Potent Inhibition of Biphasic Tubular Reabsorption of Lithium by Acetazolamide and Foscarnet in Rats.

Lithium is mainly excreted into urine, and a large fraction of lithium filtered through glomeruli is reabsorbed in the proximal tubule. However, the mechanisms responsible for lithium reabsorption remain unclear. We previously reported that the reabsorption of lithium was biphasic in rats, and that foscarnet inhibited lithium reabsorption with a high affinity type. We herein evaluated the effects of acetazolamide and foscarnet on the renal excretion of lithium in rats treated with lithium chloride at 2 doses. In rats intravenously injected with a bolus of 25 mg/kg lithium chloride, acetazolamide facilitated the urinary excretion of lithium, and increased the fractional excretion of lithium from 0.446 to 0.953, near the theoretically maximum value. At a dose of 2.5 mg/kg lithium chloride, the fractional excretion of lithium was 0.241 in control rats, 0.420 in rats administered acetazolamide, and 0.976 in rats administered acetazolamide and foscarnet. These results showed the potent inhibition of lithium reabsorption by acetazolamide and foscarnet in rats. And, it was exhibited that the effects of acetazolamide on lithium reabsorption differed with the dosages of lithium administered.

Ginsenoside-Rb1 ameliorates lithium-induced nephrotoxicity and neurotoxicity: Differential regulation of COX-2/PGE2 pathway.

To investigate the effect of Ginsenoside-Rb1 (GRb1) on lithium (Li+)-induced toxicity, GRb1 was given to rats orally (100mg/kg) for 14days. In independent groups, lithium chloride (4meq/kg/day i.p.) was administered at day 4 of the experiment for 10days, with or without GRb1. Li+ caused significant deterioration of behavioral responses including righting reflex, spontaneous motor activity and catalepsy. Li+ also caused distortion in normal renal, cerebral and cerebellum architecture and significantly worsened all kidney functional parameters tested compared to control. In addition, Li caused oxidative stress in both kidney and brain, evident by significant increase in malondialdehyde and nitric oxide levels, with decrease in reduced glutathione and catalase activity. Administration of GRb1 prior to Li+ significantly improved behavioral responses, renal and brain histopathological picture, kidney function tests and oxidative stress markers compared to sole Li+-treated group. Concomitant administration of GRb1 decreased Li+ levels by about 50% in serum, urine and brain and by 35% in the kidney. Interestingly, Li+ had a differential effect on cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) pathway, as it significantly increased COX-2 expression and PGE2 level in the kidney, while decreasing them in the brain compared to control. On the other hand, administering GRb1 with Li+ suppressed COX-2/PGE2 pathway in both kidney and brain compared to Li+ alone. In conclusion, GRb1 can alter Li+ pharmacokinetics resulting in extensively decreasing its serum and tissue concentrations. Furthermore, COX-2/PGE2 pathway has a mechanistic role in the nephro- and neuro-protective effects of GRb1 against Li+-induced toxicity.

Lithium attenuates the proconvulsant effect of adolescent social isolation stress via involvement of the nitrergic system.

In this study, we tested whether acute administration of lithium mitigates the deleterious effect of adolescent social isolation stress (SIS) on seizure susceptibility. In comparison with socially conditioned (SC) mice, isolated conditioned (IC) mice exhibited an increase in seizure susceptibility to pentylenetetrazole. Acute administration of lithium (10mg/kg) reversed the proconvulsant effect of SIS in IC mice, but this effect was not observed in SC mice. Coadministration of subthreshold doses of lithium (3mg/kg) with nitric oxide synthase (NOS) inhibitors reversed the effect of SIS on seizure susceptibility and decreased hippocampal nitrite levels in IC animals. In addition, a subthreshold dose of a nitric oxide precursor reduced the protective effect of lithium on seizure susceptibility and increased nitrite levels in the hippocampus of IC mice. These results suggest that lithium exerts a protective influence against the proconvulsant effect of adolescent SIS via a nitrergic system that includes activation of neuronal NOS in the hippocampus.

Foscarnet, an inhibitor of the sodium-phosphate cotransporter NaPi-IIa, inhibits phosphorylation of glycogen synthase kinase-3ß by lithium in the rat kidney cortex.

Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3ß (GSK3ß) by producing its phosphorylated form (p-GSK3ß). GSK3ß plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3ß is considered to contribute to protection against acute kidney injury. We previously reported that the sodium-phosphate cotransporter NaPi-IIa (SLC34A1) mediated the reabsorption of lithium in the rat kidney. In the present study, the phosphorylation status of GSK3ß in the kidney cortex of rats administered lithium chloride and foscarnet, a typical inhibitor of NaPi-IIa, was examined using Western blotting. Under a 2-h infusion of lithium chloride, the plasma concentration of lithium was 1.06 mEq/l, and its renal clearance was calculated as 1.18 ml/min/kg, which was 29.6% of creatinine clearance. The abundance of p-GSK3ß in the kidney cortex was augmented by the administration of lithium. The simultaneous infusion of foscarnet increased the renal clearance of lithium and its ratio to creatinine clearance as well as the urinary excretion of phosphate. Foscarnet also inhibited the lithium-induced phosphorylation of GSK3ß. These results suggest that the reabsorption of lithium by NaPi-IIa triggers the phosphorylation of GSK3ß in the rat kidney cortex.

Protective effects of lithium chloride on seizure susceptibility: Involvement of α2-adrenoceptor.

For more than 60years, lithium has been the mainstay in the treatment of mental disorders as a mood stabilizer. In addition to the antimanic and antidepressant responses, lithium also shows some anticonvulsant properties. In spite of the ascertained neuroprotective effects of this alkali metal, the underlying mechanisms through which lithium regulates behavior are still poorly understood. Among different targets, some authors suggest neuromodulatory effects of lithium are the consequences of interaction of this agent with the brain neurotransmitters including adrenergic system. In order to study the involvement of α2-adrenergic system in anticonvulsant effect of lithium, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice. Injection of a single effective dose of lithium chloride (30mg/kg, i.p.) significantly increased the seizure threshold (p<0.01). The anticonvulsant effect of an effective dose of lithium was prevented by pre-treatment with low and per se non-effective dose of clonidine [α2-adrenoceptor agonist] (0.05, 0.1 and 0.25mg/kg). On the other hand, yohimbine [α2-adrenoceptor antagonist] augmented the anticonvulsant effect of sub-effective dose of lithium (10mg/kgi.p.) at relatively low doses (0.1, 0.5, 1 and 2.5mg/kg). Moreover, UK14304 [a potent and selective α2-adrenoceptor agonist] (0.05 and 0.1mg/kg) and RX821008 [a potent and selective α2D-adrenoceptor antagonist] (0.05, 0.1 and 0.25mg/kg) repeated the same results confirming that these modulatory effects are conducted specifically through the α2D-adrenoceptors. In summary, our findings demonstrated that α2-adrenoceptor pathway could be involved in the anticonvulsant properties of lithium chloride in the model of chemically induced clonic seizure.

The iNOS/Src/FAK axis contributes to lithium chloride-mediated macrophage migration.

Lithium chloride (LiCl) has long been used as a mood stabilizer for bipolar mood depression patients. However, its biological effects on immune cells are unclear yet. In this study, we observed that upon LiCl stimulation, the motility and the content of total protein tyrosine phosphorylation in RAW264.7 macrophages and murine peritoneal macrophages (PEMs) were significantly increased. The inhibition of LiCl-induced macrophage migration by PP2 (an inhibitor for Src family kinases (SFKs)) suggested the involvement of SFKs in this process. Interestingly, LiCl induced NF-kB activation, and while Src was greatly induced, the expression of its myeloid relatives (i.e. Lyn, Fgr, Hck) was almost unaltered in RAW264.7 cells. Knockdown of Src suppressed LiCl-elicited movement and the level of FAK Pi-Tyr861, which could be reversed by siRNA-resistant Src. Consistent with Src and migration increment was iNOS-dependent in macrophages, markedly reduced Src expression, activity and cell migration were observed in iNOS-null PEMs treated with LiCl. Moreover, FAK knockdown suppressed LiCl-stimulated macrophage motility, suggesting the involvement of FAK in this process. Remarkably, similar increment of iNOS, Src, FAK Pi-Tyr861 and migration ability could also be detected in RAW264.7 treated with other GSK3ß inhibitors (i.e. SB216763 and Kenpaullone). These results corroborate that through inhibition of GSK3ß, the iNOS/Src/FAK axis occupies a critical role in macrophage locomotion in response to LiCl.

Inhibition of LiCl-induced conditioning of anticipatory nausea in rats following immune system stimulation: comparing the immunogens lipopolysaccharide, muramyl dipeptide, and polyinosinic: polycytidylic acid.

The effects of the bacterial endotoxins, lipopolysaccharide (LPS) and muramyl dipeptide (MDP; Experiment 1), and the viral mimetic, polyinosinic: polycytidylic acid (poly I:C; Experiment 2), on the acquisition of "conditioned gaping" behavior in the rodent model of LiCl-induced anticipatory nausea were examined. Experimentally naïve adult male Long-Evans rats were injected (intraperitoneal, i.p.) with either 200 µg/kg LPS, 1.6 mg/kg MDP, or 0.9% saline (Experiment 1), or 4.0 mg/kg poly I:C or 0.9% saline (Experiment 2), 90 min prior to treatment with 127 mg/kg LiCl or saline control and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). On a drug-free test day (72 h following conditioning day 4), each animal was re-exposed to the context for 10 min, and orofacial and aversive behavioral responses were video recorded and analyzed. The results showed that pre-treatment with LPS, MDP (Experiment 1), or poly I:C (Experiment 2) prior to LiCl+context conditioning significantly impaired the establishment of conditioned gaping behavior, thus blocking the acquisition of anticipatory nausea. Results varied in regards to peripheral acute-phase response sickness behaviors, with significantly reduced weight loss in LPS-treated animals, less robust weight loss in poly I:C-treated animals, and no significant reductions in body weight in MDP-treated animals. The learning impairments observed in the current study suggest that endotoxin treatment with bacterial and viral endotoxin may have stronger central effects on learning and memory behavior, relative to peripheral effects on body weight and other sickness-related responses.

Lithium attenuates pain-related behavior in a rat model of neuropathic pain: possible involvement of opioid system.

Lithium is a major drug for bipolar disorder and mania. Recently, many studies have shown the neuroprotective effect of lithium in different models of neurodegenerative diseases. The present study was carried out to examine the effect of lithium in a rat model of neuropathic pain induced by partial sciatic nerve ligation and the possible role of opioid system in this effect. To do so, animals received acute injection of saline, lithium (5, 10 and 15 mg/kg,) and naloxone (1 mg/kg) or the combination of naloxone (1 mg/kg) with lithium (10 mg/kg) intraperitoneally on the testing days. Thermal hyperalgesia, mechanical and cold allodynia were measured on the days 3, 5, 7, 10 and 14 after surgery. Lithium decreased thermal hyperalgesia scores with dose of 5, 10 and 15 mg/kg and cold and mechanical allodynia scores with dose of 10 and 15 mg/kg, significantly. The opioid antagonist naloxone prevented the effect of lithium on thermal hyperalgesia and mechanical allodynia while it did not show any effect on the acetone-induced cold allodynia. Our results suggest that lithium can be considered as a therapeutic potential for the treatment of some aspects of neuropathic pain and that the opioid system may be involved in the lithium-induced attenuation of thermal hyperalgesia and mechanical allodynia.

Lipopolysaccharide (LPS) blocks the acquisition of LiCl-induced gaping in a rodent model of anticipatory nausea.

The effects of systemic treatment with lipopolysaccharide (LPS) on conditioned gaping in a rodent model of anticipatory nausea were examined. Stimulation of the immune system has been found to enhance, impair, or have no effect on various learning and memory tasks. The development of anticipatory nausea is formed through a classically conditioned response to a context that has been paired previously with toxin-induced nausea and/or vomiting. Rats display a distinctive conditioned gaping response when injected with a nausea-inducing drug such as LiCl. In the present study, male Long-Evans rats were injected intraperitoneally with LPS (200microg/kg) or saline (NaCl) followed 90min later by an injection of the toxin LiCl or saline before being placed in a distinctive context on four conditioning days (72h apart). On the condition test day, rats (n=6/group) were placed in the distinctive context in a drug-free state and behavioral responses were videotaped. Rats given LPS followed by LiCl were found to have significantly fewer gaping responses when compared to rats given NaCl followed by LiCl. All groups were also found to have similar levels of spontaneous ingestive behaviors suggesting that the decrease in gaping was not due to motor impairment. The present results suggest that activation of the immune system with LPS administration significantly impairs the acquisition of anticipatory nausea.

The effects of acute corticosterone on lithium chloride-induced conditioned place aversion and locomotor activity in rats.

Acute administration of corticosterone (CORT) facilitates learning in a number of associative paradigms including lithium chloride (LiCl)-induced conditioned taste aversion learning. The present study examined the effects of acute CORT on LiCl-induced conditioned place aversions in male rats. Automated open-fields were partitioned into two chambers distinct in tactile and visual cues. Animals received either LiCl (64 mg/kg, 0.15 M) or saline (NaCl, 0.15 M) followed 10 min later by either CORT (5 mg/kg) or beta-cyclodextrin vehicle (45%) prior to placement in one of the chambers. Control rats received NaCl-Vehicle paired with both chambers. Three experimental groups received either NaCl-CORT, LiCl-Vehicle or LiCl-CORT paired with the preferred chamber and NaCl-Vehicle (control) paired with the non-preferred chamber. During extinction trials, animals were allowed to choose between the two chambers. Locomotor activity and its distribution within the chambers were assessed during both conditioning and extinction trials. CORT administration produced significant increases in a variety of measures of locomotor activity during conditioning trials. During extinction trials both LiCl groups displayed a conditioned place aversion while the NaCl-CORT group did not. In addition, significant increases in vertical activity were recorded in both LiCl groups in the LiCl-paired chamber. Moreover, CORT administration had no effect on LiCl-induced conditioned place aversion as time spent in the LiCl-paired chamber did not significantly differ between LiCl-Vehicle and LiCl-CORT groups. Significant increases in a number of measures of horizontal activity were also observed in both CORT groups. The present study shows that acute CORT administration does not significantly influence LiCl-induced conditioned place aversions and suggests that the facilitatory effects of acute CORT administration on learning are highly context-dependent.

Conditioned taste aversion: modulation by 5-HT receptor activity and corticosterone.

Two experiments were designed to elucidate the involvement of the hypothalamic-pituitary-adrenal axis and the 5-hydroxytryptamine (5-HT) system in the acquisition of lithium chloride-conditioned taste aversion. In Experiment 1, rats were administered either vehicle or 50 mg/kg nefazodone daily for 4 weeks. Rats were treated with 22 mg/kg of lithium chloride in order to produce conditioned taste aversion to a sucrose solution. Three days later, nefazodone completely blocked the lithium chloride-conditioned taste aversion. In Experiment 2, the effects of chronic corticosterone administration on lithium chloride-conditioned taste aversion were investigated. Twenty male rats received either corticosterone at a dose of (50 mg/kg) or vehicle injections over a period of 14 consecutive days. Lithium chloride-conditioned taste aversion was potentiated in rats treated with corticosterone. Additionally, corticosterone-treated animals required more trials to reach extinction. These results suggest the involvement of both the 5-HT system and the hypothalamic-pituitary-adrenal axis in lithium chloride-conditioned taste aversion.

Abnormal expression of neuronal nitric oxide synthase triggers limbic seizures and hippocampal damage in rat.

Administration of tacrine (5 mg/kg ip), an anticholinesterase agent, in rats pretreated (24 h beforehand) with lithium chloride (LiCl; 12 mEq/kg ip) provides a useful experimental model to study limbic seizures and delayed hippocampal damage. Here we report Western blotting evidence demonstrating that in rat LiCl and tacrine enhance the expression of neuronal nitric oxide synthase (nNOS), but not eNOS, enzyme protein in the hippocampus during the preconvulsive period and this triggers seizures and hippocampal damage. In fact, systemic administration of 7-nitro indazole (7-NI; 50 mg/kg given ip 30 min before tacrine), a selective inhibitor of nNOS, prevented the expression of motor and electrocortical (ECoG) seizures and abolished neuronal cell death in the hippocampus. A lower dose (5 mg/kg ip) of 7-NI was ineffective. In conclusion, the present data support a role for abnormal nNOS expression in the mechanism which triggers limbic seizures and delayed excitotoxic damage in the hippocampus of rat.

The role of CNS glucagon-like peptide-1 (7-36) amide receptors in mediating the visceral illness effects of lithium chloride.

Peripheral administration of large doses of lithium chloride (LiCl) to rats causes a spectrum of effects that are consistent with visceral illness. LiCl reduces food intake, decreases salt ingestion after sodium depletion, induces pica, and produces robust conditioned taste aversions. Because some of the effects of peripheral LiCl are mimicked by centrally administered glucagon-like peptide-1 (7-36) amide (GLP-1), we hypothesized that this peptide is involved in the neural pathways by which LiCl causes visceral illness. To test this hypothesis, we pretreated rats with a selective and potent GLP-1 receptor antagonist given directly into the third ventricle via an indwelling cannula before administration of peripheral LiCl. The GLP-1 receptor antagonist completely blocked the effect of LiCl to reduce food intake, induce pica, and produce a conditioned taste aversion. The same dose of GLP-1 receptor antagonist did not reverse the LiCl-induced reduction in NaCl intake. The data indicate a role for GLP-1 receptors in the CNS pathway that mediates some of the effects of visceral illness.

Protective effects of GABAergic drugs and other anticonvulsants in lithium-pilocarpine-induced status epilepticus.

Administration of subconvulsive dose of pilocarpine (30 mg/kg s.c.) to rats pretreated with lithium chloride (3 meq/kg i.p.) produced a state of status epilepticus in animals. The animals showed characteristic symptoms of generalized convulsions, wet dog shakes (WDS), forelimb clonus and falling back. The symptoms of status epilepticus (SE) developed within 26.8 +/- 3.6 min after administering pilocarpine and these symptoms continued uninterrupted. The phenomenon was totally reproducible, with a consistent latency of onset of seizures and a high mortality rate. The symptoms were blocked by atropine, scopolamine and the GABAergic agents GABA, sodium valproate, (+)-baclofen and clonazepam when given prior to pilocarpine, but not when administered 30 min after pilocarpine administration.

Blockade of lithium chloride-induced conditioned place aversion as a test for antiemetic agents: comparison of metoclopramide with combined extracts of Zingiber officinale and Ginkgo biloba.

The present study tests the hypothesis that the blockade of lithium chloride-induced conditioned place aversion might be a suitable model to assess antiemetic properties of drugs, especially in species that do not vomit, like rats. The effects of the known antiemetic compound metoclopramide were compared with those of zingicomb, a combination preparation of extracts of Ginkgo biloba and Zingiber officinale, also presumed to have antiemetic properties. Place conditioning was performed using a conventional three-compartment test procedure. On three successive conditioning trials, rats received an intraperitoneal (i.p.) injection of lithium chloride (125 mg/kg) and were placed into the compartment that they had preferred over three baseline trials. During the test, rats treated with lithium chloride (LiCl) spent less time in the treatment compartment, indicative of a conditioned place aversion (CPA). In the first experiment, metoclopramide (MCP) was administered intragastrically (IG) in doses of 2 or 10 mg/kg 60 min prior to LiCl injection. The pretreatment with 50 and 100 mg/kg zingicomb attenuated the LiCl-produced CPA, whereas a dosage of 10 mg/kg had no effect. These findings suggest that LiCl-induced CPA is a viable procedure with which to assess the antiemetic properties of metoclopramide. Furthermore, the data confirm the hypothesis that the phytopharmacon zingicomb might have antiemetic properties that are comparable to those of metoclopramide.