Amnesia In Mice Research Articles

Behavioral and biochemical evidences for nootropic activity of boldine in young and aged mice

Boldine, a bioactive compound, has been reported to be neuroprotective, but its effect on learning and memory has not been explored. So, the present study was aimed to study the effect of boldine on the learning and memory of the Swiss albino male young and aged mice. Boldine (1.5, 3 and 6mg/kg, po) and physostigmine salicylate (0.1mg/kg, ip) were administered to separate groups of mice for 7 successive days. Morris water maze was utilized as a behavioural model to study the effect of drugs on learning and memory of mice. Boldine and physostigmine significantly improved learning and memory of young as well as aged mice, as indicated by decrease in escape latency time during training session and increase in time spent in target quadrant during retrieval session. No significant effect on locomotor activities of mice was observed due to drug treatments. Memory-enhancing activity of boldine (3mg/kg) was found to be comparable to physostigmine. Boldine significantly reversed scopolamine-, sodium nitrite- and aging-induced amnesia in mice. Moreover, boldine attenuated oxidative stress, as shown by a significant decrease in brain malondialdehyde as well as brain nitrite levels and a significant increase in brain GSH level of young as well as aged mice. Brain acetylcholinesterase activity was also significantly inhibited by boldine in young as well as aged mice. In conclusion boldine administered for 7 successive days exhibited significant improvement of learning and memory of young and aged mice possibly through inhibition of brain acetylcholinesterase activity and alleviation of brain oxidative stress.

합환피의 인지 및 기억력 개선 효과에 대한 연구

The aim of this study was to investigate the effects of the water extract of Albizziae Cortex (AC) on the learning and memory impairments. AC was administered to normal mouse and scopolamine-injected amnesia mouse model. Passive avoidance test, Y-maze test, and Morris water maze test were conducted to confirm the cognitive-enhancing activities of AC. Acetylcholinesterase (AChE) activity and acetylcholine (Ach) content were measured after oral administration of AC. On the passive avoidance test, AC (200 mg/kg) significantly increased latency time and recovered scopolamine-impaired learning and memory in mice. In addition, AC (200 mg/kg) reduced Exploration time in target quadrant and reversed the scopolamine-induced cognitive impairments in the Y-maze test. Moreover, AC (200 mg/kg) increased exploration time in target quadrant and improved scopolamine-reduced escape latencies in the Morris water maze test. These effects were presented by regulatory effects of AC on AChE activity and Ach content. Taken together, AC increases cognitive-enhancing activities and ameliorates scopolamine-induced learning and memory impairment. AC might be a potential agent for prevention and treatment of amnesia and dementia.

Ixeris dentata (Thunb) Nakai Attenuates Cognitive Impairment in Scopolamine-induced Amnesic Mice

<i>Ixeris dentata</i> (Thunb) Nakai Attenuates Cognitive Impairment in Scopolamine-induced Amnesic Mice

Novel Vilazodone-Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation.

Depression is one of the most frequent psychiatric complications of Alzheimer's disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds; among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC50 = 3.319 ± 0.708 μM), 5-HT1A agonist (EC50 = 107 ± 37 nM), and 5-HT reuptake inhibition (IC50 = 76.3 ± 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood-brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg 1e·HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy.

AMELIORATIVE EFFECT OF SIDA CORDIFOLIA L. AGAINST SCOPOLAMINE-INDUCED COGNITIVE DEFICIT MICE MODEL

Objective: In this study, ameliorative effect of aqueous extracts of Sida cordifolia and hydroethanolic extracts of S. cordifolia L. (AESC and EESC, respectively) was evaluated against scopolamine (Sco)-induced amnesia in mice. S. cordifolia L. is a well-know Ayurvedic plant which has been administered anciently for various nervous disorders including loss of memory. Female Swiss albino mice were used for Sco-induced amnesia model and acute toxicity study.Methods: Acute toxicity study was carried out to select safe and effective doses (50, 100 and 250 mg/kg; p.o.) of AESC and EESC for further pharmacological evaluation. The AESC and EESC at selected doses and donepezil (Dpl) (5 mg/kg; p.o.) were administered to different groups for consecutive 15 days. On 15th day of treatment, Sco (0.4 mg/kg, intraperitoneally) was administered to different groups for induction of amnesia. Mice were subjected to transfer latency (TL) and step down latency (SDL) tests on the 16th day to evaluate the effect of AESC and EESC on memory.Results: Sco treatment caused a significant increase in TL and decrease in SDL. The EESC significantly and dose dependently reversed the Sco-induced amnesia. The maximum effect was seen in EESC (100 mg/kg) treated group. This effect of EESC was comparable to the group treated with Dpl. The group treated with varying doses of AESC showed no significant effect on TL and SDL.Conclusion: These findings suggested the possible therapeutic potential of EESC (70%) for diseases related to memory dysfunctions like dementia in Alzheimer’s disease.

Nose to Brain Delivery of Rivastigmine by In Situ Gelling Cationic Nanostructured Lipid Carriers: Enhanced Brain Distribution and Pharmacodynamics

Present investigation explores the potential of nanostructured lipid carriers (NLCs) for nose to brain delivery of rivastigmine (RV), which is further enhanced by incorporating into an in situ gelling system, increasing retention in nasal cavity. NLCs having particle size of 123.2 ± 2.3 nm, entrapment efficiency of 68.3 ± 3.4%, and zeta potential of 32 ± 1.2 mV was fabricated by a scalable method. Pharmacokinetics showed sustained release of intranasal (IN) and intravenous (IV) NLCs compared with RV solution by same route, with significantly higher AUC and Thalf. Biodistribution indicated blood brain barrier penetrating potential of IV NLCs (457.24 ± 38.41.12 ng/mL) and IN NLCs (736.42 ± 34.54 ng/mL) with 4.6 and 5.3-fold enhancement in brain concentrations compared with IV and IN solution of RV. Similar results reflected in pharmacodynamics, indicating faster regain of memory loss in amnesic mice with 5-fold decrease in escape latency with NLCs compared with plain RV solution by IV and IN routes respectively. Sub-acute toxicity studies demonstrated safety of developed formulations to vital organs without any hematological and biochemical changes compared with control group. Moreover, nasal toxicity studies of NLCs showed no signs of inflammation, maintaining the integrity of ciliary epithelial cells, thus confirming safety of the formulation for its intended nasal application.

Ameliorative Effects of Roots of &lt;I&gt;Asparagus adscendens&lt;/I&gt; Roxb. on Cognitive Impairments and Brain Aging Induced by Scopolamine and Diazepam in Animal Models Relevant to Alzheimer's Disease

Memory loss in dementia is often the most disabling feature of many disorders, impairing the normal daily activities of the patients and profoundly affecting their families. Treatment of cognitive disorders like dementia and Alzheimer's disease has been challenging since no potential drug is available at present with proved efficacy. In the present study, nootropic activity of methanolic extract of roots of Asparagus adscendens Roxb.(AR) was studied in mice. Elevated plus maze and passive avoidance paradigm were employed to evaluate learning and memory. Scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) were used to induce amnesia in mice. AR (50 and 100 mg/kg, p.o.) significantly attenuated amnesic deficits induced by scopolamine, diazepam and natural aging. Furthermore, it also reversed aging induced amnesia due to natural aging of mice. AR profoundly increased whole brain acetyl cholinesterase inhibition activity. Hence, AR might prove to be a useful memory restorative agent in the treatment of dementia seen in the elderly. The underlying mechanism of its action may be attributed to its antioxidant and acetyl cholinesterase inhibition properties.

Neuroprotective Effect of Green Synthesized Iron Oxide Nanoparticles Using Aqueous Extract of Convolvulus Pluricaulis Plant in The Management of Alzheimer’s Disease

To evaluate the neuroprotective effect of green synthesized iron oxide nanoparticles using aqueous extract of whole plant of Convolvulus pluricaulis (CPIO) in scopolamine induced amnesia model. CPIO were orally tested at the dose of 100 mg/kg, 200 mg/kg and 400 mg/kg for neuroprotective effect in scopolamine induced amnesia mice. In addition, neurobehavioral studies were carried out using elevated plus maze, Morris water maze to evaluate learning and memory in mice in normal and scopolamine induced amnesia mice. CPIO 400 mg/kg showed a significant improvement in learning and memory in the normal and scopolamine induced amnesia mice in exteroceptive models. Significant differences were observed in lipid peroxidation, catalase and acetylcholinesterase by 400 mg/kg of CPIO treated amnesic animals, when compared with untreated and scopolamine group animals. The highest dose of CPIO exhibited significant neuroprotective effect in normal and scopolamine induced amnesia mice. They also showed significant improvement in learning and memory in exteroceptive and interoceptive models and so might be of value in Alzheimer’s treatment.

Differential proteome profiling in the hippocampus of amnesic mice.

Amnesia or memory loss is associated with brain aging and several neurodegenerative pathologies including Alzheimer's disease (AD). This can be induced by a cholinergic antagonist scopolamine but the underlying molecular mechanism is poorly understood. This study of proteome profiling in the hippocampus could provide conceptual insights into the molecular mechanisms involved in amnesia. To reveal this, mice were administered scopolamine to induce amnesia and memory impairment was validated by novel object recognition test. Using two-dimensional gel electrophoresis coupled with MALDI-MS/MS, we have analyzed the hippocampal proteome and identified 18 proteins which were differentially expressed. Out of these proteins, 11 were downregulated and 7 were upregulated in scopolamine-treated mice as compared to control. In silico analysis showed that the majority of identified proteins are involved in metabolism, catalytic activity, and cytoskeleton architectural functions. STRING interaction network analysis revealed that majority of identified proteins exhibit common association with Actg1 cytoskeleton and Vdac1 energy transporter protein. Furthermore, interaction map analysis showed that Fascin1 and Coronin 1b individually interact with Actg1 and regulate the actin filament dynamics. Vdac1 was significantly downregulated in amnesic mice and showed interaction with other proteins in interaction network. Therefore, we silenced Vdac1 in the hippocampus of normal young mice and found similar impairment in recognition memory of Vdac1 silenced and scopolamine-treated mice. Thus, these findings suggest that Vdac1-mediated disruption of energy metabolism and cytoskeleton architecture might be involved in scopolamine-induced amnesia.

Alantolactone and Isoalantolactone Prevent Amyloid β25–35‐induced Toxicity in Mouse Cortical Neurons and Scopolamine‐induced Cognitive Impairment in Mice

Given the evidence for detoxifying/antioxidant enzyme-inducing activities by alantolactone (AL) and isoalantolactone (IAL), the purpose of this study was to investigate the effects of AL and IAL on Aβ25-35 -induced cell death in mouse cortical neuron cells and to determine their effects on scopolamine-induced amnesia in mice. Our data demonstrated that both compounds effectively attenuated the cytotoxicity of Aβ25-35 (10μM) in neuronal cells derived from the mouse cerebral cortex. It was also found that the production of intracellular reactive oxygen species, including superoxide anion induced by Aβ25-35 , was inhibited. Moreover, the administration of the sesquiterpenes reversed scopolamine-induced cognitive impairments as assessed by Morris water, Y-maze, and the passive avoidance tests, and the compounds decreased acetylcholinesterase (AChE) activities in a dose-dependent manner. Interestingly, AL and IAL did not improve scopolamine-induced cognitive deficit in Nrf2-/- mice, suggesting that memory improvement by sesquiterpenes was mediated not only by the activation of the Nrf2 signaling pathway but also by their inhibitory activity against AChE. In conclusion, our results showed that AL and IAL had neuroprotective effects and reversed cognitive impairments induced by scopolamine in a mouse model. Therefore, AL and IAL deserve further study as potential therapeutic agents for reactive oxygen species-related neurodegenerative diseases. Copyright © 2017 John Wiley & Sons, Ltd.

COGNITIVE-ENHANCING PROPERTIES OF MORINDA LUCIDA (RUBIACEAE) AND PELTOPHORUM PTEROCARPUM (FABACEAE) IN SCOPOLAMINE-INDUCED AMNESIC MICE.

Background:Cognitive disorders associated with aging have been successfully managed by African traditional medical practitioners using various plants. This study evaluated the cognitive enhancing potentials of Morinda lucida (L) Rubiaceae and Peltophorum pterocarpum (DC) ex. K Heyne in scopolamine induced amnesic animals.Materials and Methods:The anti-amnesic activity of the ethyl acetate extracts of Morinda lucida and Peltophorum pterocarpum at doses of 4 mg/kg, 6 mg/kg and 8 mg/kg were assessed in scopolamine induced amnesic mice using Morris water maze test model. Effect of the extracts on the histology of the hippocampus was also evaluated.Results:The ethyl acetate extract of Morinda lucida and Peltophorum pterocarpum ameliorated scopolamine induced memory deficit in the animals under study. There was no effect of the extract on the histology of the hippocampus. However, there was an increase in the density of cells in the hippocampus of treated group as compared to the untreated.Conclusion:Morinda lucida and Peltophorum pterocarpum showed considerable enhancement of cognition in scopolamine induced amnesic mice.

Standardized extract of Lactuca sativa Linn. and its fractions abrogates scopolamine-induced amnesia in mice: A possible cholinergic and antioxidant mechanism

Objectives: The present study was designed to evaluate the efficacy of Lactuca sativa (LS) Linn. (Asteraceae) against scopolamine-induced amnesia and to validate its traditional claim as memory enhancer.Methods: Ethanol extract of fresh LS leaves (LSEE), standardized on the basis of quercetin content, was successively partitioned using various solvents viz., hexane, ethyl acetate, and n-butanol in increasing order of polarity. LSEE (50, 100, and 200 mg/kg) and its various fractions (at a dose equivalent to dose of LSEE exhibiting maximum activity), administered orally for 14 days, were evaluated for their memory enhancing effect against scopolamine-induced (1 mg/kg, i.p.) amnesia in 3–4 months old male Laca mice (n = 6 in each group). The memory enhancing effect was evaluated using behavioural (elevated plus maze, novel object recognition and Morris water maze tests) and biochemical parameters (acetylcholinesterase activity, malonaldehyde, superoxide dismutase, nitrite, catalase, and reduced gultathione content). The results of the test substances were compared with both scopolamine and donepezil that was used as a standard memory enhancer and acetylcholinesterase inhibitor.Results: Scopolamine elicit marked deterioration of memory and alteration in biochemical parameters in comparison to the control group. LSEE and its n-butanol and aqueous fractions significantly (P < 0.05) attenuated the scopolamine-induced amnesia that was evident in all the behavioural and biochemical test parameters. LSEE (200 mg/kg) and n-butanol fraction (15 mg/kg) exhibited maximum anti-amnesic effect among various tested dose levels.Discussion: The results exhibited that LS prophylaxis attenuated scopolamine-induced memory impairment through its acetylcholinesterase inhibitory and antioxidant activity validating its traditional claim.

Exploring the Effect of Ginsenoside Rh1 in a Sleep Deprivation-Induced Mouse Memory Impairment Model.

Panax ginseng C.A. Meyer (Araliaceae) has been used in traditional Chinese medicine for enhancing cognition for thousands of years. Ginsenoside Rh1, a constituent of ginseng root, as with other constituents, has memory-improving effects in normal mice and scopolamine-induced amnesic mice. Sleep deprivation (SD) is associated with memory impairment through induction of oxidative stress. The present study investigated the effect of Rh1 against SD-induced cognitive impairment and attempted to define the possible mechanisms involved. Ginsenoside Rh1 (20μmol/kg; 40μmol/kg) and modafinil (0.42g/kg) were administered to the mice intraperitoneally for 23days. After 14-day SD, locomotor activity was examined using the open field test, and the object location recognition and Morris water maze tests were used to evaluate cognitive ability. The cortex and hippocampus were then dissected and homogenized, and levels and activities of antioxidant defense biomarkers were evaluated to determine the level of oxidative stress. The results revealed that Rh1 prevented cognitive impairment induced by SD, and its ability to reduce oxidative stress in cortex and hippocampus may contribute to the mechanism of action. Copyright © 2017 John Wiley & Sons, Ltd.

Cognitive enhancing of pineapple extract and juice in scopolamine-induced amnesia in mice

The objective of the present study was to evaluate the cognitive enhancing of pineapple juice and ethanolic extract in scopolamine-induced cognitive deficit mice. The ethanolic extract of pineapple (Ananas comosus (L.) Merr.) was prepared by maceration method and its juice was obtained by a homogenizer. Object recognition task was used to evaluate the mice memory. Exploration time in the first and second trial was recorded. The differences in exploration time between a familiar and a novel object in the second trial were taken as a memory index. Animals were randomly assigned into 15 groups of 6 each including: control group (normal saline + vehicle), positive control group (scopolamine + rivastigmine), seven experimental groups (received scopolamine alone or scopolamine + ethanolic extract of pineapple in different doses), six other experimental groups were treated by ethanolic extract or juice of pineapple in different doses. Scopolamine (100 μL, 1 mg/kg, i.p.) and pineapple juice or extract (50, 75 and 100 mg/kg, i.p.) were administered 40 and 30 min before starting the second trial in the experimental groups. Object discrimination was impaired after scopolamine administration. Results showed that juice and ethanolic extract of pineapple significantly restored object recognition ability in mice treated with scopolamine. These finding suggested that pineapple had a protective role against scopolamine-induced amnesia, indicating its ability in management of cognitive disorders.

Neuroprotective effect of Cubebin: A dibenzylbutyrolactone lignan on scopolamine-induced amnesia in mice.

Background & objectives:Acetylcholinesterase (AChE) inhibitors represent a major class of drugs which provide symptomatic relief and improvement in cognitive function in Alzheimer's disease (AD). In this study, cubebin, a dibenzylbutyrolactone lignan, was isolated from Piper cubeba and investigated for its AChE inhibitory activity in an attempt to explore its potential for memory-enhancing activities in mice.Methods:Molecular docking of cubebin was carried out followed by in vitro AChE activity. Mice were treated with cubebin (25 & 50 mg/kg; i.p.), for three days and memory impairment was induced by scopolamine (3 mg/kg; i.p.). Memory function was evaluated by Morris water maze (MWM) test. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain.Results:Molecular docking study revealed that cubebin was well bound within the binding site of the AChE enzyme showing interactions such as π-π stacking and hydrogen bonding with residues present therein. Cubebin inhibited AChE enzyme in an in vitro assay with IC50 value of 992 μM. Scopolamine administration caused a significant impairment of learning and memory in mice, as indicated by a marked decrease in MWM performance. Scopolamine administration also produced a significant enhancement of brain AChE activity and oxidative stress in mice brain. Pre-treatment of cubebin (25 and 50 mg/kg; i.p.) significantly prevented scopolamine-induced learning and memory deficits along with attenuation of scopolamine-induced rise in brain AChE activity and oxidative stress level.Interpretation & conclusions:Cubebin showed promising protective activity in scopolamine-induced spatial memory impairment in mice. This could be attributed to its brain AChE inhibition and antioxidant activity.

Statins: Are they also memory enhancers? A study in relation to their hypocholesterolemic and antioxidant effects in Swiss albino mice

Background: The most common cause of dementia with progressive loss of memory is Alzheimer’s disease (AD), a neurodegenerative disorder that occurs due to increased oxidative stress, deposition of amyloid protein, and loss of cholinergic neurons. Statins, by their hypocholesterolemic, antioxidant, and other activities may be helpful in this regard. Aims and Objectives: The aim of this study is to examine the relation between memory restoring effect, lipid lowering effect as well as the antioxidant properties of statins in experimental dementia models using Swiss albino mice. Materials and Methods: Cognitive ability was tested in randomly selected young Swiss albino mice with two exteroceptive behavioral models, passive avoidance paradigm, and Morris Water Maze (MWM) by assigning 30 animals divided equally into 5 groups for each model. Amnesia was induced by feeding high-fat-diet for 90 days in 4 groups of mice. The 5th group served as control with young mice. Piracetam, atorvastatin, and simvastatin were given, respectively, to 3 of the amnesic groups of each model whereas the 4th group treated with vehicle served as positive control. Results: Step-down latency was significantly higher in young mice as well as amnesic mice treated with piracetam, simvastatin, or atorvastatin in comparison to vehicle-treated amnesic mice. Similar result was also seen during retrieval test in MWM, although all the groups performed comparably during acquisition trial. Brain malondialdehyde (MDA) levels were significantly low in all the groups who performed well in either of the exteroceptive behavioral models. Cholesetrol levels in young control and statin-treated groups were significantly low in comparison to piracetam- or vehicle-treated mice. Conclusions: Atorvastatin and simvastatin improved the cognitive ability in terms of learning as well as retrieval of learned experience which may be attributed to their hypocholesterolemic and antioxidant properties.

Antioxidant and anti‐acetylcholinesterase activities of anchovy (Coilia mystus) protein hydrolysates and their memory‐improving effects on scopolamine‐induced amnesia mice

SummaryAnchovy protein hydrolysates (APHs) were prepared through hydrolysis for 2, 4 or 8 h (APH‐2, APH‐4 and APH‐8, respectively). The chemical analyses, in vitro assessments [antioxidant activity and acetylcholinesterase (AchE) inhibitory activity] and in vivo mice tests were evaluated. Results revealed that APH‐8 exhibited the strongest reducing power and AchE inhibitory capacity (IC50 = 159.76 ± 0.03 mg mL−1), which may be due to its specific amino acid composition and newly formed peptides. In addition, AchE inhibitory kinetics of amino acids suggested that lysine was featured of both competitive and noncompetitive inhibitors. Furthermore, the results of in vivo study showed that all APHs exhibited memory‐improving action on scopolamine‐induced amnesia mice especially, APH‐8, indicating that anchovy protein is a potential source for health‐promoting peptides.

Improvement of Learning and Memory of Mice by Plumbagin

Roots of Plumbago zeylanica have been reported to improve learning and memory of mice, but the effect of plumbagin on learning and memory of mice and the possible mechanisms for its effect on memory have not been explored till date. So the present study was designed to evaluate the effect of plumbagin on learning and memory of Swiss young male albino mice. Plumbagin (4, 8, 16 mg/kg, p.o.) and physostigmine (0.1 mg/kg,i.p.) per se were administered for 15 successive days to separate groups of mice. Behavioral parameters of learning and memory were recorded using Morris water maze. Acetylcholinesterase activity was estimated in brain of mice. Effect of plumbagin on scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.)-induced amnesia was also investigated. Locomotor activities of mice were also recorded. Plumbagin (8 and 16 mg/kg) and physostigmine significantly improved learning and memory of mice, as indicated by decrease in escape latency during training and increase in time spent in target quadrant of Morris water maze during retrieval. The drugs did not show any significant effect on locomotor activities of mice. Memory improving activity of plumbagin (16 mg/kg) was equivalent to physostigmine. Plumbagin significantly reversed scopolamine- and diazepam- induced amnesia in mice. Plumbagin and physostigmine also significantly reduced brain acetylcholinesterase activity of mice. In conclusion, plumbagin significantly improved memory of mice possibly through inhibition of brain acetylcholinesterase activity and through involvement of GABA-benzodiazepine pathway. Thus, plumbagin may be explored further for management of cognitive dysfunction.

Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents.

Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI > 196; 5t, IC50 = 0.067 μM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.

Epigenetic regulation of neuronal immediate early genes is associated with decline in their expression and memory consolidation in scopolamine-induced amnesic mice.

Recently, we reported a correlation of scopolamine mediated decline in memory consolidation with increase in the expression of DNA methyltransferase 1 (DNMT1) and histone deacetylase 2 (HDAC2) in the mouse hippocampus. Memory consolidation is a protein synthesis-dependent process which involves the expression of synaptic plasticity genes, particularly neuronal immediate early genes (IEGs). However, the mechanism of regulation of these genes during decline in memory is poorly understood. Therefore, we have studied the epigenetic regulation of expression of neuronal IEGs in scopolamine-induced amnesic mice. Scopolamine significantly impaired memory consolidation as tested by radial arm maze, and the expression of neuronal IEGs was downregulated in the hippocampus as revealed by qRT-PCR and Western blotting. Further, methylated DNA immunoprecipitation (MeDIP) analysis showed increase in DNA methylation, while chromatin immunoprecipitation (ChIP) revealed decrease in H3K9/14 acetylation at the promoter of neuronal IEGs. Taken together, the present study shows that increased DNA methylation and decreased histone acetylation at the promoter of neuronal IEGs are associated with decline in their expression and memory consolidation during scopolamine-induced amnesia. These findings suggest that the epigenetic regulation through altered DNA methylation and histone acetylation might be explored further to develop potential therapeutic interventions for amnesia.