lithium-chloride and Learning-Disabilities

Advancements in fetal intervention procedures have led to increases in the number of pregnant women undergoing general anesthesia during the second trimester-a period characterized by extensive proliferation of fetal neural stem cells (NSCs). However, few studies have investigated the effects of mid-gestational sevoflurane exposure on fetal NSC proliferation or postnatal learning and memory function. In the present study, pregnant rats were randomly assigned to a control group (C group), a low sevoflurane concentration group (2%; L group), a high sevoflurane concentration group (3.5%; H group), a high sevoflurane concentration plus lithium chloride group (H + Li group), and a lithium chloride group (Li group) at gestational day 14. Rats received different concentrations of sevoflurane anesthesia for 2 h. The offspring rats were weaned at 28 days for behavioral testing (i.e., Morris Water Maze [MWM]), and fetal brains or postnatal hippocampal tissues were harvested for immunofluorescence staining, real-time PCR, and Western blotting analyses in order to determine the effect of sevoflurane exposure on NSC proliferation and the Wnt/β-catenin signaling pathway. Our results indicated that maternal exposure to 3.5% sevoflurane (H group) during the mid-gestational period impaired the performance of offspring rats in the MWM test, reduced NSC proliferation, and increased protein levels of fetal glycogen synthase kinase-3 beta (GSK-3β). Such treatment also decreased levels of β-catenin protein, CD44 RNA, and Cyclin D1 RNA relative to those observed in the C group. However, these effects were transiently attenuated by treatment with lithium chloride. Conversely, maternal exposure to 2% sevoflurane (L group) did not influence NSC proliferation or the Wnt signaling pathway. Our results suggest that sevoflurane exposure during the second trimester inhibits fetal NSC proliferation via the Wnt/β-catenin pathway and impairs postnatal learning and memory function in a dose-dependent manner.

Topics: Anesthetics, Inhalation; Animals; Cell Division; Cyclin D1; Dose-Response Relationship, Drug; Female; Fetus; Gestational Age; Glycogen Synthase Kinase 3 beta; Hippocampus; Hyaluronan Receptors; Learning Disabilities; Lithium Chloride; Maze Learning; Memory Disorders; Methyl Ethers; Nerve Tissue Proteins; Neural Stem Cells; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Sevoflurane; Spatial Behavior; Wnt Signaling Pathway

Rodent models of traumatic brain injury (TBI) reproduce secondary injury sequela and cognitive impairments observed in patients afflicted by a TBI. Impaired neurotransmission has been reported in the weeks following experimental TBI, and may be a contributor to behavioral dysfunction. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, the machinery facilitating vesicular docking and fusion, is a highly-conserved mechanism important for neurotransmission. Following TBI, there is a reduction in both the formation of the SNARE complex and the abundance of multiple SNARE proteins, including the chaperone protein cysteine string protein α (CSPα). Treatment with lithium in naïve rats reportedly increases the expression of CSPα. In the context of TBI, brain-injured rats treated with lithium exhibit improved outcome in published reports, but the mechanisms underlying the improvement are poorly understood. The current study evaluated the effect of lithium administration on the abundance of SNARE proteins and SNARE complex formation, hemispheric tissue loss, and neurobehavioral performance following controlled cortical impact (CCI). Sprague Dawley rats were subjected to CCI or sham injury, and treated daily with lithium chloride or vehicle for up to 14days. Administration of lithium after TBI modestly improved spatial memory at 14days post-injury. Semi-quantitative immunoblot analysis of hippocampal lysates revealed that treatment with lithium attenuated reductions in key SNARE proteins and SNARE complex formation at multiple time points post-injury. These findings highlight that treatment with lithium increased the abundance of synaptic proteins that facilitate neurotransmission and may contribute to improved cognitive function after TBI.

Topics: alpha-Synuclein; Analysis of Variance; Animals; Antimanic Agents; Brain Injuries, Traumatic; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Learning Disabilities; Lithium Chloride; Male; Psychomotor Disorders; Rats; Rats, Sprague-Dawley; SNARE Proteins; Spatial Learning; Synaptophysin; Synaptosomal-Associated Protein 25; Time Factors; Vesicle-Associated Membrane Protein 2

Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences.. A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits.. Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits.. This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.

Topics: Animals; Anticonvulsants; Brain; Cholinergic Agents; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Ketamine; Learning Disabilities; Lithium Chloride; Male; Maze Learning; Midazolam; N-Methylscopolamine; Pilocarpine; Rats; Rats, Sprague-Dawley; Status Epilepticus; Valproic Acid

Lithium has been reported to have neuroprotective effects, but the preventive and treated role on cognition impairment and the underlying mechanisms have not been determined. In the present study, C57Bl/6 mice were subjected to repeated bilateral common carotid artery occlusion to induce the learning and memory deficits. 2 mmol/kg or 5 mmol/kg of lithium chloride (LiCl) was injected intraperitoneally per day before (for 7 days) or post (for 28 days) the operation. This repeated cerebral ischemia-reperfusion (IR) induced dynamic overexpression of ratio of Bcl-2/Bax and BDNF in hippocampus of mice. LiCl pretreatment and treatment significantly decreased the escape latency and increased the percentage of time that the mice spent in the target quadrant in Morris water maze. 2 mmol/kg LiCl evidently reversed the morphologic changes, up-regulated the survival neuron count and increased the BDNF gene and protein expression. 5 mmol/kg pre-LiCl significantly increased IR-stimulated reduce of Bcl-2/Bax and p-CREB/CREB. These results described suggest that pre-Li and Li treatment may induce a pronounced prevention on cognitive impairment. These effects may relay on the inhibition of apoptosis and increasing BDNF and p-CREB expression.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Brain Ischemia; Brain-Derived Neurotrophic Factor; Carotid Artery Diseases; Cell Survival; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Hippocampus; Learning Disabilities; Lithium Chloride; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Neurons; Nootropic Agents; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Reperfusion Injury; Spatial Memory

Maternal infection during pregnancy is associated with an increased risk of neurodevelopmental injury. Our aim was to investigate whether prenatal immune challenge could alter susceptibility to seizure-induced brain injury in adulthood. Pregnant Wistar rats were injected intraperitoneally with lipopolysaccharide (LPS) or normal saline (NS) at days 15 and 16 of gestation. At postnatal day 45, seizure susceptibility was assessed in response to lithium-pilocarpine (LiPC) in adult offspring. Four groups were studied, including normal control (NS-NS), prenatal inflammation (LPS-NS), adult seizure (NS-LiPC), and "two-hit" (LPS-LiPC) groups. Our results demonstrated that adult rat offspring of LPS-exposed dams showed significantly greater susceptibility to LiPC-induced seizures, as well as enhanced hippocampal neuronal injury after seizures. Furthermore, animals in the "two-hit" group performed significantly worse than those from the NS-LiPC group in the open field test and Morris water maze. Our findings suggest that prenatal immune activation can cause a long-lasting increase in seizure susceptibility and predispose the brain to the damaging effect of seizures later in life.

Topics: Age Factors; Animals; Animals, Newborn; Brain Injuries; Disease Models, Animal; Disease Susceptibility; Exploratory Behavior; Female; Hippocampus; Learning Disabilities; Lipopolysaccharides; Lithium Chloride; Male; Maze Learning; Muscarinic Agonists; Pilocarpine; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Seizures; Time Factors

We investigated whether the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine (DCS, 20 microg/side) microinfused into the basolateral amygdala (BLA) would reverse stress-induced impairment of extinction in two aversive learning paradigms: contextual fear conditioning and conditioned taste aversion (CTA). We found that DCS in the BLA show differential involvement in the extinction of these two paradigms and in its modulation of stress-induced impairment of extinction. This may suggest that the dysfunctional extinction of fear and taste aversion following exposure to a stressful experience may be modulated by different mechanisms.

Topics: Amygdala; Analysis of Variance; Animals; Antimetabolites; Avoidance Learning; Conditioning, Psychological; Cycloserine; Exploratory Behavior; Extinction, Psychological; Fear; Learning Disabilities; Lithium Chloride; Locomotion; Male; Rats; Rats, Wistar; Stress, Psychological; Taste

Rats were taught a conditioned taste aversion (CTA) by pairing a 10% sucrose solution (CS) with lithium chloride (LiCl)-induced poisoning (UCS). The CS-UCS interval was 30 min. The LiCl dose (20 ml/kg) was either strong (0.15 M) or weaker (0.075 M). Electroconvulsive shock (ECS) (80 mA for 600 msec) was interpolated within the CS-UCS interval at either 15 or 30 min. ECS caused a significant disruption of CTA only when the aversion was established with the weaker dose of LiCl. There was also no indication that interference with CTA was dependent upon close temporal contiguity between the ECS and LiCl. In a second experiment a CTA was established with LiCl (0.15 M) which was heated to 45 degrees C. Under these conditions ECS produced a similar disruption of learning to that when the UCS was the weaker dose of LiCl (0.075 M). The results suggest that an apparent differential loss of learning within the CS-UCS interval described in a previous report was accidentally created when some groups of animals were poisoned with warm and others with cold LiCl.

Topics: Animals; Avoidance Learning; Chlorides; Electroshock; Learning Disabilities; Lithium; Lithium Chloride; Male; Rats; Sucrose; Taste; Temperature