Amnesia In Mice Research Articles

Dimemorfan enhances acetylcholine release from rat hippocampal slices

Our previous study reported that an antitussive drug, dimemorfan, attenuates cholinergic dysfunction-induced amnesia in mice and acts like a σ 1 receptor agonist. This study further showed that dimemorfan (30 μM), like the putative σ 1 receptor agonist (+)-SKF-10047 (10 μM), significantly enhanced 25 mM KCl-evoked [ 3H]acetylcholine release from rat hippocampal but not striatal slices, which was antagonized by a σ 1 receptor antagonist haloperidol (0.3 μM).

P.4.047 Memory deficits and neuropathology induced by central amyloid-beta injections in rats

Oxidative stress is a major factor implicated in the degeneration of cholinergic neurons in Alzheimer's disease. Presently, cholinesterase inhibitors are the mainstay of therapy for Alzheimer's disease. However, the potential of cholinesterase inhibitors as antioxidants, an important aspect for neuroprotection, has not been properly investigated. Therefore, the present study was designed to investigate the influence of antidementia drugs, tacrine and donepezil, on biochemical markers of oxidative stress, glutathione (GSH) and malondialdehyde (MDA), and acetylcholinesterase activity in the brain in a streptozotocin-induced experimental model of dementia in mice. Intracerebral (i.c.) injection of streptozotocin at a dose of 0.5 mg/kg on 1st and 3rd days caused significant deficits in memory function, as evaluated in a passive avoidance test and Morris Water Maze (spatial memory) test 14 days after the 1st dose. Mice were treated with tacrine and donepezil at a dose of 5 mg/kg orally in separate groups. Both tacrine- and donepezil-treated mice showed a significant improvement of the streptozotocin (i.c.)-induced memory impairment. Streptozotocin (i.c.) administration caused a significant decrease in GSH and increase in MDA as compared to control, indicating a state of oxidative stress in the brain of streptozotocin (i.c.) amnesic mice. Treatment of streptozotocin (i.c.) amnesic mice with tacrine or donepezil did not cause significant changes in GSH and MDA levels in the brain as compared to control. Streptozotocin amnesic mice had raised acetylcholinesterase activity in the brain while there was a significant decrease in brain acetylcholinesterase activity in tacrine- and donepezil-treated streptozotocin (i.c.) mice. Thus, results indicate that tacrine and donepezil, beside inhibition of acetylcholinesterase, may also suppress oxidative stress.

Nootropic activity of Albizzia lebbeck in mice

The effect of saponin containing n-butanolic fraction (BF) extracted from dried leaves of Albizzia lebbeck on learning and memory was studied in albino mice using passive shock avoidance paradigm and the elevated plus maze. Significant improvement was observed in the retention ability of the normal and amnesic mice as compared to their respective controls. We have also studied the effects of BF on the behavior influenced by serotonin (5-HT), noradrenaline and dopamine. The brain levels of serotonin, gamma-aminobutyric acid (GABA) and dopamine were also estimated to correlate the behavior with neurotransmitter levels. The brain concentrations of GABA and dopamine were decreased, whereas the 5-HT level was increased. The data indicate the involvement of monoamine neurotransmitters in the nootropic action of BF of A. lebbeck.

Melatonin reduces memory changes and neural oxidative damage in mice treated with D-galactose.

To investigate the role of melatonin in D-galactose-induced amnesic mice, the avoidance/escape and water maze tests were performed to evaluate their learning and memory function. Spectrophotometry was employed to determine the content of thiobarbituric acid-reactive substances (TBARS) and the activities of antioxidative enzymes in the brain. The present results demonstrate that D-galactose-induced amnesic mice had significantly decreased learning and memory function. The reduced activities of superoxide dismutase and glutathione peroxidase and increased levels of TBARS were found in brain tissue of the amnesic mice. Melatonin, administered (ig) at doses of 0.1, 1, or 10 mg/kg to the D-galactose-treated mice for 3 months, was sufficient to block these changes. These data suggest that D-galactose is involved in accelerating the brain aging process by elevating free radical generation and reducing antioxidative enzyme activities in vivo. Furthermore, the antioxidative activity of melatonin on the D-galactose-treated mice may account for, at least partially, the improvement of learning and memory function in the aging and amnesic model.

Studies of the interaction between behavioral stereotypes and the effects of activation of presynaptic dopamine receptors during extinction and amnesia in mice.

The involvement of presynaptic dopamine receptors in the retention of a conditioned passive avoidance reflex through extinction and amnesia was studied in C57BL/6J mice selected in a 20-day aggressive conflict test for aggressive and submissive behavioral stereotypes. These experiments showed that in aggressive mice, activation of presynaptic receptors with the agonist (+)3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+)3PPP] at a dose of 2 mg/kg degraded learning, significantly decreased the retention time of the acquired conditioned habit in extinction, and increased the effect of an amnesia-inducing treatment. Mice showing submissive behavior in daily confrontations with aggressors responded to administration of (+)3PPP with long-lasting reproduction of the conditioned passive avoidance reaction during extinction and showed no changes in the development of amnesia. These data on the relationship between the effects of activating presynaptic dopamine receptors in reproduction of the memory trace in conditions of trace disruption on the one hand and behavioral status on the other are assessed from the point of view of different basal levels of dopaminergic system operation in aggressive and submissive mice.

Posttraining administration of gastrin-releasing peptide improves memory loss in scopolamine- and hypoxia-induced amnesic mice

We examined memory improvement with respect to the effects of gastrin-releasing peptide (GRP) in male C57BL/6J mice under conditions of experimentally induced amnesia. GRP was administered following training in a one-trial passive avoidance test. In Experiment 1, the drug scopolamine (1 or 2 mg/kg, ip) was used to induce amnesia prior to training, and GRP (32 nmol/kg, ip) or saline (control) was administered immediately after training. Results indicate that GRP at this dose improved memory only when the dosage of scopolamine was relatively low (1 mg/kg). In Experiment 2, CO 2-induced amnesia was employed. Mice were placed in a chamber filled with CO 2 or air (control) immediately after acquisition training. Subsequently, they were administered either saline or GRP (32 nmol/kg, ip). Significantly longer light–dark latency was observed in all mice that received GRP (both experimental and control groups). In total, our results indicate that the effect of GRP at this dose on the improvement of impaired memory is dependent on the degree of impairment. Furthermore, because CO 2-induced hypoxia is known to decrease acetylcholine release in the brain, our results also suggest that GRP and its receptor may interact with the cholinergic system in the central nervous system.

Nootropic and anxiolytic activity of saponins of Albizzia lebbeck leaves

The effect of saponin containing, n-butanolic fraction (BF), extracted from dried leaves of Albizzia lebbeck, was studied on cognitive behavior and anxiety in albino mice. The elevated plus maze was used for assessment of both nootropic and anxiolytic activity. The nootropic activity was evaluated by recording the effect of BF (0, 10, 25, and 50 mg/kg) on the transfer latency, whereas anxiolytic activity was assessed by studying its effect on the duration of occupancy in the closed arm. Results showed significant improvement in the retention ability of the normal and amnesic mice as compared to their respective controls. Animals treated with BF (25 mg/kg) spent more time in the open arm in a dose-dependent manner. The BF was without any significant effect on motor coordination. However, it significantly inhibited passivity and hypothermia induced by baclofen (10 mg/kg), a GABA B agonist. The data emanated in the present study suggests involvement of gamma-aminobutyric acid (GABA) in the nootropic and anxiolytic activity of saponins obtained from A. lebbeck.

Dehydroevodiamine attenuates β-amyloid peptide-induced amnesia in mice

Dehydroevodiamine has been reported to have anticholinesterase activity and an anti-amnesic effect. This study examined the effects of dehydroevodiamine on scopolamine- and β-amyloid peptide-(25–35)-induced amnesia in mice, using a step-through passive avoidance test. Similarly to the cholinesterase inhibitor, physostigmine (0.03–0.3 mg/kg, i.p.), dehydroevodiamine (0.75–12.0 mg/kg, i.p.) administered 30 min before the training trial, immediately after the training trial, and 30 min before the retention test significantly improved scopolamine- and β-amyloid peptide-(25–35)-induced amnesia. In β-amyloid peptide-(25–35)-induced amnesia, the rank order of anti-amnesic potency in these three administration schedules for dehydroevodiamine was different from that for physostigmine. Furthermore, dehydroevodiamine was more potent to improve β-amyloid peptide-(25–35)-induced amnesia than scopolamine-induced amnesia when administered before the training trial. These results suggested that dehydroevodiamine may have an action other than that of an anticholinesterase and may be a novel and effective ligand for improvement of β-amyloid type amnesia.

Effect of Butea monosperma on Memory and Behaviour Mediated via Monoamine Neurotransmitters in Laboratory Animals

Objective: To identify the fraction responsible for the nootropic activity of Butea monosperma and to correlate nootropic activity with monoamine and acetyl choline mediated behaviour. Materials and methods: The acetone soluble part of petroleum ether and ethanolic extracts of dried flowers of Butea monosperma exhibited nootropic activity in the elevated plus maze paradigm and active avoidance learning. The effect of active fraction was observed on clonidine-induced hypothermia (noradrenaline mediated behaviour), haloperidol-induced catalepsy (dopamine mediated behaviour), lithium-induced head twitches (serotonin mediated behaviour) and sodium nitrate induce respiratory arrest (acetylcholine mediated behaviour). Results: The elevated plus maze paradigm indicated that the nootropic activity resides in the ethyl acetate (PEF) fraction of petroleum ether extract and ethyl acetate fraction (AEF) and methanolic fraction (AMF) of alcoholic extract. These fractions reversed scopolamine-induced amnesia in mice. The fractions influenced the monoamine-mediated behavior differentially. The approximate LD 50 of PEF, AEF and AMF were estimated as 0.3g/kg, >5.0g/kg and 3g/kg i.p. respectively. Conclusion: The PEF, AEF and AMF exhibited significant nootropic activity had differential effect on the monoamine mediated behaviour indicating different modes of their nootropic activity. These fractions need to be investigated further to understand mechanism of their action.

AG-4: a nicotinic agonist endowed with antiamnesic properties

The effect of the nicotinic agonist AG-4 on memory processes was evaluated in the mouse passive avoidance test. AG-4 (100 μg per mouse icv) prevented amnesia induced by scopolamine (1.5 mg kg -1 ip), mecamylamine (20 mg kg -1 ip), and dihydro-β-erythroidine (10 pg per mouse icv). In the same experimental conditions, AG-4 (100 μg per mouse icv) also prevented baclofen (2 mg kg -1 ip), clonidine (0.125 mg kg -1 ip), and diphenhydramine (20 mg kg -1 ip) amnesia in mice. AG-4 exerted an antiamnesic effect comparable to that produced by nicotine (2 mg kg -1 ip), physostigmine (0.2 mg kg -1 ip), and the nootropic drug piracetam (30 mg kg -1 ip). At the active dose, AG-4 did not impair mice motor coordination and spontaneous motility as revealed, respectively, by Rota-rod test and Animex apparatus. Present results evidence the antiamnesic activity of the nicotinic agonist AG-4 suggesting a potential employment of this compound in the symptomatic treatment of cognitive impairments.

The effects of some K + channel blockers on scopolamine- or electroconvulsive shock-induced amnesia in mice

The effects of three K + channel blockers, 4-aminopyridine, 3,4-diaminopyridine and apamin, on scopolamine- or electroconvulsive shock-induced amnesia were investigated in mice by using a one-trial step-down passive avoidance system. Scopolamine and electroconvulsive shock reduced the retention latency of passive avoidance, which indicated the amnestic effect of these treatments. 4-Aminopyridine, 3,4-diaminopyridine and apamin injected immediately after the acquisition trial, reversed the amnestic effect of scopolamine or electroconvulsive shock in a dose-dependent manner. None of the drugs or electroconvulsive shock treatment affected the rotarod or activity cage performance of the mice. These results indicate that K + channel blockers may improve cognitive deficits when memory is impaired by a drug or any other manipulation.

Anesthesia induced retrograde amnesia is ameliorated by ephrinA5-IgG in mice: EphA receptor tyrosine kinases are involved in mammalian memory

EphA receptors and their ephrin-A ligands were previously thought to play a role only in embryonic development of the brain. Recently, however, these proteins were shown to be expressed in the adult mouse brain, primarily in the hippocampus, and were implicated in hippocampal synaptic plasticity and learning. What aspects of learning EphA receptors mediate have not been studied? Using the fear conditioning paradigm we demonstrate that EphA receptors play roles in memory. We show that post-training surgical anesthesia leads to robust context specific retrograde amnesia in mice, and post-anesthesia activation of EphA receptors induces a significant amelioration of this amnesia. As acquisition was left unaffected and performance factors were found unaltered, we suggest that the amelioration was due to changes in cognition leading to improved memory. Our data represent the first pieces of evidence for the involvement of EphA receptor tyrosine kinase receptors in mammalian memory, a finding that opens a new avenue into the functional analysis of the largest receptor tyrosine kinase subfamily in the brain.

Dynorphin A-(1-13) and (2-13) improve beta-amyloid peptide-induced amnesia in mice.

The anti-amnesic effects of dynorphins on beta-amyloid peptide-(25-35)-induced impairment of learning and/or memory in mice were investigated using a Y-maze task and a passive avoidance test. Administration of beta-amyloid peptide-(25-35) (betaAP(25-35); 8.2 nmol, i.c.v.) 7 and 14 days before behavioral tests induced a decrease in both alternation behavior and latency in passive avoidance tests. Dynorphin A-(1-13) and A-(2-13) (0.5 and/or 1.5 nmol, i.c.v.) 30 min before behavioral tests improved the beta-amyloid peptide-(25-35)-induced impairment of alternation performance and shortened the step-down latency. Nor-binaltorphimine (4.9 nmol, i.c.v.) partially blocked the effects of dynorphin A-(1-13), but not A-(2-13). These results indicate that dynorphin A-(1-13) and A-(2-13) improve amnesia induced by betaAP-(25-35) via not only kappa opioid receptors, but also by non-opioid mechanisms.

P-480 - Improving effect of fermented papaya preparation on scopolamine-induced amnesia in mice

P-480 - Improving effect of fermented papaya preparation on scopolamine-induced amnesia in mice

Effect of Intracerebroventricular Administration of Soybean Lecithin Transphosphatidylated Phosphatidylserine on Scopolamine-Induced Amnesic Mice

The effect of intracerebroventricularly administered soybean lecithin transphosphatidylated phosphatidylserine (SB-tPS) on memory impairment was evaluated by a passive avoidance task. SB-tPS significantly prolonged the step-through latency induced by scopolamine treatment as in our previous report where SB-tPS was orally administered. The same doses of soybean phosphatidylcholine were ineffective. This result indicates that SB-tPS can act on the brain without any peripheral modification.

Improvement of cognitive functions by the acetylcholine releaser SM 21

The effect of administration of SM 21 on memory processes was evaluated in the mouse passive avoidance and in the rat social learning tests. SM 21 (10–20 mg kg−1 i.p.) prevented amnesia induced by scopolamine and dicyclomine as tested by the mouse passive avoidance test and prevented memory disruption by AF-64A and benehexol ascertained by the rat passive avoidance test. Both SM 21 enantiomers were able to abolish dicyclomine-induced amnesia in mice. SM 21, starting from the dose of 10 mg kg−1 i.p., antagonized the memory impairment produced by mecamylamine, baclofen, and diphenhydramine in mice, as well as amnesia induced by diazepam in rats. SM 21, at doses ranging between 10 and 30 mg kg−1 i.p., prevented memory reduction in mice by hypoxia in the passive avoidance test. In the social learning test, SM 21 (10 mg kg−1 i.p.) injected in adult rats reduced the duration of active exploration of a familiar partner in the second session of the test. SM 21 prevented amnesia in both mice and rats comparable to that of the cholinesterase inhibitor physostigmine (0.2 mg kg−1 i.p.), the M1 selective agonist AF-102B (10 mg kg−1 i.p.), and the nootropic drug piracetam (30 mg kg−1 i.p.). These results demonstrated the ability of SM 21 to modulate memory functions and suggests that SM 21 could be useful in the treatment of cognitive deficits. Drug Dev. Res. 47:118–126, 1999. © 1999 Wiley-Liss, Inc.

The attenuation of learning impairments induced after exposure to CO or trimethyltin in mice by sigma (sigma) receptor ligands involves both sigma1 and sigma2 sites.

1. Sigma (sigma) receptor ligands were previously reported to alleviate learning and memory impairments on several pharmacological and pathological rodent models of amnesia. Such effect was demonstrated as involving the sigma1 subtype of sigma receptor. 2. In this study, we characterized the pharmacological effect mediated by sigma ligands on two lesional models of amnesia in mice: (1) the hypoxia-related learning and memory impairment model induced by repeated exposure to carbon monoxide (CO) gas; and (2) the intoxication with trimethyltin (1 mg kg(-1)). 3. The selective sigma1 ligand PRE-084 (1 mg kg(-1)) or the non-selective sigma1/sigma2 compounds DTG (0.1 mg kg(-1)), BD1008 (3 mg kg(-1)), and haloperidol (0.1 mg kg(-1)) reversed significantly the spontaneous alternation deficits observed 7 days after exposure to CO or 14 days after intoxication with trimethyltin. 4. The selective sigma1 receptor antagonist NE-100 (1 mg kg(-1)) was ineffective by itself, but blocked completely the PRE-084 effects, partially the DTG effects, and did not affect the effects induced by BD1008 or haloperidol. 5. A similar pharmacological profile was observed in the step-down type passive avoidance test performed 8 days after exposure to CO. 6. These results show that, in contrast to the previously reported amnesia models, the impairments induced after exposure to CO or intoxication with trimethyltin could be alleviated not only by sigma1 receptor agonists but also by sigma2 agonists. The particular pattern of neurodegeneration observed in these lesional models may explain these differences.

Antiamnesic activity of the nicotinic agonist DBO-83 in mice

The effect of administration of DBO-83 on memory processes was evaluated in the mouse passive avoidance test. DBO-83 (1–5 mgkg–1 ip) prevented amnesia induced by scopolamine (1.5 mgkg–1 ip), mecamylamine (20 mgkg–1 ip) and dihydro-β-erythroidine (10 μg per mouse i.c.v.). In the same experimental conditions, DBO-83 (10 mgkg–1 ip) also prevented baclofen (2 mgkg–1 ip), clonidine (0.125 mgkg–1 ip) and diphenhydramine (20 mgkg–1 ip) amnesia in mice. The antiamnesic effect of DBO-83 was comparable to that exerted by nicotine (2 mgkg–1 ip), physostigmine (0.2 mgkg–1 ip), and the nootropic drug, piracetam (30 mgkg–1 ip). In the antiamnesic dose-range, DBO-83 did not impair mouse motor coordination and spontaneous motility, as revealed, respectively, by the Animex apparatus and rotarod test. These results demonstrated the ability of DBO-83 to modulate memory functions and suggest that DBO-83 could be useful in the treatment of cognitive deficits. Drug Dev. Res. 45:45–51, 1998. © 1998 Wiley-Liss, Inc.

Possible Mechanism of Alprazolam-Induced Amnesia in Mice

Alprazolam produced anterograde as well as retrograde amnesia in mice assessed using elevated plus-maze. Flumazenil (10 mg/kg i.p.) attenuated anterograde and retrograde amnesia produced by alprazolam. It is proposed that anterograde amnesia produced by alprazolam may be mediated through the activation of benzodiazepine receptors. Retrograde amnesia of alprazolam may be mediated through the blockade of PAF receptors. Moreover, flumazenil facilitates learning and memory perhaps by modulating the release of PAF and consequently attenuated alprazolam and BN-50730-(PAF receptor antagonist)-induced retrograde amnesia.

Sigma1 (σ1) receptor agonists and neurosteroids attenuate β25–35-amyloid peptide-induced amnesia in mice through a common mechanism

The sigma1 (σ1) receptor agonists exert potent anti-amnesic effects, as they apparently block the learning impairments either induced by the muscarinic receptor antagonist scopolamine, the N-methyl-d-aspartate receptor antagonist dizocilpine or inherently due to the age-related deficits in senescence-accelerated mice. We recently described the amnesia induced by the β-amyloid-related peptide β25–35, administered centrally in an aggregated form, in mice. The deficits were sensitive to cholinomimetics or to N-methyl-d-aspartate/glycine modulatory site agonists. Herein, we examined the effects of σ1 receptor ligands on the β25–35 peptide-induced amnesia. The effects of neuro(active) steroids, which interact in vitro and in vivo with σ1 receptors were examined in parallel. Mnesic capacity was evaluated seven days after administration of aggregated β25–35 peptide (3nmol), using spontaneous alternation in the Y-maze for spatial short-term memory, or after 14 days, using the step-down type passive avoidance test for long-term memory. The σ1 receptor agonists (+)-pentazocine, PRE-084, or SA4503 attenuated, in a dose-dependent and bell-shaped manner, the β25–35 peptide-induced deficits on both tests. These effects were antagonized by haloperidol or BMY-14 802, confirming the σ1 receptor pharmacology. Pregnenolone, dehydroepiandrosterone, and their sulphate esters, but not progesterone, also dose-dependently attenuated the β25–35 peptide-induced deficits. Progesterone blocked the beneficial effects of each other neurosteroid, behaving as an antagonist. Furthermore, haloperidol blocked the effects induced by neurosteroids, whereas progesterone antagonized the effects of the non-steroidal σ1 receptor agonists, showing a clear crossed pharmacology of different drug classes.These results demonstrate that: (i) the anti-amnesic effect of σ1 receptor agonists may be of therapeutic relevance in pathological states affecting the cholinergic and/or glutamatergic systems, such as in pathological aging; (ii) neurosteroids play an important role in learning processes and may collectively constitute a therapeutic target; (iii) the interaction between σ1 systems and neurosteroids appears indeed of behavioural relevance.