Administration Of Lithium Chloride Research Articles

Paraventricular oxytocin neurons impact energy intake and expenditure: projections to the bed nucleus of the stria terminalis reduce sucrose consumption

BackgroundThe part played by oxytocin and oxytocin neurons in the regulation of food intake is controversial. There is much pharmacological data to support a role for oxytocin notably in regulating sugar consumption, however, several recent experiments have questioned the importance of oxytocin neurons themselves.MethodsHere we use a combination of histological and chemogenetic techniques to investigate the selective activation or inhibition of oxytocin neurons in the hypothalamic paraventricular nucleus (OxtPVH). We then identify a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis using the cell-selective expression of channel rhodopsin.ResultsOxtPVH neurons increase their expression of cFos after both physiological (fast-induced re-feeding or oral lipid) and pharmacological (systemic administration of cholecystokinin or lithium chloride) anorectic signals. Chemogenetic activation of OxtPVH neurons is sufficient to decrease free-feeding in OxtCre:hM3Dq mice, while inhibition in OxtCre:hM4Di mice attenuates the response to administration of cholecystokinin. Activation of OxtPVH neurons also increases energy expenditure and core-body temperature, without a significant effect on locomotor activity. Finally, the selective, optogenetic stimulation of a pathway from OxtPVH neurons to the bed nucleus of the stria terminalis reduces the consumption of sucrose.ConclusionOur results support a role for oxytocin neurons in the regulation of whole-body metabolism, including a modulatory action on food intake and energy expenditure. Furthermore, we demonstrate that the pathway from OxtPVH neurons to the bed nucleus of the stria terminalis can regulate sugar consumption.

Patterns of ingestion of rats during chronic oral administration of lithium chloride

Chronic lithium administration to rodents is used to explore the potential neural mechanisms of mood stabilization, as well as to model the side effects of chronic lithium on multiple organ systems. Oral administration of lithium in the maintenance diet or drinking water is convenient, but lithium can acutely affect intake and it can mediate acquisition of conditioned taste aversions (CTA). We compared ad libitum food and fluid intake by male rats with LiCl or NaCl solutions as their sole source of fluid across 20 days, with a commonly used dosage of LiCl (24 mM: 1 g / L LiCl). To quantify the pattern of intake, rats were housed in cages equipped with lickometers to detect licks and infrared photobeams to detect food access with 6-s resolution. To determine if rats formed a CTA to LiCl, they were subsequently tested with access to NaCl. Rats showed an immediate avoidance of the LiCl solution, as seen on the first day of access by an increased latency to initiate drinking and a decreased size of drinking bouts. Rats showed a differential response to LiCl vs. NaCl after as few as 5 licks. Chronic consumption of LiCl solution led to significantly decreased food and fluid intake compared to baseline, with concomitant weight loss. The decreased intake was realized by marked changes in the pattern of drinking and feeding bouts: a decrease in per-lick volume and a decrease in licks per drinking bout, and an increase in feeding bout duration resulting in an overall decrease in eating rate. Conversely, chronic NaCl access led to an increase in drinking bout number and licks/bout. The avoidance of LiCl was likely a combination of toxic effects of ingested LiCl and rapid acquisition of a learned aversion to the taste of LiCl, as shown by an extinguishable generalized aversion to NaCl solution during subsequent NaCl test days. The marked effect of chronic oral LiCl on ingestion may impact the oral dosing of lithium as well as the rat's metabolic status.

Identification of genes responsible for the social skill in the earthworm, Eudrilus eugeniae

Social abilities are an essential factor in our normal life. Many disorders are associated with social abilities. The molecular depth of social abilities is still obscure. In water, the earthworms form a self-assemblage which is a social ability of the earthworm. The brain amputees regenerate their brain in eight days and they lack the social ability and fail to establish self-assemblage. In the present study, we harnessed the earthworm, Eudrilus eugeniae as a model to understand the molecular depth of social ability using their behaviour of self-assemblage. We show that the administration of lithium chloride in the brain amputee restored the ability of self assemblage. Total mRNA sequencing by Ion torrent sequencing platform identified the differentially regulated social skill responsive genes of the brain and nerve cords in the control worm vs 2nd & 3rd-day regenerating worms with and without Lithium chloride injection. Functional annotation and bioinformatics data analysis showed that 899 brain-specific genes are expressed in the nerve cord upon LiCl injection. Of them, 227 genes are autism-linked. Since G-quadruplexes have a role in neurological disorders we have scanned G-quadruplexes in the draft genome and transcriptome. Found 53 transcripts triggered during LiCl treatment. Future experiments in the worm could lead to a functional depth of the socially responsible genes.

Lithium Attenuates Graft-Versus-Host Disease Via Effects on the Intestinal Stem Cell Niche

Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy for the majority of hematological malignancies but is limited by graft-versus-host disease (GVHD) and opportunistic infections. Severe acute GVHD in the gastrointestinal (GI) tract is a major determinant of mortality and causes progressive epithelial and crypt loss leading to denudation of intestinal mucosa. Since the current approaches to prevent severe GVHD to date focus on the immune suppression of T cells with calcineurin inhibitors, anti-metabolites or alkylating agents, therapeutic strategies that protect intestinal epithelium from immune injury represents an attractive alternative approach. The renewal of intestinal stem cells (ISC) and their progeny, intestinal epithelial cells (IEC), is critical for the maintenance of gut integrity after transplantation. Multiple signaling pathways including WNT-β-Catenin signaling regulate this process. Lithium inhibits glycogen synthase kinase-3 (GSK-3), a pluripotent kinase that antagonizes WNT signaling, resulting in cellular proliferation and epithelial regeneration. In a clinical pilot study conducted at Fred Hutchinson Cancer Research Center (FHCRC) and the University of Washington, twenty patients with steroid-refractory gut GVHD and mucosal denudation at endoscopy were treated with oral lithium carbonate in addition to second line therapy. Ten of the 20 patients (50 %) had a complete remission, and 7 (35 %) survived more than 2 years 1. These results were encouraging since only 10% of the patients with steroid-refractory stage 3-4 intestinal GVHD at FHCRC survived for more than 2-years historically1. We thus investigated the activity of lithium in gastrointestinal GVHD in preclinical models. The administration of oral lithium chloride (LiCl) from 2 days before HCT to day 7 after T cell-replete HCT (B6 donors → B6D2F1 recipients) significantly decreased the GVHD-related mucosal injury in the ileum (pathology score: 7.4 ± 0.6 in control vs 4.6 ± 0.6 in LiCl (mean ± sem), p = 0.0049) but not the colon (13.4 ± 0.5 in control vs 12.4 ± 0.9 in LiCl, p > 0.05). We undertook multispectral immunofluorescence analysis in a second BALB/c → B6 system where recipient ISC were marked by Lgr5-driven GFP. LiCl significantly increased the frequency of Paneth cells (6.14 ± 0.4 % in control vs 15.0 ± 1.5 % in LiCl (mean ± sem), p = 0.0031) and their antimicrobial lysozyme content (% cytoplasm occupancy: 61.1 ± 0.7 % in control vs 65.0 ± 0.8 % in LiCl (mean ± sem), p = 0.0055). Lgr5+ ISCs in the ileum were not quantitatively different at this early timepoint. Given that Paneth cells are primarily distributed in the small intestine rather than the colon, these data explain the protection from GVHD afforded by LiCl in the ileum but not the colon. Since ISC regeneration is ultimately essential to repair severe ulceration of the epithelium, we examined the renewal of ISC at later timepoints. Compared to the vehicle control, LiCl treatment significantly increased the percentage of Lgr5+ ISCs (2.33 ± 0.2 % in control vs 4.80 ± 0.6 % in LiCl (mean ± sem), p = 0.0129) in the ileum on day 10. LiCl did not alter the frequencies of CD4+ and CD8+ T cells infiltrating the ileum. These findings suggest that LiCl exerts a protective effect in GVHD by promoting Paneth cell function and subsequent ISC regeneration. Our findings provide further rationale for studies of GSK inhibition, direct WNT activation, and other agents such as IL-22 and IL-28 that provide support of the ISC niche during GVHD, as a complement to immune suppression. Reference:Steinbach G, Hockenbery DM, Huls G, et al. Pilot study of lithium to restore intestinal barrier function in severe graft-versus-host disease. PloS one. 2017;12(8):e0183284.

Lithium promotes long-term neurological recovery after spinal cord injury in mice by enhancing neuronal survival, gray and white matter remodeling, and long-distance axonal regeneration.

Spinal cord injury (SCI) induces neurological deficits associated with long-term functional impairments. Since the current treatments remain ineffective, novel therapeutic options are needed. Besides its effect on bipolar mood disorder, lithium was reported to have neuroprotective activity in different neurodegenerative conditions, including SCI. In SCI, the effects of lithium on long-term neurological recovery and neuroplasticity have not been assessed. We herein investigated the effects of intraperitoneally administered lithium chloride (LiCl) on motor coordination recovery, electromyography (EMG) responses, histopathological injury and remodeling, and axonal plasticity in mice exposed to spinal cord transection. At a dose of 0.2, but not 2.0 mmol/kg, LiCl enhanced motor coordination and locomotor activity starting at 28 days post-injury (dpi), as assessed by a set of behavioral tests. Following electrical stimulation proximal to the hemitransection, LiCl at 0.2 mmol/kg decreased the latency and increased the amplitude of EMG responses in the denervated hindlimb at 56 dpi. Functional recovery was associated with reduced gray and white matter atrophy rostral and caudal to the hemitransection, increased neuronal survival and reduced astrogliosis in the dorsal and ventral horns caudal to the hemitransection, and increased regeneration of long-distance axons proximal and distal to the lesion site in mice receiving 0.2 mmol/kg, but not 2 mmol/kg LiCl, as assessed by histochemical and immunohistochemical studies combined with anterograde tract tracing. Our results indicate that LiCl induces long-term neurological recovery and neuroplasticity following SCI.

Gender Difference in Lithium-Induced Sodium Current Dysregulation and Ventricular Arrhythmogenesis in Right Ventricular Outflow Tract Cardiomyocytes.

Lithium intoxication induces Brugada-pattern ECG, ventricular arrhythmia, and sudden death with the predominant preference for the male over the female gender. This study investigated the mechanisms of gender difference in lithium-induced arrhythmogenesis. The ECG parameters were recorded in male and female rabbits before and after the intravenous administration of lithium chloride (LiCl) (1, 3, 10 mmol/kg). Patch clamps were used to study the sodium current (INa) and late sodium current (INa-late) in the isolated single male and female right ventricular outflow tract (RVOT) cardiomyocytes before and after LiCl. Male rabbits (n = 9) were more prone to developing lithium-induced Brugada-pattern ECG changes (incomplete right bundle branch block, ST elevation and QRS widening) with fatal arrhythmia (66.7% vs. 0%, p = 0.002) than in female (n = 7) rabbits at 10 mmol/kg (but not 1 or 3 mmol/kg). Compared to those in the female RVOT cardiomyocytes, LiCl (100 μM) reduced INa to a greater extent and increased INa-late in the male RVOT cardiomyocytes. Moreover, in the presence of ranolazine (the INa-late inhibitor, 3.6 mg/kg iv loading, followed by a second iv bolus 6.0 mg/kg administered 30 min later, n = 5), LiCl (10 mmol/kg) did not induce Brugada-pattern ECG changes (p < 0.005). The male gender is much predisposed to lithium-induced Brugada-pattern ECG changes with a greater impact on INa and INa-late in RVOT cardiomyocytes. Targeting INa-late may be a potential therapeutic strategy for Brugada syndrome-related ventricular tachyarrhythmia.

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.

A Subregion of Insular Cortex Is Required for Rapid Taste-Visceral Integration and Consequent Conditioned Taste Aversion and Avoidance Expression in Rats.

Postingestive signals are important for shaping appetitive and consummatory responses, but the brain mechanisms required to assimilate interoceptive events with those at the frontlines of ingestion (taste-guided) are poorly understood. Here, we investigated whether an insular cortex (IC) region, which receives viscerosensory input, including gustatory, is required to modify taste-elicited consummatory reactions in response to a real-time interoceptive change using a serial taste reactivity (TR) test where the rats’ oromotor and somatic reactions to intraoral (IO) infusions of sucrose were periodically assessed over 45 min following lithium chloride (LiCl) administration. Results showed that neurally-intact rats shifted from an ingestive repertoire to an aversive one as LiCl took effect. Overall, this hedonic shift was delayed in rats with bilateral neurotoxic IC lesions. Rats with greater neuronal loss in posterior gustatory IC displayed fewer aversive reactions to sucrose following this initial LiCl injection. We further assessed whether the failure to integrate interoceptive feedback with ongoing taste-guided behavior impaired acquisition and/or expression of conditioned aversion and/or avoidance in these same rats. Although, as a group, LiCl-injected rats with IC lesions subsequently avoided the sugar in a 48-h two-bottle test, their preference for sucrose was significantly greater than that of the LiCl-injected neurally-intact rats. Overall lesion size, as well as proportion of the posterior gustatory and/or anterior visceral IC were each associated with impaired avoidance. These findings reveal new roles for the posterior gustatory and anterior visceral ICs in multisensory integrative function.

Lithium promotes recovery after spinal cord injury.

Lithium is associated with oxidative stress and apoptosis, but the mechanism by which lithium protects against spinal cord injury remains poorly understood. In this study, we found that intraperitoneal administration of lithium chloride (LiCl) in a rat model of spinal cord injury alleviated pathological spinal cord injury and inhibited expression of tumor necrosis factor α, interleukin-6, and interleukin 1 β. Lithium inhibited pyroptosis and reduced inflammation by inhibiting Caspase-1 expression, reducing the oxidative stress response, and inhibiting activation of the Nod-like receptor protein 3 inflammasome. We also investigated the neuroprotective effects of lithium intervention on oxygen/glucose-deprived PC12 cells. We found that lithium reduced inflammation, oxidative damage, apoptosis, and necrosis and up-regulated nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 in PC12 cells. All-trans retinoic acid, an Nrf2 inhibitor, reversed the effects of lithium. These results suggest that lithium exerts anti-inflammatory, anti-oxidant, and anti-pyroptotic effects through the Nrf2/heme oxygenase-1 pathway to promote recovery after spinal cord injury. This study was approved by the Animal Ethics Committee of Xi'an Jiaotong University (approval No. 2018-2053) on October 23, 2018.

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.

Chronic Lithium Treatment Affects Anxious Behaviors and theExpression of Serotonergic Genes in Midbrain Raphe Nuclei of Defeated Male Mice

There is experimental evidence that chronic social defeat stress is accompanied by the development of an anxiety, development of a depression-like state, and downregulation of serotonergic genes in midbrain raphe nuclei of male mice. Our study was aimed at investigating the effects of chronic lithium chloride (LiCl) administration on anxiety behavior and the expression of serotonergic genes in midbrain raphe nuclei of the affected mice. A pronounced anxiety-like state in male mice was induced by chronic social defeat stress in daily agonistic interactions. After 6 days of this stress, defeated mice were chronically treated with saline or LiCl (100 mg/kg, i.p., 2 weeks) during the continuing agonistic interactions. Anxiety was assessed by behavioral tests. RT-PCR was used to determine Tph2, Htr1a, Htr5b, and Slc6a4 mRNA expression. The results revealed anxiolytic-like effects of LiCl on social communication in the partition test and anxiogenic-like effects in both elevated plus-maze and social interaction tests. Chronic LiCl treatment upregulated serotonergic genes in midbrain raphe nuclei. Thus, LiCl effects depend on the treatment mode, psycho-emotional state of the animal, and experimental context (tests). It is assumed that increased expression of serotonergic genes is accompanied by serotonergic system activation and, as a side effect, by higher anxiety.

FOXO3 Regulates Sevoflurane-Induced Neural Stem Cell Differentiation in Fetal Rats.

With the increase in fetal surgeries, the effect of maternal anesthesia on progeny has attracted much attention. Our previous studies have demonstrated that 3.5% sevoflurane maternal exposure resulted in over-activated autophagy and cognitive impairment in the offspring. The autophagy activation resulted in increased apoptosis and decreased proliferation. However, the effects of sevoflurane on neural stem cell (NSC) differentiation is unclear. There is evidence that autophagy might participate in anesthesia-induced NSC differentiation. Firstly, we examined the effects of sevoflurane on NSC differentiation and explored possible mechanisms. Then, we investigated whether autophagy was related to differentiation. On gestational day 14 (G14), rats were exposed to 2% or 3.5% sevoflurane for 2h, then markers of neurons and astrocytes, and the FOXO3 expression was measured in fetal brains 48h later. The differentiation of NSCs was detected after autophagy inhibition by 3-MA. Changes in NSC differentiation, autophagy level, and FOXO3 were examined after administration of lithium chloride. After 3.5% sevoflurane exposure, the expressions of β-Tubulin III, NeuN, SYP, GFAP and FOXO3 increased. Autophagy inhibition alleviates improper NSC differentiation. Lithium chloride attenuated FOXO3 and autophagy activation, ameliorated NSC differentiation and the decline of Nestin expression. Our results demonstrated that maternal exposure to 3.5% sevoflurane for 2h during the mid-trimester induced NSC differentiation in the fetal brain through the activation of FOXO3. Autophagy inhibitor or lithium chloride reversed the improper differentiation of NSCs.

Glycogen Synthase Kinase 3β Promotes Postoperative Cognitive Dysfunction by Inducing the M1 Polarization and Migration of Microglia.

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system complication, especially in the elderly. It has been consistently reported that the pathological process of this clinical syndrome is related to neuroinflammation and microglial proliferation. Glycogen synthase kinase 3β (GSK-3β) is a widely expressed kinase with distinct functions in different types of cells. The role of GSK-3β in regulating innate immune activation has been well documented, but as far as we know, its role in POCD has not been fully elucidated. Lithium chloride (LiCl) is a widely used inhibitor of GSK-3β, and it is also the main drug for the treatment of bipolar disorder. Prophylactic administration of lithium chloride (2 mM/kg) can inhibit the expression of proinflammatory mediators in the hippocampus, reduce the hippocampal expression of NF-κB, and increase both the downregulation of M1 microglial-related genes (inducible nitric oxide synthase and CD86) and upregulation of M2 microglial-related genes (IL-10 and CD206), to alleviate the cognitive impairment caused by orthopedic surgery. In vitro, LiCl reversed LPS-induced production of proinflammatory mediators and M1 polarization of microglia. To sum up these results, GSK-3β is a key contributor to POCD and a potential target of neuroprotective strategies.

Expression of hyperphosphorylated Tau protein in retrograde degeneration of neurons

Objective To explore the expression of hyperphosphorylated Tau protein in the retrograde degeneration of spinal central neurons after cervical 7 nerve transection, so as to provide a new idea for the protection of retrograde degeneration of central neurons after peripheral nerve injury. Methods Thirty-six adult female Sprague-Dawley rats were randomly divided into three groups (sham operation group, transection group, transection+drug intervention group). The rats in transection group and transection+drug intervention group were treated with bilateral cervical 7 nerve cutting to make models, and the rats in transection+drug intervention group were treated with 1 mmol/kg lithium chloride intraperitoneally every day. After 2 and 4 weeks, the spinal cords of cervical 7 of the rats were taken, and the apoptosis of neurons was analyzed by HE staining and flow cytometry. The expression of Tau protein and related protein was analyzed by Western blot. Results HE staining and flow cytometry showed that the apoptotic degree of the transection group at 2 weeks was less than that at 4 weeks. The resutls of Western blot showed that as time went on, the amount of total Tau protein decreased due to the transection of cervical 7 nerve, and the proportion of phosphorylated Tau protein increased. The difference was statistically significant. After lithium chloride administration, the degree of apoptosis and the proportion of phosphorylated Tau protein decreased significantly. Conclusion The mechanism of Tau protein hyperphosphorylation lies in the process of retrograde degeneration of spinal cord central neurons after cervical 7 transection, and lithium chloride can reduce the degree of retrograde degeneration. Key words: Tau proteins; Brachial plexus; Neuron retrograde degeneration; Hyperphosphorylation

The effect of lithium chloride on the attenuation of cognitive impairment in experimental hypoglycemic rats

BackgroundHypoglycemia is the most common complication in the treatment of diabetes mellitus. Accumulating evidence indicated that severe hypoglycemia could induce cognitive impairment. However, the molecular mechanism of regulating this progress is largely unknown. MethodsWe established a model of insulin-induced recurrent hypoglycemia in adult male Wistar rats (n = 40). Lithium chloride was injected after hypoglycemia once a day for consecutive 30 days. The loss of cognition function was evaluated by water maze test in these hypoglycemic rats. Glial cells activation and Wnt and inflammatory cytokines IL-1β, IL-6, IL-4, IL-10, TGFβ and TNFα expression were further examined to determine the mechanism of cognitive function impairment. ResultsHypoglycemia could induce impairment of cognitive function in rats and administration of lithium chloride could partly attenuate cognitive impairment compared to the control (p < 0.05). Lithium chloride could significantly up-regulate Wnt signaling and reduce hypoglycemia-induced neuronal death, glial cells activation and inflammatory response in the hippocampus of rats compared to the control (p < 0.05). The efficacy of lithium chloride could be reversed by injecting canonical Wnt signaling antagonist the dickkopf homolog 1. ConclusionLithium chloride attenuated hypoglycemia-induced cognitive function impairment in rats; and it was associated with Wnt signaling up-regulation and reduction of inflammatory response. Our results suggested that activating Wnt signaling pathways and inhibiting inflammatory response were the therapeutic potential to prevent hypoglycemia-induced neurological damage.

RNA-Seq and protein mass spectrometry in microdissected kidney tubules reveal signaling processes initiating lithium-induced nephrogenic diabetes insipidus

Lithium salts, used for treating bipolar disorder, frequently induce nephrogenic diabetes insipidus (NDI) thereby limiting therapeutic success. NDI is associated with loss of expression of the gene coding for the molecular water channel, aquaporin-2, in the renal collecting duct (CD). Here, we use systems biology methods in a well-established rat model of lithium-induced NDI to identify signaling pathways activated at the onset of polyuria. Using single-tubule RNA-Seq, full transcriptomes were determined in microdissected cortical collecting ducts (CCDs) of rats after 72 hours without or with initiation of lithium chloride administration. Transcriptome-wide changes in mRNA abundances were mapped to gene sets associated with curated canonical signaling pathways, showing evidence for activation of NF-κB signaling with induction of genes coding for multiple chemokines and most components of the Major Histocompatibility Complex Class I antigen-presenting complex. Administration of anti-inflammatory doses of dexamethasone to lithium chloride-treated rats countered the loss of aquaporin-2. RNA-Seq also confirmed prior evidence of a shift from quiescence into the cell cycle with arrest. Time course studies demonstrated an early (12 hour) increase in multiple immediate early response genes including several transcription factors. Protein mass spectrometry in microdissected CCDs provided corroborative evidence and identified decreased abundance of several anti-oxidant proteins. Thus, in the context of prior observations, our study can be best explained by a model in which lithium increases ERK activation leading to induction of NF-κB signaling and an inflammatory-like response that represses Aqp2 transcription.

Study of the Potential Use of Lithium in Treatment of Acute Kidney Injury in Rat Model

Background: Management of acute kidney injury is still facing a big problem. It is only dependent up till now on supportive measures, like fluid resuscitation and renal replacement therapy. No current drug therapy has been approved for the treatment of acute kidney injury. Acute kidney injury situations in a lot of cases can be predicted so, finding a drug for AKI will really benefit many patients. The pathophysiology of AKI is complex and many signaling pathways are involved in it. The Glycogen synthase kinase 3B enzyme is an important member in some of these pathways. The effect of its inhibition by the FDA approved drug, lithium on AKI is still under study.Material &amp; Methods: The current study was conducted on28 Male Sprague–Dawley rats. We classified the rats into groups. We induced acute kidney injury to rats with cisplatin. We administered lithium chloride to treat AKI in comparison with saline treatment. We have done renal functions and histopathological examinations to all rats enrolled in our study.Results: Single intraperitoneal injection of cisplatin (5 mg/kg) in rat induced acute kidney injury. The effect of lithium chloride treatment with dose (80 mg/kg) on serum creatinine and blood urea levels showed significant regression in the rising of serum creatinine and blood urea in lithium chloride treated rats in comparison to saline-treated rats. Pathological pictures and scores demonstrated an improvement in lithium chloride treated rats than saline-treated but results were not significant.Conclusion:Administration of lithium may be a promising treatment for acute kidney injury.Journal of Nobel Medical CollegeVolume 6, Number 2, Issue 11 (July-December, 2017) Page:14-19

Nonlinear disposition of lithium in rats and saturation of its tubular reabsorption by the sodium-phosphate cotransporter as a cause.

We previously reported the contribution of sodium-phosphate cotransporter to the tubular reabsorption of lithium in rats. In the present study, the dose dependency of the renal handling of lithium was examined in rats. When lithium chloride at 1.25mg/kg, 2.5mg/kg and 25mg/kg was intravenously injected as a bolus, the areas under the plasma concentration-time curve of lithium until 60minutes were calculated to be 6.23mEq·min/l, 8.77mEq·min/l and 64.6mEq·min/l, respectively. The renal clearance of lithium and its fractional excretion increased with increments in the dose administered. The renal clearance of lithium strongly correlated with the urinary excretion rate of phosphate in the 1.25mg/kg group (r = 0.840) and 2.5mg/kg group (r = 0.773), whereas this correlation was weak in the 25mg/kg group (r = 0.306). The infusion of foscarnet, a typical inhibitor of sodium-phosphate cotransporter, decreased the fractional reabsorption of lithium in rats administered lithium chloride at 2.5mg/kg, but did not affect it in rats administered 25mg/kg. These results demonstrate the nonlinearity of the renal excretion of lithium in rats, with the saturation of lithium reabsorption by the sodium-phosphate cotransporter potentially being involved.

C-Fos activity in the insular cortex, nucleus accumbens and basolateral amygdala following the intraperitoneal injection of saccharin and lithium chloride

This study examined c-Fos expression in selected brain areas consequent to intraperitoneal (IP) administration of saccharin and lithium chloride. Rats were tested for aversion to the saccharin as measured by flavor consumption and orofacial reactions in the taste reactivity (TR) test. It was found that intraperitoneal conditioning resulted in the reduction in voluntary consumption but not in the production of aversive orofacial responses to the saccharin. The immunohistochemistry quantification revealed increased c-Fos activity in the insular cortex, the shell and core regions of the nucleus accumbens, and the basolateral nucleus of the amygdala. These results show that a conditioned taste aversion can be induced without direct oropharyngeal gustatory stimulation at the time of conditioning. In addition, this study provide evidence of increased neural activity in response to intraperitoneal saccharin injections.

Doping control analysis of lithium in horse urine and plasma by inductively coupled plasma mass spectrometry.

Lithium salts are commonly prescribed to treat bipolar disorder in humans. They are effective for the treatment of acute mania and the prophylaxis of manic relapses through long-term use. Although there is no reported legitimate therapeutic use of lithium in horses, its potential mood-stabilizing effect, low cost, and ready availability make lithium salt a potential agent of abuse in equine sports, especially for equestrian competition horses. Lithium can be found in soil, plants, and water, as such it is naturally present in the equine body, thus a threshold is necessary to control its misuse in horses. This paper describes the validation of quantification methods for lithium in equine urine and plasma using inductively coupled plasma mass spectrometry (ICP-MS). Based on a population study of lithium in horse urine and an administration study using a single oral dose of lithium chloride (100mg) to mimic the daily lithium intake from a diet rich in lithium, a urinary threshold of 5μg/mL was proposed. Applying this urinary threshold to two other administration studies (a single oral dose of 65g of lithium chloride, and a single intravenous dose of 2.54g of lithium chloride), excessive lithium in urine could be detected for 8days and 2.5days respectively. The concentrations of lithium in plasma following these three lithium chloride administration trials were also studied. Copyright © 2017 John Wiley & Sons, Ltd.