Step-through Passive Avoidance Task Research Articles

Cannabidiol improves memory and decreases IL-1β serum levels in rats with lipopolysaccharide-induced inflammation.

Memory improving and anti-inflammatory properties of cannabidiol (CBD) were investigated in an experimental model of lipopolysaccharide (LPS)-induced inflammation.

Restorative effects of probiotics on memory impairment in sleep-deprived mice

ABSTRACT Background Insufficient sleep is a serious public health epidemic in modern society, impairing memory and other cognitive functions. In this study, partial sleep deprivation (SD) was used to induce cognitive impairment in mice to determine the effects of probiotics on subsequent cognitive deficits. Methods Lactiplantibacillus plantarum Lp-115 (Lp-115), Lacticaseibacillus paracasei Lpc-37 (Lpc-37), Bifidobacterium animalis subsp. lactis 420 (B420) and their combination were administered to mice subjected to partial SD and compared with non-SD and SD vehicle groups. Mice were administered a daily oral gavage containing either 1 × 109 colony forming units (CFU) of single-strain, 1.5 × 109 CFU of multi-strain (5 × 108 CFU/strain), or vehicle for thirty days prior to and for nine days during a behavioural test paradigm. The novel object recognition (NOR) test, spontaneous alternation Y-maze (Y-maze), and the step-through passive avoidance (STPA) task were applied to evaluate learning and memory performance following partial SD. Results Partial SD had a significant impact on cognitive function in vehicle mice. Intervention with Lpc-37 significantly improved recognition memory deficits in the NOR test, spatial working memory deficits in the Y-maze, and contextual long-term memory impairments in the STPA task, in mice subjected to partial SD compared to the SD vehicle group. The multi-strain significantly improved recognition memory deficits in the NOR test and spatial working memory deficits in the Y-maze in mice subjected to partial SD compared to the SD vehicle group. Conclusions These findings demonstrate that Lpc-37 and the multi-strain may play a role in alleviating memory impairments and improve cognitive function in partially sleep-deprived mice.

Effects of Yokukansankachimpihange on Memantine-induced Dizziness in Mice with Memory Impairment

Memantine (Mem) is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of Alzheimer's disease. However, side effects, including dizziness, headache and confusion, have been reported. Therefore, although it reduces the symptoms of dementia, such as memory loss, its use is limited by side effects for patients at risk of injury. In the present study, we investigated the effects of the Japanese Kampo medicine yokukansankachimpihange (YKSCH) on Mem-induced dizziness in a mouse model of memory impairment. Mem (20 mg/kg B.W., p.o.) reduced the performance score during the beam balance test and walking time on a rotarod, confirming the disrupted sense of balance and motor coordination. In contrast, YKSCH (750 mg/kg B.W., p.o.) significantly suppressed this disruption of balance and motor coordination in mice. Moreover, YKSCH did not attenuate the ameliorative effects of Mem on learning and memory impairment in the Y-maze test or step-through passive avoidance task. Spatial learning and memory significantly recovered in the Mem-treated group and Mem plus YKSCH-treated group, suggesting no pharmacological interaction between Mem and YKSCH in mice. Therefore, YKSCH may be effective at alleviating the Mem-induced equilibrium disturbance in mice with memory impairment without reducing its memory disorder improvement effects. Our study may be useful for future studies on the combined use of Mem and YKSCH in the treatment of Alzheimer's disease.

The Protective Effects of Nicotine and Bucladesine on Impaired Avoidance Memory Caused by Sodium Arsenate Toxicity in Mice

Background: The toxic effect of sodium arsenate on nervous system has been shown; but the protective effects of several compounds against sodium arsenate are not clear. This study aimed to investigate the protective effects of nicotine and bucladesine, two positive modulators of neuronal function, on sodium arsenate toxicity against avoidance memory impairment. Methods: Male mice (N=154) were assigned to 22 groups (12 experimental and 10 control) of seven animals each and were treated as follows: sodium arsenate (2.5, 5, or 10 mg/kg) for 28 days, nicotine (1 mg/kg) for either 1, 2, or 4 days, bucladesine (600 nM/mouse) for either 1, 2, or 4 days, and nicotine (1 mg/kg)+bucladesine (600 nM/mouse)+sodium arsenate (2.5 mg/kg). The last group was treated with 2.5 mg/kg sodium arsenate first, and then received the combination of nicotine and bucladesine for 1, 2, or 4-days. The corresponding control groups did not receive any drug but either saline, deionized water, or combination of deionized water and DMSO, but went through the same procedure as other animals. All mice were trained 24 h in the step-through passive avoidance task. The avoidance memory retention was assessed at 24, 48, 96, and 168 h after the training period by measuring the time they stayed in a dark chamber. Results: All sodium arsenate doses significantly reduced the time stayed in the dark chamber regardless of the treatment duration (24, 48, 96 & 168 h) after training. Both nicotine and bucladesine, whether used singly or combined for 1, 2, and 4 days significantly enhanced the time latency compared to the controls at all of the experimental timepoints following the training. Conclusion: Nicotine and bucladesine showed synergistic effects and reversed the sodium arsenate-induced avoidance memory deficits in mice.

Effects of Quercetin and Resveratrol on Zinc Chloride- and Sodium Metavanadate-Induced Passive Avoidance Memory Retention Deficits in Male Mice.

Quercetin and resveratrol are found in a variety of fruits and vegetables and have several biological and pharmacological properties. In this study, the effects of quercetin [50 mg/kg, intraperitoneal (i.p.)] and resveratrol (50 mg/kg, i.p.) on zinc chloride (ZnCl2; 75 mg/kg/d, 2 weeks oral gavage) and sodium metavanadate (SMV; 22.5 mg/kg/d, 2 weeks oral gavage) induced passive avoidance memory retention were investigated in step-through passive avoidance tasks. ZnCl2 was dissolved in saline and SMV was dissolved in drinking water. Mice received ZnCl2 or SMV orally for two weeks and were administered quercetin or resveratrol by i.p. injection on day 14, days 12 and 14, or days 10, 12, and 14. At the end of treatment, animals were trained for one day in a step-through passive avoidance task, then alterations in avoidance memory retention were evaluated after 24, 48, 96, and 168 h. Oral consumption of ZnCl2 and SMV decreased latency time compared with control groups. Both quercetin and resveratrol (50 mg/kg, i.p.) prevented ZnCl2- and SMV-induced avoidance memory retention impairments and did not significantly alter muscle strength, as demonstrated in rotarod tasks. No significant differences were observed between mice who received single, double, or triple doses of quercetin or resveratrol. The results suggest that quercetin and resveratrol may have preventive effects on ZnCl2- and SMV-induced memory impairment in male mice.

Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

BackgroundDue to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice.Materials and methodsAs a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry.ResultsSotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study.ConclusionSotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

Acute and chronic treatment with moclobemide, a reversible MAO-inhibitor, potentiates the antielectroshock activity of conventional antiepileptic drugs in mice

BackgroundDue to enhancing serotonergic and noradrenergic neurotransmission, moclobemide may influence seizure phenomena. In this study, we examined the effect of both acute and chronic treatment with moclobemide on seizures and the action of first-generation antiepileptic drugs: valproate, carbamazepine, phenobarbital and phenytoin. MethodsThe effect of moclobemide on seizures was assessed in the electroconvulsive threshold test, while its influence on antiepileptic drugs was estimated in the maximal electroshock test in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. ResultsGiven acutely, moclobemide at 62.5 and 75 mg/kg increased the electroconvulsive threshold. In contrast, chronic treatment with moclobemide up to 75 mg/kg did not influence this parameter. Acute moclobemide applied at subthreshold doses (up to 50 mg/kg) enhanced the antielectroshock effects of carbamazepine, valproate and phenobarbital. Chronic moclobemide (37.5‐75 mg/kg) increased the action of all four antiepileptic drugs. All revealed interactions, except these between moclobemide and phenobarbital, seem to have pharmacokinetic nature, because the antidepressant drug, either in acute or in chronic treatment, increased the brain concentrations of respective antiepileptic drugs. In terms of undesired neurotoxic effects, acute and chronic moclobemide, antiepileptic drugs, and their combinations did not produce significant motor or long-term memory impairment. ConclusionsAcute and chronic therapy with moclobemide can increase the effectiveness of some antiepileptic drugs against the maximal electroshock test. In mice, this effect was, at least partially, due to pharmacokinetic interactions. So far as the results of experimental studies can be transferred to clinical conditions, moclobemide seems safe for the application in patients with epilepsy and depression. Possibly, in the case of certain antiepileptic drugs combined with moclobemide, their doses should be adjusted downwards.

The neuroprotective effect of NeuroAid on morphine-induced amnesia with respect to the expression of TFAM, PGC-1α, ΔfosB and CART genes in the hippocampus of male Wistar rats.

Morphine is a natural alkaloid which derived from the opium poppy Papaver somniferum. Many studies have reported the effect of morphine on learning, memory and gene expression. CART (cocaine-amphetamine regulated transcript)is an important neuropeptide which has a critical role in physiological processes including drug dependence and antioxidant activity. ΔfosB is a transcription factor which modulates synaptic plasticity and affects learning and memory. TFAM (the mitochondrial transcription factor A) and PGC-1α (Peroxisome proliferator-activated receptor γ coactivator-1α) are critically involved in mitochondrial biogenesis and antioxidant pathways. NeuroAid is a Chinese medicine that induces neuroprotective and anti-apoptotic effects. In this research, we aimed to investigate the effect of NeuroAid on morphine-induced amnesia with respect to the expression of TFAM, PGC-1α, ΔfosB and CART in the rat's hippocampus. In this study, Morphine sulfate (at increasing doses), Naloxone hydrochloride (2.5mg/kg) and NeuroAid (2.5mg/kg) were administered intraperitoneal and real-time PCR reactions were done to assess gene expression. The results showed, morphine impaired memory of step-through passive avoidance, while NeuroAid had no effect. NeuroAid attenuated (but not reversed) morphine-induced memory impairment in morphine-addicted rats. Morphine increased the expression of PGC-1α and decreased the expression of CART. However, NeuroAid increased the expression of TFAM, PGC-1α, ΔfosB and CART. NeuroAid restored the effect of morphine on the expression of CART and PGC-1α. In conclusion, morphine impaired memory of step-through passive avoidance and NeuroAid attenuated this effect. The effect of NeuroAid on morphine-induced memory impairment/gene expression may be related to its anti-apoptotic and neuroprotective effects.

Dracocephalum moldavica attenuates scopolamine-induced cognitive impairment through activation of hippocampal ERK-CREB signaling in mice

Ethnopharmacological relevanceDracocephalum moldavica (Moldavian balm) has been traditionally used for the treatment of intellectual disabilities, migraines and cardiovascular problems in East Asia. Recent scientific studies have demonstrated the usefulness of this plant to treat neurodegenerative disorders, including Alzheimer's disease. Aim of the studyThis study aimed to investigate the effects of the ethanolic extract of D. moldavica leaves (EEDM) on scopolamine-induced cognitive impairment in mice and the underlying mechanisms of action. Materials and methodsThe behavioral effects of EEDM were examined using the step-through passive avoidance and Morris water maze tasks. To elucidate the underlying mechanism, we tested whether EEDM affects acetylcholinesterase activity and the expression of memory-related signaling molecules including extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus. ResultsEEDM (25, 50 or 100 mg/kg) significantly ameliorated the scopolamine-induced step-through latency reduction in the passive avoidance task in mice. In the Morris water maze task, EEDM (50 mg/kg) significantly attenuated scopolamine-induced memory impairment. Furthermore, the administration of EEDM increased the phosphorylation levels of ERK and CREB in the hippocampus but did not alter acetylcholinesterase activity. ConclusionsThese findings suggest that EEDM significantly attenuates scopolamine-induced memory impairment in mice and may be a promising therapeutic agent for improving memory impairment.

Nebivolol attenuates the anticonvulsant action of carbamazepine and phenobarbital against the maximal electroshock-induced seizures in mice

BackgroundDue to co-occurrence of seizures and cardiovascular disorders, nebivolol, a widely used selective β1-blocker with vasodilatory properties, may be co-administered with antiepileptic drugs. Therefore, we wanted to assess interactions between nebivolol and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital in the screening model of tonic–clonic convulsions.MethodsSeizure experiments were conducted in the electroconvulsive threshold and maximal electroshock tests in mice. The chimney test served as a method of assessing motor coordination, whereas long-term memory was evaluated in the computerized step-through passive-avoidance task. To exclude or confirm pharmacokinetic interactions, we measured brain concentrations of antiepileptic drugs using the fluorescence polarization immunoassay.ResultsIt was shown that nebivolol applied at doses 0.5–15 mg/kg did not raise the threshold for electroconvulsions. However, nebivolol at the dose of 15 mg/kg reduced the anti-electroshock properties of carbamazepine. The effect of valproate, phenytoin, and phenobarbital remained unchanged by combination with the β-blocker. Nebivolol significantly decreased the brain concentration of valproate, but did not affect concentrations of remaining antiepileptic drugs. Therefore, contribution of pharmacokinetic interactions to the final effect of the nebivolol/carbamazepine combination seems not probable. Nebivolol alone and in combinations with antiepileptic drugs did not impair motor performance in mice. Nebivolol alone did not affect long-term memory of animals, and did not potentiate memory impairment induced by valproate and carbamazepine.ConclusionsThis study indicates that nebivolol attenuated effectiveness of some antiepileptic drugs. In case the results are confirmed in clinical settings, this β-blocker should be used with caution in epileptic patients.

Sesame Lignans Suppress Age-Related Cognitive Decline in Senescence-Accelerated Mice.

Sesame lignans, which are biologically active compounds present in sesame seeds and oil, are known to have neuroprotective effects in several models of brain dysfunction. However, the effects of sesame lignans on age-related brain dysfunction are not clear and were thus investigated in the present study using a senescence-accelerated mouse (SAMP10). Two-month-old male SAMP10 mice were administrated a basal diet with 0% or 0.05% sesame lignans for two months, or with 0%, 0.02%, or 0.05% sesame lignans for 10 months and subjected to step-through passive avoidance tasks and forced swim tests. Reactive carbonyl species (RCs) were evaluated as markers of oxidative stress using a recently developed comprehensive analytical method. Both learning time in passive avoidance tasks and immobile time in forced swim tests became longer with aging (p < 0.05). However, the administration of sesame lignans significantly ameliorated age-related effects in both tests (p < 0.05). Age-related increases in RCs such as 4-hydroxy-2-nonenal in the cerebral cortex and liver were reduced in mice fed sesame lignans. These results suggest that sesame lignans can prevent age-related brain dysfunction via anti-oxidative activity.

Impact of the metabotropic glutamate receptor7 (mGlu7) allosteric agonist, AMN082, on fear learning and memory and anxiety-like behavior

The present study was conducted to evaluate the influence of AMN082, the metabotropic glutamate receptor subtype 7 (mGlu7) allosteric agonist on different stages of memory processes connected with fear conditioning in the passive avoidance (PA) learning task in mice and negative emotional state (anxiety-like) induced by ethanol- and morphine-withdrawal in the elevated plus maze (EPM) test in rats. To perform the PA test, AMN082 (1.25, 2.5 and 5 mg/kg, i. p.) was injected to interfere with (or inhibit) acquisition, consolidation, and retrieval processes. The retention latency in each group was recorded using a step-through passive avoidance task 24 h after training. In turn, in ethanol- and morphine-withdrawal rats, the influence of AMN082 on anxiety-like behavior was estimated in the EPM test 24 h- (ethanol) and 72- h (morphine) after the last dose of repeated drug administrations. In all experimental groups, AMN082 at the dose of 5 mg/kg significantly decreased the step-through latency of long-term memory in the PA task. These AMN082 effects were reversed by MMPIP (10 mg/kg), the antagonist of mGlu7 receptor. AMN082 (2.5 and 5 mg/kg) also decreased ethanol- and morphine withdrawal-induced anxiety-like behavior in the EPM test, and this AMN082 (5 mg/kg) effect was counteracted by MMPIP pretreatment. Taken together, the results show that mGlu7 is involved in fear learning to the context and anxiety-like state connected with unpleasant experiences after ethanol- and morphine withdrawal in rodents. However, it appears that functional dissociation exists between these two AMN082 effects.

Glycogen synthase kinase-3 inhibition as a potential pharmacological target for vascular dementia: In silico and in vivo evidence

Vascular dementia is a serious problem as it creates significant disability and dependency in the affected person. Lives of these patients can be improved through the advent of novel drug targets which can be targeted by pharmacological therapies. However, finding a precise and druggable target for vascular dementia is experimentally impossible and challenging task owing to a complex and mostly unknown interplay between the cognitive abilities of the brain with a diversity of vascular diseases. To address this issue, we have systematically analyzed the literature reports by using well-known methods and approaches of bioinformatics (viz. network pharmacology, reverse pharmacology, enrichment analysis of KEGG pathways, biological processes of Gene Ontology and DIAMOnD algorithm). Because glycogen synthase kinase-3 (GSK-3) seems to be one of the most promising targets, therefore, we have tested the capacity of lithium carbonate, a classical inhibitor of GSK-3, for treatment of dementia resulting from mild chronic cerebral hypoperfusion in mice. To this end, our study shows in-vivo validation of predicted target, i.e., pharmacological deactivation of GSK-3 enzyme and its impact on cognitive abilities employing a behavioral test battery, i.e., object recognition task, step-through passive avoidance task, elevated plus maze task and water maze task. In this framework, we observed that lithium carbonate attenuates recognition, emotion, spatial and fear-motivated learning and memory impairments along with attenuation of oxidative stress, cholinergic dysfunction and glutamate-induced excitotoxicity in cerebral cortex and hippocampus. In conclusion, we propose GSK-3 as a promising drug target for vascular dementia in light of experimental results and in-silico predictions.

The role of nucleus accumbens shell on acquisition and retrieval stages of morphine state dependent learning.

In the present study, the effect of transient inactivation of the shell subregion of the nucleus accumbens (NAC shell) by lidocaine on the acquisition and retrieval stages of passive avoidance learning (PAL) and memory and morphine state-dependent learning (SDL) in male wistar rats was investigated. Adult male wistar rats weighing (220-250 g) were used. Lidocaine hydrochloride was bilaterally injected into the shell area of the nucleus accumbens 5 min before of subcutaneous morphine administration. pre-training and pre-test infusion of lidocaine into the NAC shell significantly impaired PAL and memory. Furthermore, Pre-training administration of morphine (5 mg/kg, s.c.) in a step-through passive avoidance task induced state-dependent learning with impaired memory retrieval on the test day. The impairment of memory was restored after pre-test administration of the same dose of morphine. This phenomenon has been named as morphine state dependent learning (SDL). Moreover, Pre-training and pre-test inactivation of the NAC shell impaired morphine SDL. The results suggest the role of NAC shell as a common structure in the PAL and morphine SDL. It is suggested that NAC shell as a common area plays a critical role in the acquisition and retrieval stages of PAL and also morphine SDL.

Protective Effects of Dietary Supplements Containing Probiotics, Micronutrients, and Plant Extracts Against Lead Toxicity in Mice.

Lead (Pb) intoxication is a serious food safety issue, and the development of relevant dietary strategies is an area of ongoing research. In this study, two different dietary supplements were designed and evaluated for their effects against Pb toxicity in mice. Dietary supplement A contained grape seed extract, tea polyphenols and Lactobacillus plantarum CCFM8661, and dietary supplement B contained vitamin C, calcium carbonate, zinc acetate, and L. plantarum CCFM8661. The results showed that both dietary supplements could effectively decrease Pb levels, protect aminolevulinic acid dehydratase, superoxide dismutase and catalase activities and recover glutathione, zinc protoporphyrin and malondialdehyde levels in tissues and blood of mice. A step-through passive avoidance task confirmed that the dietary supplements could recover the learning and memory capacities of Pb-exposed mice. The protective effects of both dietary supplements to alleviate oxidative stress and cognitive impairments were superior to the chelator treatment. Administration of the dietary supplements during Pb exposure offered more significant protection than administration after Pb exposure. Animal safety evaluation also indicated that these dietary supplements barely induced side effects in the mice. This study provides evidence that dietary supplements containing probiotics, micronutrients, and plant extracts can be considered a new dietary strategy against Pb toxicity.

Interactions of Mexiletine with Novel Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis

The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs: lamotrigine, oxcarbazepine, topiramate and pregabalin in the maximal electroshock test in mice (MES). The isobolographic analysis was used to assess the nature of interactions between the tested drugs. Total brain concentrations of antiepileptics were also measured to detect possible pharmacokinetic interactions. The results obtained indicated that the mixture of mexiletine and pregabalin at the fixed ratios of 1:1 and 3:1 led to supra-additive interaction in terms of seizure suppression, while the proportion of 1:3 occurred additive. Synergism was also demonstrated for the combination of mexiletine and topiramate in all three proportions. Combinations of mexiletine with lamotrigine and mexiletine with oxcarbazepine were found to be additive. Adverse-effect profiles of mexiletine, antiepileptics and drug combinations were evaluated in the chimney test (motor coordination) and step-through passive-avoidance task (long-term memory). Mexiletine and drug combinations did not impair long-term memory. Moreover, all combinations of mexiletine with lamotrigine, oxcarbazepine and topiramate had no significant effect on motor coordination. However, the results from the chimney test indicated that pregabalin, administered alone at its ED50 dose from the MES-test, significantly impaired motor performance. Similar adverse effects were observed when mexiletine was co-administered with pregabalin at the fixed-dose ratio combinations of 1:1 and 1:3. However, reduction of pregabalin dose at the fixed ratio of 3:1 seems to prevent significant motor impairment. The results may indicate that mexiletine can be considered as an adjunctive drug in antiepileptic treatment, particularly in patients with concomitant cardiac arrhythmia.

The role of verapamil and SL-327 in morphine- and ethanol-induced state-dependent and cross state-dependent memory

Drugs of abuse trigger a very specific type of memory called state-dependent memory (SDM). Both memory process and drug addiction are underlain by neuroplasticity, which depends on calcium concentration and protein kinase activity.Within the scope of this study was to evaluate the impact of verapamil, an L-type voltage-gated calcium channel (VGCC) blocker, and SL-327, a selective MAPK/ERK kinase inhibitor, on morphine and ethanol SDM including the cross effects between these drugs with an additional influence of nicotine. To assess SDM in mice a step-through passive avoidance task was used.Our results show that amnestic effects of morphine (10.0 mg/kg, s.c.) and ethanol (1.0 g/kg, i.p.) can be reversed by pre-test administrations of morphine (10.0 mg/kg, s.c.), ethanol (1.0 g/kg, i.p.) and nicotine (0.1 mg/kg, s.c.), indicating morphine and ethanol SDM, as well as morphine-ethanol, morphine-nicotine, ethanol-morphine and ethanol-nicotine cross SDM. Pre-test co-treatment of verapamil (10.0 mg/kg, i.p.) with morphine/ethanol/nicotine increased all investigated SDM and cross SDM effects. Pre-test co-treatment of SL-327 (10.0 mg/kg, i.p.) diminished morphine- and ethanol-induced SDM along with the cross effects except ethanol-morphine cross SDM. In conclusion, SDM depends on ERK1/2 activation and also verapamil affects this type of memory, although the exact mechanism of its cognitive action has not been investigated in this study.

Verapamil Blocks Scopolamine Enhancement Effect on Memory Consolidation in Passive Avoidance Task in Rats.

Our recent data have indicated that scopolamine, a non-selective muscarinic receptor antagonist, improves memory consolidation, in a passive avoidance task, tested in rats. It has been found that verapamil, a phenylalkylamine class of the L-type voltage-dependent calcium channel antagonist, inhibits [3H] N-methyl scopolamine binding to M1 muscarinic receptors. However, there are no data about the effect of verapamil on memory consolidation in the passive avoidance task, in rats. The purpose of the present study was to examine the effects of verapamil (0.5, 1.0, 2.5, 5.0, 10, or 20 mg/kg i.p.) as well as the interaction between scopolamine and verapamil on memory consolidation in the step-through passive avoidance task, in Wistar rats. Our results showed that verapamil (1.0 and 2.5 mg/kg) administered immediately after the acquisition task significantly increased the latency of the passive avoidance response, on the 48 h retested trial, improving memory consolidation. On the other hand, verapamil in a dose of 5 mg/kg, that per se does not affect memory consolidation, significantly reversed the memory consolidation improvement induced by scopolamine (1 mg/kg, i.p., administered immediately after verapamil treatment) but did not change the passive avoidance response in rats treated by an ineffective dose of scopolamine (30 mg/kg). In conclusion, the present data suggest that (1) the post-training administration of verapamil, dose-dependently, improves the passive avoidance response; (2) verapamil, in ineffective dose, abolished the improvement of memory consolidation effect of scopolamine; and (3) exists interaction between cholinergic muscarinic receptors and calcium homeostasis-related mechanisms in the consolidation of emotional memory.

TETRAHYDROXYSTILBENE GLUCOSIDE AMELIORATES MEMORY AND MOVEMENT FUNCTIONS, PROTECTS SYNAPSES AND INHIBITS α-SYNUCLEIN AGGREGATION IN HIPPOCAMPUS AND STRIATUM IN AGED MICE

Aging is the greatest risk factor of senile neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and dementia of Lewy body (DLB). Synaptic dysfunction plays an important role in the progression of cognitive impairment and movement disorder among these neurodegenerative diseases. Synaptic degeneration occurs early in the progression of AD involving neocortical and limbic system circuitries. Accumulating oligomeric α-synuclein may mediate early synaptic pathology in PD and DLB by disrupting synaptic vesicles. Polygonum multiflorum has been widely used in China as an anti-aging agent since ancient times. 2,3,5,4’-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active component extracted from the root of Polygonum multiflorum. The purpose of this study was to investigate the effects of TSG on the memory and movement functions and its mechanisms related to synapses and a-synuclein in aged mice. The memory ability of mice was detected by step-through passive avoidance task. The movement function was measured by the pole test and rotarod test. Transmission electron microscopy was used to observe the synaptic ultrastructure. Western blotting was applied to measure the expression of synapse-related proteins and a-synuclein. Intragastrical administration of TSG for 3 months significantly improved the memory and movement functions in aged mice. TSG treatment obviously protected the synaptic ultrastructure and increased the number of synaptic connections in the hippocampal CA1 region and striatum; enhanced the expression of synaptophysin, phosphorylated synapsin I and postsynaptic density protein 95 (PSD-95), elevated phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMK II) expression, and inhibited the overexpression and aggregation of a-synuclein in the hippocampus, striatum and cerebral cortex of aged mice. TSG improved the memory and movement functions in aged mice through protecting synapses and inhibiting a-synuclein overexpression and aggregation in multiple brain regions. The results suggest that TSG may have the potential to treat Alzheimer's disease, Parkinson's disease dementia and dementia of Lewy body.

Neurochemical and neuropharmacological characterization of ASP2905, a novel potent selective inhibitor of the potassium channel KCNH3

KCNH3 (BEC1) is a member of the ether-à-go-go (KCNH) family of voltage-gated K+ channels. The aim of this study was to determine the pharmacological profiles in vitro and in vivo of a KCNH3 inhibitor N-(4-fluorophenyl)-N′-phenyl-N′′-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine (ASP2905). We analyzed the effects of ASP2905 on channel activity in vitro and its neuropharmacological properties in young and aged rats as well as in mice. ASP2905 potently inhibited potassium currents in CHO cells expressing KCNH3 (IC50 = 9.0nM). In contrast, ASP2905 (≤ 10μM) minimally bound with low affinities to 55 transmembrane proteins. ASP2905 (0.1µM, 1µM) decreased the frequency of spontaneous inhibitory postsynaptic currents in cultured rat hippocampal neurons. In mice, ASP2905 reversed the disruption of spontaneous alternation behavior induced by MK-801 and scopolamine (minimum effective dose of ASP2905: 0.0625mg/kg, po). ASP2905 ameliorated the cognitive deficits of aged rats in step-through passive avoidance (0.0313 and 0.0625mg/kg, po) and Morris water-maze tasks (0.01mg/kg, po) and effectively penetrated the brain. The mean plasma and brain concentrations of ASP2905 reached their maxima (Cmax = 0.399ng/ml and 1.77ng/g, respectively) 1h after a single oral administration and then decreased (t1/2 = 1.5–1.6h) (brain plasma ratio = 2.7–4.9). The present study suggests that ASP2905 is a selective, orally administered inhibitor of KCNH3, which can enhance cognitive performance.