lithium-chloride and Cognition-Disorders

A lower incidence of dementia in bipolar patients treated with lithium has been described. This metal inhibits the phosphorylation of glycogen-synthase-kinase 3-α and β, which are related to amyloid precursor protein processing and tau hyperphosphorylation in pathological conditions, respectively. Following the same rationale, a group just found that lithium has disease-modifying properties in amnestic mild cognitive impairment with potential clinical implications for the prevention of Alzheimer's Disease (AD) when a dose ranging from 150 to 600 mg is used. As lithium is highly toxic in regular doses, our group evaluated the effect of a microdose of 300 μg, administered once daily on AD patients for 15 months. In the evaluation phase, the treated group showed no decreased performance in the mini-mental state examination test, in opposition to the lower scores observed for the control group during the treatment, with significant differences starting three months after the beginning of the treatment, and increasing progressively. This data suggests the efficacy of a microdose lithium treatment in preventing cognitive loss, reinforcing its therapeutic potential to treat AD using very low doses.

Topics: Adjuvants, Immunologic; Aged; Alzheimer Disease; Analysis of Variance; Cognition Disorders; Double-Blind Method; Female; Humans; Lithium Chloride; Male; Psychiatric Status Rating Scales

Estrogen deprivation is a high risk of cognitive dysfunction in neurodegenerative diseases, and the early used estrogen replacement has been proved effective in many studies. Because of the adverse actions, selective estrogen receptor modulating has been raised to substitute for estrogen replacement. In this study, we observed in hippocampus of bilaterally ovariectomized rats that the level of estrogen receptor α (ERα) was decreased in nuclei with activated glycogen synthase kinase-3β (GSK-3β) in cytoplasm at 8 weeks after operation. The level of nuclear ERα is important for its transcriptional property, and the inhibition of GSK-3β benefits to ERα nuclear translocation. Then, we used 4,4k,4a-(4-propyl-[1H]-pyrazole-1, 3, 5-triyl) trisphenol (PPT) (1 mg/kg/day), an agonist of ERα, combined with LiCl (40 mg/kg/day), an inhibitor of GSK-3β, to treat the ovariectomized rats. After the combination treatment of these two drugs (PPT + LiCl), the improved learning and memory abilities of ovariectomized rats in Morris water maze, increased dendritic spines in CA1 region, and decreased tau phosphorylation at Ser-396 in hippocampus were observed. Furthermore, PPT + LiCl treatment significantly increased ERα level in the nuclear fraction of hippocampus, and in the cytoplasmic fraction, the total level of GSK-3β was declined after treatment with its increased phosphorylation at Ser-9 (inactivation form). This study suggested that PPT + LiCl treatment could inhibit the activation of cytoplasmic GSK-3β and promote the nuclear translocation of ERα, and ERα together with GSK-3β maybe the targets to preserve hippocampus-dependent cognitive ability after long-term ovariectomy.

Topics: Animals; Cell Nucleus; Cognition Disorders; Estrogen Receptor alpha; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Lithium Chloride; Maze Learning; Ovariectomy; Phenols; Phosphorylation; Phosphoserine; Pyrazoles; Rats, Sprague-Dawley; Spatial Memory; Up-Regulation

Recent studies suggest the importance of combined treatment of glycogen synthase kinase-3β (GSK-3β) and histone deacetylase (HDAC) inhibition in various in vitro and in vivo models of neurological diseases. Lithium chloride (LiCl) and valproate (VPA), two well-known mood stabilizers, have been reported to act through GSK-3β and HDAC inhibition, respectively. The present study was designed to investigate the potential of low-dose combination of LiCl and VPA in intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive deficits in rats. STZ was injected twice (3 mg/kg ICV) on alternate days (day 1 and day 3) in rats. The ICV-STZ-treated rats received LiCl (60 mg/kg, i.p.), VPA (200 mg/kg, i.p.), and combination of both LiCl (60 mg/kg, i.p.) and VPA (200 mg/kg, i.p.) drugs for a period of 3 weeks. The ICV-STZ administration results in significant memory impairment, elevated oxidative-nitrosative stress, and reduced brain-derived neurotrophic factor (BDNF) levels. Using a battery of behavioral and biochemical tests, we observed that co-treatment of both drugs showed synergistic effect in improving the spatial learning and memory impairment as well as significantly attenuated the oxidative stress markers in STZ-treated rats as compared to either drug alone. Moreover, the combination of both drugs reversed the hyperinsulinemic brain condition and improved the BDNF levels in STZ-treated rats. Based upon these results, it could be suggested that a low-dose combination of LiCl and VPA produces synergistic and more consistent neuroprotective effects in ICV-STZ-induced cognitive deficits in rats.

Topics: Acetylcholinesterase; Animals; Avoidance Learning; Brain; Brain-Derived Neurotrophic Factor; Cognition Disorders; Drug Synergism; Drug Therapy, Combination; Glutathione; Glycogen Synthase Kinase 3; Histone Deacetylase Inhibitors; Insulin; Lithium Chloride; Malondialdehyde; Memory; Memory Disorders; Neuroprotective Agents; Nitrates; Nitrites; Rats, Wistar; Spatial Learning; Streptozocin; Valproic Acid

Though the pathogenesis of postoperative cognitive dysfunction (POCD) remains unclear, evidence is accumulating for a pivotal role of neuroinflammation in the disease process. Advanced age and severe surgical trauma are two main risk factors for POCD. Lithium, a neuroprotective agent, can alleviate peripheral surgery-induced memory impairment in aged rats. The results of in vivo and in vitro experiments also showed that toll like receptor 4 (TLR4) was associated with the occurrence and development of neuroinflammation and POCD. So we hypothesized that inhibition of TLR4 signaling in the hippocampus maybe involved in the protective effects of prophylactic lithium on the occurrence of inflammation and POCD. In the present study, we incubated BV-2 microglia with 1μg/ml lipopolysaccharide (LPS) to mimic neuroinflammation in vitro. We found that pretreatment with 10mM of lithium or 100nM of TLR4 siRNA could inhibit the tumor necrosis factor (TNF)-α and TLR4 mRNA expression induced by LPS in BV-2 microglia. Furthermore, combination of prophylactic lithium and TLR4 siRNA even decreased their mRNA expression to the baseline levels, which showed that TLR4 signaling may be vital in protective effects of prophylactic lithium on neuroinflammation. So we further undergone the in vivo experiment. Then, we firstly demonstrated that prophylactic 2mM/kg of lithium alleviated splenectomy-induced cognitive impairments, decreased splenectomy-associated systemic, central, and hippocampal TNF-α and interleukin (IL)-1β expression and reduced the increase of CD11b(+) area in hippocampal CA1 region caused by the surgery. Then, we also found that splenectomy merely increased hippocampal TLR2 and TLR4 mRNA levels in aged rats. At last, we confirmed that prophylactic lithium reduced the increased levels of hippocampal TLR4/NF-κB induced by splenectomy. Taken together, these results demonstrate that TLR4 signaling inactivation may contribute to the protective effects of prophylactic lithium on the occurrence of POCD by inhibiting systemic inflammation and especially neuroinflammation.

Topics: Aging; Animals; CD11b Antigen; Cell Line; Cognition Disorders; Disease Models, Animal; Interleukin-1beta; Lipopolysaccharides; Lithium Chloride; Male; Mice; Microglia; Neuroimmunomodulation; NF-kappa B; Nootropic Agents; Random Allocation; Rats, Sprague-Dawley; RNA, Messenger; RNA, Small Interfering; Splenectomy; Toll-Like Receptor 2; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Topics: Aged; Athetosis; Bipolar Disorder; Chorea; Cognition Disorders; Diagnosis, Differential; Female; Humans; Lithium Chloride; Long-Term Care

Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes.. We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor-dependent long-term potentiation at medial perforant path synapses onto dentate granule cells and dentate gyrus-dependent cognitive behavioral tasks.. GSK3 inhibitors completely rescued deficits in long-term potentiation at medial perforant path-dentate granule cells synapses in FX mice. Furthermore, synaptosomes from the dentate gyrus of FX mice displayed decreased inhibitory serine-phosphorylation of GSK3β compared with wild-type littermates. The potential therapeutic utility of GSK3 inhibitors was further tested on dentate gyrus-dependent cognitive behaviors. In vivo administration of GSK3 inhibitors completely reversed impairments in several cognitive tasks in FX mice, including novel object detection, coordinate and categorical spatial processing, and temporal ordering for visual objects.. These findings establish that synaptic plasticity and cognitive deficits in FX mice can be improved by intervention with inhibitors of GSK3, which may prove therapeutically beneficial in FXS.

Topics: Animals; Cognition; Cognition Disorders; Disease Models, Animal; Disks Large Homolog 4 Protein; Electric Stimulation; Excitatory Amino Acid Antagonists; Fragile X Mental Retardation Protein; Fragile X Syndrome; Glycogen Synthase Kinase 3; Guanylate Kinases; Hippocampus; In Vitro Techniques; Lithium Chloride; Long-Term Potentiation; Membrane Proteins; Mice; Mice, Transgenic; Patch-Clamp Techniques; Protein Kinase Inhibitors; Synapses

Cognitive impairment is a common comorbidity in temporal lobe epilepsy (TLE) and is often considered more detrimental to quality of life than seizures. While it has been previously shown that the encoding of memory during behavior is impaired in the pilocarpine model of TLE in rats, how this information is consolidated during the subsequent sleep period remains unknown. In this study, we first report marked deficits in spatial memory performance and severe cell loss in the CA1 layer of the hippocampus lower spatial coherence of firing in TLE rats. We then present the first evidence that the reactivation of behavior-driven patterns of activity of CA1 place cells in the hippocampus is intact in TLE rats. Using a template-matching method, we discovered that real-time (3-5 s) reactivation structure was intact in TLE rats. Furthermore, we estimated the entropy rate of short time scale (∼250 ms) bursting activity using block entropies and found that significant, extended temporal correlations exist in both TLE and control rats. Fitting a first-order Markov Chain model to these bursting time series, we found that long sequences derived from behavior were significantly enriched in the Markov model over corresponding models fit on randomized data confirming the presence of replay in shorter time scales. We propose that the persistent consolidation of poor spatial information in both real time and during bursting activity may contribute to memory impairments in TLE rats.

Topics: Action Potentials; Animals; CA1 Region, Hippocampal; Cognition Disorders; Comorbidity; Disease Models, Animal; Epilepsy, Temporal Lobe; Lithium Chloride; Markov Chains; Maze Learning; Models, Neurological; Pilocarpine; Pyramidal Cells; Rats, Sprague-Dawley; Seizures; Sleep; Spatial Memory; Time Factors

Cognitive dysfunction in bipolar disorder has been well-established in cross-sectional studies; however, there are few data regarding the longitudinal course of cognitive performance in bipolar disorder. The aim of this study was to examine the course of cognitive function in a sample of euthymic patients with bipolar disorder during a five-year follow-up period.. Eighty euthymic outpatients with a DSM-IV diagnosis of bipolar disorder and 40 healthy control comparison subjects were neuropsychologically assessed at baseline (T1) and then at follow-up of five years (T2). A neurocognitive battery including the main cognitive domains of speed of processing, working memory, attention, verbal memory, visual memory, and executive function was used to evaluate cognitive performance.. Repeated-measures multivariate analyses showed that progression of cognitive dysfunction in patients was not different to that of control subjects in any of the six cognitive domains examined. Only a measure from the verbal memory domain, delayed free recall, worsened more in patients with bipolar disorder. Additionally, it was found that clinical course during the follow-up period did not influence the course of cognitive dysfunction.. Cognitive dysfunction that is characteristic of bipolar disorder is persistent and stable over time. Only dysfunction in verbal recall was found to show a progressive course that cannot be explained by clinical or treatment variables.

Topics: Adult; Analysis of Variance; Anticonvulsants; Antimanic Agents; Bipolar Disorder; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Lithium Chloride; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Statistics as Topic

The present study examined whether status epilepticus (SE) induced by LiCl-pilocarpine in immature rats (postnatal day [P]12) interferes with normal development; leads to progressive epileptogenesis, or cognitive decline and to pathology similar to that seen in human temporal lobe epilepsy. We correlated the extent of pathologic changes with the severity of functional alterations or epilepsy. SE-induced changes were compared with those of rats with SE induced at P25. Animals of both ages were exposed to a battery of behavioral tests for up to 3months after SE. Rats with SE at P12 showed mild retardation of psychomotor development and delayed habituation, whereas rats with SE at P25 showed no habituation. Assessment in adulthood using the Morris water maze test revealed that SE at both P12 and P25 led to cognitive impairment and that the severity of the impairment increased with age. A handling test revealed increased aggression in rats with SE at P25, but not in rats with SE at P12. Epilepsy was diagnosed with continuous video-electroencephalographic (EEG) monitoring for up to 7d. P25 rats were monitored at 5months after SE and seizures were detected in 83.3% of animals. P12 animals were divided into two groups and monitored at 5 or 7months after SE. Both the severity and incidence of spontaneous recurrent seizures tended to progress with time, and their incidence increased from 50% to 87.5% at 5 and 7months, respectively. Morphometric analysis and stereologic assessment of hilar neurons performed after video-EEG monitoring revealed atrophy of temporal brain structures, enlargement of lateral ventricles, and loss of hilar neurons in both age groups. In P12 rats, morphologic damage also tended to progress over time. Performance of animals in the Morris water maze correlated with the severity of damage, but not with seizure parameters.

Topics: Aggression; Aging; Animals; Animals, Newborn; Antimanic Agents; Atrophy; Behavior, Animal; Brain; Cerebral Ventricles; Cognition Disorders; Disease Progression; Electroencephalography; Hippocampus; Lithium Chloride; Male; Maze Learning; Motor Activity; Muscarinic Agonists; Pilocarpine; Psychomotor Performance; Rats; Rats, Wistar; Status Epilepticus

Epilepsy is commonly associated with cognitive impairment. Astrocyte activation and oxidative stress occur following seizures, and play a role in the pathological injury of epilepsy with cognitive impairment. The peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to exhibit neuroprotective and antioxidative effects in CNS diseases. Thus, we hypothesized that rosiglitazone, a PPARγ agonist, would prevent cognitive impairment by inhibiting astrocyte activation and regulating glutathione (GSH) homeostasis after status epilepticus (SE). Using a lithium pilocarpine-induced SE model, we found that rosiglitazone significantly prevented cognitive impairment induced by SE, and potently inhibited astrocyte activation with maintenance of GSH homeostasis in the hippocampus after SE. These protective effects were significantly reversed by co-treatment with the PPARγ antagonist T0070907. These data suggest that rosiglitazone can improve cognitive impairment, and inhibit astrocyte activation and oxidative damage following SE. Rosiglitazone may be a promising agent for treatment of epilepsy involving SE-induced cognitive impairment.

Topics: Analysis of Variance; Animals; Astrocytes; Benzamides; Cell Count; Cognition Disorders; Disease Models, Animal; Glial Fibrillary Acidic Protein; Glutathione; Glutathione Disulfide; Hippocampus; Lithium Chloride; Male; Maze Learning; Oxidative Stress; Pilocarpine; PPAR gamma; Pyridines; Rats; Rats, Sprague-Dawley; Rosiglitazone; Status Epilepticus; Systole; Thiazolidinediones

Little is known regarding the relationship between treatment adherence and residual cognitive dysfunction in euthymic bipolar disorder patients. This study aimed to investigate whether poor treatment adherence is associated with cognitive impairment in euthymic bipolar patients and whether other factors may be associated with both adherence and cognitive functioning.. Euthymic DSM-IV bipolar I or II disorder patients (N = 103: 61 with high levels of treatment adherence and 42 with poor treatment adherence) were assessed using a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions and compared with 35 healthy controls of similar age, sex distribution, and education. Data were collected from September 2005 to June 2007.. Bipolar patients with poor treatment adherence had more hospitalizations than those with high adherence. After controlling for age, gender, estimated IQ score, and Young Mania Rating Scale and 17-item Hamilton Rating Scale for Depression scores, non-treatment-adherent patients performed less well than normal controls in verbal learning and some executive functions. Among treatment-adherent and poorly adherent bipolar disorder patients, performance was similar in attention tasks and short-term and long-term verbal recall, but non-treatment-adherent patients were more impaired in ability to inhibit interferences and in spatial working memory. Poorer treatment adherence also was associated with the bipolar I subtype and with greater illness severity, as indicated by number of manic episodes and hospitalizations and history of psychosis. Pharmacologic factors, such as treatment with lithium, may also influence the relationship between neurocognition and adherence.. There is a close relationship between poor treatment adherence and cognitive impairment, but the causal inferences of these findings are uncertain. Poor treatment adherence may worsen the course of bipolar disorder and so indirectly worsen cognitive performance, or cognitive impairment may contribute to poor treatment adherence and reflect more severe illness.

Topics: Adult; Bipolar Disorder; Cognition Disorders; Comorbidity; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Lithium Chloride; Male; Memory; Neuropsychological Tests; Patient Compliance; Psychiatric Status Rating Scales; Psychomotor Performance; Severity of Illness Index; Verbal Learning

We assessed performance on the Wisconsin Card Sorting Test (WCST), measuring executive functions, in 30 patients showing different prophylactic effect of lithium (excellent lithium responders-ER, partial responders-PR and non-responders-NR), and in fifty persons of their offspring (12 of ER, 26 of PR, and 12 of NR). Age- and gender head-to-head matched population consisted of 30 subjects for lithium group and 50 subjects for the offspring of lithium patients. In lithium patients, NR had significantly worse results compared to the remaining groups and to control subjects on perseverative errors (WCST-P) and conceptual responses (WCST-%conc). No differences were observed in the offspring of patients with different effect of lithium, however, they showed an impairment on WCST-P and WCST-%conc compared to matched healthy controls. Therefore, the favorable effect of lithium prophylaxis may be associated with a preservation of executive cognitive functions and the offspring of bipolar patients shows an impairment of such functions.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antimanic Agents; Bipolar Disorder; Cognition Disorders; Executive Function; Female; Humans; Lithium Chloride; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Young Adult

Patients with bipolar disorder have been reported to have neurocognitive deficits; however, it is not known whether the cognitive dysfunctions are state-dependent or a stable trait. Lithium and valproate, 2 of the most widely used mood stabilizers in the treatment of bipolar disorder, have also been associated with cognitive impairment. However, the degree and pattern of neurocognitive impairment in euthymic bipolar patients on either monotherapy with lithium or valproate have not been compared before in depth.. We compared 17 euthymic outpatients with bipolar disorder (BD) on lithium monotherapy to 11 euthymic outpatients with BD on valproate monotherapy and 29 comparison subjects using tests measuring immediate verbal memory and executive functions in addition to 3 subtests of the Wechsler Adult Intelligence Scale Revised. The groups were similar in terms of level of education, duration and severity of illness, and gender distribution. Patients on lithium monotherapy were older than patients on valproate and healthy controls. Mood symptoms as assessed by standardized scales were mild to non-existent in both patient groups.. Immediate verbal memory was impaired in both patient groups compared to controls, where the main effect of age was not significant. No significant differences could be found on the other cognitive measures.. Both lithium and valproate may be associated with immediate verbal memory impairment, sparing other cognitive functions. Presence of a similar verbal memory deficit in the lithium and valproate groups suggests that this deficit might be intrinsic to BD or that the 2 medications influence immediate verbal memory similarly. Larger samples of remitted bipolar patients on monotherapy should be studied for more precise conclusions.

Topics: Adolescent; Adult; Antimanic Agents; Bipolar Disorder; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Evaluation Studies as Topic; Female; Humans; Intelligence Tests; Lithium Chloride; Male; Memory; Middle Aged; Multivariate Analysis; Neuropsychological Tests; Problem Solving; Valproic Acid; Verbal Learning

Curative cancer treatment regimens often require cranial irradiation, resulting in lifelong neurocognitive deficiency in cancer survivors. This deficiency is in part related to radiation-induced apoptosis and decreased neurogenesis in the subgranular zone of the hippocampus. We show that lithium treatment protects irradiated hippocampal neurons from apoptosis and improves cognitive performance of irradiated mice. The molecular mechanism of this effect is mediated through multiple pathways, including Akt/glycogen synthase kinase-3beta (GSK-3beta) and Bcl-2/Bax. Lithium treatment of the cultured mouse hippocampal neurons HT-22 induced activation of Akt (1.5-fold), inhibition of GSK-3beta (2.2-fold), and an increase in Bcl-2 protein expression (2-fold). These effects were sustained when cells were treated with lithium in combination with ionizing radiation. In addition, this combined treatment led to decreased expression (40%) of the apoptotic protein Bax. The additional genes regulated by lithium were identified by microarray, such as decorin and Birc1f. In summary, we propose lithium treatment as a novel therapy for prevention of deleterious neurocognitive consequences of cranial irradiation.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cell Line; Cell Survival; Cells, Cultured; Cognition Disorders; Cranial Irradiation; Dose-Response Relationship, Radiation; Female; Gene Expression; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Lithium Chloride; Male; Mice; Mice, Inbred C57BL; Neurons; Neuroprotective Agents; Pregnancy; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Signal Transduction