner membrane of carotid arteries and H2O2-induced primary rat aortic endothelial cells. Inspiringly, floralozone prevented the upregulation of NHE1 in vivo and in vitro. Notably, the administration of NHE1 activator LiCl significantly weakened the protective effect of floralozone on endothelial dysfunction in vivo and in vitro. Our study demonstrated that floralozone exerted its protective effect on endothelial dysfunction in atherosclerosis by ameliorating NHE1. NHE1 maybe a drug target for the treatment of atherosclerosis, and floralozone may be an effective drug to meet the urgent needs of atherosclerosis patients by dampening NHE1.

The intervention of intestinal Wnt/β-catenin pathway alters inflammation and disease severity of CIA.

Autoreactive T cell is one of the leading causes of immunological tolerance defects in the chronic inflammatory lesions of rheumatoid arthritis (RA). There have been several extracellular signals and intracellular pathways reported in regulating this process but largely remain unknown yet. In this study, we explored the roles of intestinal Wnt/β-catenin on disease severity during collagen-induced arthritis model (CIA), an animal model of RA. We first testified the activity pattern Wnt/β-catenin shifted by intragastric administration of LiCl and DKK-1 in the intestine by real-time PCR and WB analysis. The arthritis scores showing the disease severity in the DKK-1 group was significantly ameliorated compared with the control group at the late stage of the disease, while in the LiCl group, the scores were significantly elevated which was consistent with pathology score analysis of H&E staining. Next, ELISA was performed and showed that TNF-α and IL-17 in the LiCl group were significantly higher than that of the control group. IL-10 in the DKK-1 group was significantly higher than that in the LiCl-1 group and control group, P < 0.05. Flow cytometry of spleen T cells differentiation ratio showed that: Th1 from the DKK-1 and LiCl groups and Th17 from the LiCl group was significantly different from that of the blank model group, P < 0.05. Finally, we explored the effects of intestinal Wnt/β-catenin on T cell differentiation regulator ROR-γt and TCF1 and found that both transcription factors were up-regulated in the LiCl group. Together, these data suggested the pro-information role of Wnt/β-catenin pathway from the intestine in the CIA mouse, implying its use as a potential therapeutic target for the treatment of inflammatory diseases such as RA.

Cortical neurochemical signaling of gustatory stimuli and their visceral consequences during the acquisition and consolidation of taste aversion memory

The insular cortex (IC) has a crucial role in taste recognition memory, including conditioned taste aversion (CTA). CTA is a learning paradigm in which a novel taste stimulus (CS) is associated with gastric malaise (US), inducing aversion to the CS in future encounters. The role of the IC in CTA memory formation has been extensively studied. However, the functional significance of neurotransmitter release during the presentation of taste stimuli and gastric malaise-inducing agents remains unclear. Using microdialysis in free-moving animals, we evaluated simultaneous changes in glutamate, norepinephrine and dopamine release in response to the presentation of an innate appetitive or aversive gustatory novel stimulus, as well as after i.p. administration of isotonic or hypertonic gastric malaise-inducing solutions. Our results demonstrate that the presentation of novel stimuli, regardless of their innate valence, induces an elevation of norepinephrine and dopamine. Administration of a gastric malaise inducing agent (LiCl) promotes an elevation of glutamate regardless of its concentration. In comparison, norepinephrine release is related to the LiCl concentration and its equimolar NaCl control. Additionally, we evaluated their functional role on short and long-term taste aversion memory. Results indicate that the blockade of noradrenergic β1,2 receptors in the IC spares CTA acquisition and memory consolidation. In contrast, blockade of dopamine D1/D5 receptors impaired CTA consolidation, whereas the NMDA receptor blockade impedes both acquisition and consolidation of CTA. These results suggest that dopaminergic and noradrenergic release are related to the salience of conditioned taste stimuli. However, only cortical D1/D5 dopaminergic activity, but not the noradrenergic β1,2 activity, is involved in the acquisition and consolidation of taste memory formation. Additionally, glutamatergic activity signals visceral distress caused by LiCl administration and activates NMDA receptors necessary for the acquisition and consolidation of long-lasting taste aversion memory.

Lithium chloride represses abdominal aortic aneurysm via regulating GSK3β/SIRT1/NF-κB signaling pathway

Lithium chloride (LiCl), a pharmacological compound, was effective in reducing inflammation, but whether it can protect against abdominal aortic aneurysm (AAA) is largely unknown. This study is designed to investigate therapeutic effects of LiCl on AAA and the potential mechanism. Rat AAA models were induced by periaortic application of CaCl2. AAA rats were treated by daily intraperitoneal injection of LiCl or vehicle alone to study the protection effects of LiCl in vivo. Rat primary vascular smooth muscle cells (VSMCs) stimulated with tumor necrosis factor (TNF)-α served as an in vitro model. LiCl treatment prevented the development of AAA through inhibiting the inflammatory cells infiltration and inflammatory cytokines overproduction, as well as attenuating superoxide production and elastin degradation in aorta of AAA rats. Additionally, the downregulation of p-GSK3β(Ser9) and SIRT1, upregulation of NF-κB(p-65), MMP-2 and MMP-9 in AAA were abolished by LiCl treatment. In vitro by upregulating p-GSK3β(Ser9), LiCl significantly induced SIRT1 expression, along with inhibition of the NF-κB activation and decreased elastin level elicited in VSMCs by TNF-α stimulation. SIRT1 activator SRT1720 achieved similar repressive effects as LiCl on TNF-α-induced NF-κB activation and decreased elastin in VSMCs. Moreover, administration of LiCl also caused regression of established rats AAA. This study provided the first evidence that LiCl prevented the development of AAA through inhibiting inflammation, MMPs, and superoxide production, and facilitating the biosynthesis of elastin. The beneficial effect of LiCl may be mediated by regulation GSK3β/SIRT1/NF-κB cascade.

Small Molecule Inhibitors of Microenvironmental Wnt/β-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia.

Simple SummaryConsidering the pivotal role of Wnt/β-catenin signaling in AML development and persistence, the current study addresses in AML, the prognostic value of Wnt/β-catenin signaling molecules and the anti-leukemic value of Wnt/β-catenin inhibition. In silico analysis of RNAseq data from AML patients and flow cytometric analysis of primary AML samples revealed that higher levels of Wnt/β-catenin pathway is a poor prognostic marker. Next, we found that pharmacological interference, through small molecule inhibitors of Wnt and/or GSK-3 signaling reduces AML cell survival by sensitizing the leukemia cells to chemotherapeutic agents both in vitro and in vivo. Overall, our findings suggested that Wnt-inhibitory therapy could overcome the prognostic significance of patient risk stratification, standing as a therapeutic response for all subgroups of AML.Wnt/β-catenin signaling has been reported in Acute Myeloid leukemia, but little is known about its significance as a prognostic biomarker and drug target. In this study, we first evaluated the correlation between expression levels of Wnt molecules and clinical outcome. Then, we studied—in vitro and in vivo—the anti-leukemic value of combinatorial treatment between Wnt inhibitors and classic anti-leukemia drugs. Higher levels of β-catenin, Ser675-phospho-β-catenin and GSK-3α (total and Ser 9) were found in AML cells from intermediate or poor risk patients; nevertheless, patients presenting high activity of Wnt/β-catenin displayed shorter progression-free survival (PFS) according to univariate analysis. In vitro, many pharmacological inhibitors of Wnt signalling, i.e., LRP6 (Niclosamide), GSK-3 (LiCl, AR-A014418), and TCF/LEF (PNU-74654) but not Porcupine (IWP-2), significantly reduced proliferation and improved the drug sensitivity of AML cells cultured alone or in the presence of bone marrow stromal cells. In vivo, PNU-74654, Niclosamide and LiCl administration significantly reduced the bone marrow leukemic burden acting synergistically with Ara-C, thus improving mouse survival. Overall, our study demonstrates the antileukemic role of Wnt/β-catenin inhibition that may represent a potential new therapeutics strategy in AML.

Maternal lithium chloride exposure alters the neuroendocrine-cytokine axis in neonatal albino rats.

The aim of this work was to clarify whether maternal lithium chloride (LiCl) exposure disrupts the neonatal neuroendocrine-cytokine axis. Pregnant Wistar rats were orally administrated 50mg LiCl/kg b.wt. from gestational day (GD) 1 to postpartum day 28. Maternal administration of LiCl induced a hypothyroid state in both dams and their neonates compared to the control dams and neonates at lactation days (LDs) 14, 21 and 28, where the levels of serum free triiodothyronine (FT3) and free thyroxin (FT4) were decreased and the level of serum thyrotropin (TSH) level was increased. A noticeable depression in maternal body weight gain, neonatal body weight and neonatal serum growth hormone (GH) was observed on all examined postnatal days (PNDs; 14, 21 and 28). A single abortion case was recorded at GD 17, and three dead neonates were noted at birth in the LiCl-treated group. Maternal administration of LiCl disturbed the levels of neonatal serum tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interleukin-1 beta (IL-1β), interferon-gamma (INF-γ), leptin, adiponectin and resistin at all tested PNDs compared to the control group. This administration produced a stimulatory action on the level of neonatal cerebral serotonin (5-HT) at PND 14 and on the level of neonatal cerebral norepinephrine (NE) at PNDs 21 and 28. However, this administration produced an inhibitory action on the level of neonatal cerebral dopamine (DA) at all examined PNDs and on the level of neonatal cerebral NE at PND 14 and the level of neonatal cerebral 5-HT at PNDs 21 and 28 compared to the corresponding control group. Thus, maternal LiCl exposure-induced hypothyroidism disrupts the neonatal neuroendocrine-cytokine system, which delay cerebral development.

Nitric oxide and glutamate are contributors of anti-seizure activity of rubidium chloride: A comparison with lithium

The neuro-protective effects of rubidium and lithium as alkali metals have been reported for different central nervous system dysfunctions including mania and depression. The aim of this study was evaluating as well as comparing the effects of rubidium chloride (RbCl) and lithium chloride (LiCl) on different seizures paradigms in mice and determining the involvement of NMDA receptors and nitrergic pathway.To assess the seizures threshold, animals received intravenous pentylenetetrazole (PTZ, 0.5%; 1 mL/min). Male NMRI mice (6–8 weeks) received intraperitoneal (i.p.) injections of different doses of RbCl and LiCl. Doses greater than 10 mg/kg of RbCl showed a significant anticonvulsant activity 60 min after administration; the anticonvulsant effects of LiCl was observed at the doses more than 5 mg/kg and after 30 min in PTZ-induced seizure threshold. But, RbCl (10, 20 mg/kg, i.p) or LiCl (5, 10 mg/kg, i.p) injection did not induce protection against maximal electroshock (MES) or intraperitoneal injection of PTZ lethal dose (80 mg/kg)-induced seizure models.Pre-treatment with L-NAME (non-selective nitric oxide synthase (NOS) inhibitor, 10 mg/kg; i.p.) and 7-nitroindazole (selective neuronal NOS inhibitor, 30 mg/kg; i.p.) enhanced the anticonvulsive effects of both RbCl (5 mg/kg, i.p.) and LiCl (1 mg/kg, i.p.) in PTZ-induced seizure threshold model. Injection of MK-801 (NMDA receptor antagonist, 0.05 mg/kg; i.p.) before RbCl (5 mg/kg, i.p.; P < 0.001) and LiCl (1 mg/kg, i.p.; P < 0.001) administration increased the anti-seizure activity. But, treatment with L-arginine (precursor of nitric oxide, 100 mg/kg; i.p.) decreased the seizure threshold of both RbCl (20 mg/kg, i.p.; P < 0.001) and LiCl (10 mg/kg, i.p.; P < 0.001). Measurement of nitrite levels in hippocampus of animals revealed a remarkable reduction after treatment with RbCl (20 mg/kg, i.p; P < 0.05) and LiCl (10 mg/kg, i.p; P < 0.01).To conclude, rubidium may protect central nervous system against seizures in PTZ-induced seizures threshold model through NMDA/nitrergic pathways with a similarity to lithium effects in mice.

Ameliorative effect of lithium chloride against d-galactose induced behavioral and memory impairment, oxidative stress and alteration in serotonin function in rats.

Aging is a phenomenon that all living organisms surely face. d-galactose (D-gal) has been used to develop an aging model of brain. Lithium (Li) has been proposed to have neuroprotective properties in relation to several neurological disorders. The goal of the current studyis to evaluate the effect of Lithium Chloride (LiCl) on D-gal induced neurological disorders and oxidative stress. Rats were treated with D-gal at a dose of 300 mg/ml/kg and various doses of LiCl (20, 40 and 80 mg/ml/kg) for 14 days. After that behavioral analysis (Elevated plus maze (EPM); Light dark box test (LDT); Morris water maze (MWM); Forced swim test (FST)) were performed. Animals were decapitated after behavioral tests and brain samples were collected for biochemical (malondialdehyde (MDA); superoxide dismutase (SOD); catalase (CAT); glutathione peroxidase (GPx); acetylcholiesterase (AChE)) and neurochemical analysis (5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA)). The results showed that administration of LiCl at all doses ameliorates D-gal induced, decreased time spent in the open arm and light box in EPM and LDT respectively, increased immobility in FST, increased latency escape in MWM, increased MDA levels, decreased antioxidant enzyme, increased AChE activity and decreased 5-HT metabolism. In conclusion, the present study indicated that D-gal induced anxiety/depression like symptoms and memory impairment were ameliorated by LiCl (at all doses) possibly via its antioxidant effects and normalizing 5-HT function.

Role of NHE3 and dietary phosphate in lithium pharmacokinetics

Lithium (Li+) is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, Li+ has been used to determine proximal tubule (PT) reabsorption based on the assumption that Li+ and Na+ transport go in parallel in the PT. However, the exact mechanism by which Li+ is reabsorbed remains elusive. The majority of PT Na+ reabsorption is directly or indirectly mediated by the Na+‐H+ exchanger 3 (NHE3). In addition, Na+‐phosphate cotransporters (Npt2a/c) have been implicated in renal Li+ reabsorption. We hypothesized that either NHE3 and/or Npt2a/c are mediating Li+ reabsorption. We studied Li+ pharmacokinetics in: i) tubule‐specific NHE3 knockout mice (NHE3loxloxPax8Cre), and ii) mice challenged with low or high phosphate diets. Intravenous (LiCl 5 mmol/kg, 2 μl/g BW) or oral administration (5 mmol/kg, 1% of BW via oral gavage) of LiCl did not result in differences in Li+ bioavailability (~80% in all groups), half‐life or urinary Li+/creatinine ratios between control and NHE3loxloxPax8Cre mice. After one week of dietary phosphate challenges, Li+ bioavailability was ~30% lower on low vs high dietary phosphate (64±4 vs 93±3%, P&lt;0.05), possibly the consequence of a smaller area under the curve after oral administration (21±1 vs 25±1 mmol × L−1 × h, P&lt;0.05). This was associated with lower urinary Li+/creatinine ratios on low vs high dietary phosphate (15±2 vs 47±7 mmol/mmol, P&lt;0.05). Our data indicate that renal NHE3 does not play a role in Li+ pharmacokinetics; however, dietary phosphate has an indirect effect on Li+ bioavailability and Li+ disposition.Support or Funding InformationTR is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK110621). JX was supported by an American Heart Association Predoctoral Fellowship (18PRE33990236) and LT by a Postdoctoral Fellowship (19POST34400026).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.