Scopolamine-induced Amnesia In Mice Research Articles

New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids

Five new piperidine alkaloids were designed from natural (−)-3- O-acetyl-spectaline and (−)-spectaline that were obtained from the flowers of Senna spectabilis (sin. Cassia spectabilis, Leguminosae). Two semi-synthetic analogues ( 7 and 9) inhibited rat brain acetylcholinesterase, showing IC 50 of 7.32 and 15.1 μM, and were 21 and 9.5 times less potent against rat brain butyrylcholinesterase, respectively. Compound 9 (1 mg/kg, ip) was fully efficacious in reverting scopolamine-induced amnesia in mice. The two active compounds ( 7 and 9) did not show overt toxic effects at the doses tested in vivo.

ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, significantly improved scopolamine-induced memory impairment in mice

We assessed the effects of oral treatments of ESP-102, a standardized combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, on learning and memory deficit. The cognition-enhancing effect of ESP-102 was investigated in scopolamine-induced (1 mg/kg body weight, s.c.) amnesic mice with both passive avoidance and Morris water maze performance tests. Acute oral treatment (single administration prior to scopolamine treatment) of mice with ESP-102 (doses in the range of 10 to 100 mg/kg body weight) significantly reduced scopolamine-induced memory deficits in the passive avoidance performance test. Another noteworthy result included the fact that prolonged oral daily treatments of mice with much lower amounts of ESP-102 (1 and 10 mg/kg body weight) for ten days reversed scopolamine-induced memory deficits. In the Morris water maze performance test, both acute and prolonged oral treatments with ESP-102 (single administration of 100 mg/kg body weight or prolonged daily administration of 1 and 10 mg/kg body weight for ten days, respectively, significantly ameliorated scopolamine-induced memory deficits as indicated by the formation of long-term and/or short-term spatial memory. In addition, we investigated the effects of ESP-102 on neurotoxicity induced by amyloid-β peptide (Aβ 25–35) or glutamate in primary cultured cortical neurons of rats. Pretreatment of cultures with ESP-102 (0.001, 0.01 and 0.1 μg/ml) significantly protected neurons from neurotoxicity induced by either glutamate or Aβ 25–35. These results suggest that ESP-102 may have some protective characteristics against neuronal cell death and cognitive impairments often observed in Alzheimer's disease, stroke, ischemic injury and other neurodegenerative diseases.

Effect of a Nutritive-Tonic Drink on Scopolamine-Induced Memory Impairment in Mice

The effects of a liquid nutritive and tonic drug (NTD) selected from a modification of the "Kai-xin-shou-yu-shen-qi-wan" prescription, on scopolamine-induced amnesia in mice were investigated using the passive avoidance and water-maze tasks. A popular NTD in Japan that contains 17 crude (natural) drug extracts together with synthetic drugs such as taurine, caffeine, various vitamins and ethanol, and the natural drug extracts is based on a prescription of "Kampo" origin in Chinese medicine. Scopolamine (0.4 mg/kg, i.p.) reduces the step-through latency of the passive avoidance test and fear reaction behavior at 24 and 48 h after treatment. A single oral administration of the NTD (10 ml/kg) increased the step-through latency and the fear reaction behavior score in scopolamine-treated mice. Administration of the natural drug extracts found in the NTD tended to extend the step-through latency in the retention test at 48 h, but not 24 h after the initial scopolamine trial. However, administration of the synthetic drugs found in the NTD did not improve either the step-through latency or the behavioral score. The NTD and the natural drug extracts also improved the scopolamine-induced spatial memory impairment as assessed using the Morris water-maze test. In contrast, the synthetic drugs did not affect the escape latencies. Both NTD and the synthetic drugs increased the locomotor activity in scopolamine-treated mice, whereas the natural drug extracts did not. These results suggest that NTD improves scopolamine-induced amnesia, and that this action is attributable to the natural drug extracts in the NTD.

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.

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.

Peripherally administered GM-CSF interferes with scopolamine-induced amnesia in mice: involvement of interleukin-1

We studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on the classical behavioral test of scopolamine-induced amnesia for a passive avoidance response in the mouse. Pre-training intraperitoneal administration of this cytokine (1.25, 2.5, 5.0 or 10 μg/mouse) partially, although significantly, reduced the amnesic action of the muscarinic receptor antagonist. The peripheral administration of a specific interleukin-1 receptor antagonist (IL-1 ra, 50 μg/mouse i.p.) blocked the effect of GM-CSF. Our results suggest that GM-CSF is able to exert neuromodulatory actions and that it is involved (probably via IL-1) in the interactions between the immune system and the central nervous system.

Peripherally administered GM-CSF interferes with scopolamine-induced amnesia in mice: involvement of interleukin-1

We studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on the classical behavioral test of scopolamine-induced amnesia for a passive avoidance response in the mouse. Pre-training intraperitoneal administration of this cytokine (1.25, 2.5, 5.0 or 10 μg/mouse) partially, although significantly, reduced the amnesic action of the muscarinic receptor antagonist. The peripheral administration of a specific interleukin-1 receptor antagonist (IL-1 ra, 50 μg/mouse i.p.) blocked the effect of GM-CSF. Our results suggest that GM-CSF is able to exert neuromodulatory actions and that it is involved (probably via IL-1) in the interactions between the immune system and the central nervous system.

Peripherally administered IL-1 α interferes with scopolamine-induced amnesia in mice

We studied the effects of human recombinant interleukin-1 α on scopolamine-induced amnesia for a passive avoidance response in the mouse. Post-training intraperitoneal administration of the cytokine (0.25 or 0.50 μg/mouse) significantly reduced the amnesic effect of scopolamine (1.0 mg/kg i.p.). Our results indicate that peripheral interleukin-1 α can influence behavior and suggest the involvement of the cholinergic system in the neuromodulatory actions of this cytokine.

Effects of sustained release formation of thyrotropin-releasing hormone on learning impairments caused by scopolamine and AF64A in rodents

The efffects of a sustained-release formulation of thyrotropin-releasing hormone (TRH-SR) on learning impairment induced by scopolamine and a cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), were examined on rodents. Subcutaneous injection of TRH-SR (2.8 mg/kg as free TRH) produced a sustained increase in immonoreactive plasma TRH levels up to about 2 weeks after dosing in rats. TRH-SR (0.56 and 2.8 mg/kg) given subcutaneously 7 days before the aquisition trial markedly ameliorated scopolamine-induced amnesia in mice, as evaluated with a passive avoidance task. Repeated administration of TRH for 7 days at doses of 0.2–6 mg/kg s.c. elicited a dose-dependent recovery from amnesia induced by scopolamine, whereas only the group treated with 5 mg/kg/day showed a significant improvement. The rat with bilateral intracerebroventricular injection of AF64A (3.75 nmol/brain) showed a significant impairment in the water maze task 2 weeks after surgery. TRH-SR (0.56 and 2.8 mg/kg) also exhibited a dose-dependent ameliorating action on the deficit. These findings indicate that TRH-SR ameliorates learning impairments produced by scopolamine and AF64A, and suggest that continuous infusion of TRH may have a potent learning and memory improving action at low doses.

Amnesia-reversal activity of a series of 5-alkoxy-1-arylcarbonyl-2-pyrrolidinones and 5-alkoxy-1-arylmethyl-2-pyrrolidinones

A series of 5-alkoxy-1-arylcarbonyl-2-pyrrolidinones ( 1–27) were prepared by condensation of arylcarbonyl chlorides with 5-alkoxy-2 pyrrolidinones in the presence of butyl lithium in tetrahydrofuran. Alkylation of these intermediates with substituted benzyl bromides or chlorides, under solid/liquid phase-transfer conditions (KOH/Bu 4NBr) in tetrahydrofuran, yielded 5-alkoxy-1-arylmethyl-2-pyrrolidinones ( 28–48). In the first series, the compounds with a 5- n-pentyloxy group had maximal ECS-induced amnesia reversing activity in mice, and in the second series, those with a 5- n-octyloxy group. In both series, substitutions on the phenyl ring had detrimental effects. The two most promising compounds 1-benzoyl-5- n-pentyloxy-2-pyrrolidinone ( 14) and 1-benzyl-5- n-octyloxy-2-pyrrolidinone ( 37) were more potent than piracetam and aniracetam and active over broader dose ranges: 50–200 and 50–400 mg/kg, po. Both compounds also reversed scopolamine-induced amnesia in mice, from 50 to 400 mg/kg, po ( 14) and from 100 to 400 mg/kg, po ( 37). Finally, 37 showed remarkable activity in protecting the mouse brain against chemically induced hypoxia, with a minimal effective dose of 50 mg/kg, ip, or 100 mg/kg, ip, in NaNO 2- or KCN-induced hypoxia.

Attenuation of scopolamine-induced amnesia in mice.

Numerous studies suggest that age-related declines in memory storage are related to impairment of central cholinergic systems. Scopolamine, a muscarinic cholinergic antagonist, has been used with young humans and other animal species as a model of the cognitive impairment that often accompanies normal and pathological aging. The present study examined whether amnesia induced by scopolamine could be counteracted in mice by arecoline, a cholinergic agonist, or by other drugs, epinephrine or glucose, which have been found to enhance memory in aged rodents and humans. Young mice were administered scopolamine (3 mg/kg, IP) or saline prior to training on an inhibitory avoidance apparatus. Immediately after training, animals received injections of epinephrine (0.01, 0.05, 0.1, and 0.2 mg/kg), glucose (10, 100, and 250 mg/kg), arecoline (0.5, 1, 2, 5, 10, and 20 mg/kg), or saline. The results indicate that pre-training scopolamine reliably impaired retention assessed in test trials 48 h after training. This impairment was not attenuated by any post-training dose of arecoline; however, immediate post-training injections of both epinephrine (at 0.05 mg/kg) and glucose (at 100 mg/kg) significantly reduced the amnesia. Neither of these drugs was effective if injections were delayed by 1 h after training. These results support the value of scopolamine as a model of age-related memory impairments, but suggest further that these memory deficits may be particularly susceptible to attenuation with non-cholinergic treatments.

Hoe 288: Indications on the memory‐enhancing effects of a peptidase inhibitor

AbstractSeveral neuropeptides have recently been found to be involved in motivational, memory, and learning processes. Therefore, we tested the hypothesis that the peptidase (EC 3.4.15.1) inhibitor Hoe 288 modulated cognitive functions. Hoe 288 exhibited nootropic effects in uphill avoidance in mice (30 mg/kg orally administered [p.o.]). Scopolamineinduced amnesia in mice and rats was antagonized after subchronic administration for two or three days (1–10 mg/kg p.o. or intraperitoneally [i.p.]) in step‐through avoidance and an eight‐arm‐radial maze, respectively. The resulting bell‐shaped dose‐response curves had a maximum effect at 3 mg/kg. To elucidate the underlying neurochemical effects, ex vivo experiments in rats were performed: acute or repeated administration of Hoe 288 (0.03 – 3 mg/kg i.p.) induced a significant decrease of acetylcholine (ACh) content in certain brain areas that lasted up to 6 hr after treatment. The reduced brain ACh content was most likely due to an enhanced ACh release, as coadministration of the choline uptake inhibitor hemicholinium‐3 (HC‐3) and Hoe 288 potentiated the decrease of ACh induced by HC‐3. Choline acetyltransferase activity in brain increased after acute and subchronic administration of the peptidase inhibitor. Receptor‐mediated effects of ACh were estimated indirectly by its stimulation of guanylate cyclase. Hoe 288 increased cGMP content in a comparable dose range (0.3 – 1 mg/kg i.p.). The converting enzyme inhibitor Hoe 288 was shown to influence acquisition and retention of information in rodents, and the effects on ACh metabolism are in concordance with results obtained with potential nootropics in animal experiments.