Amnesia Model Research Articles

Neuroprotective effect of Citrus limon juice against scopolamine induced amnesia in Wistar rats: Role of cholinergic neurotransmission monitoring and beta-actin signaling

Lemon (Citrus limon) Rutaceae) is one of the most popular world fruit crops, contains active phytochemicals that are polyphenolic compounds, flavonoids, vitamin C, folic acid, potassium, pectin etc. The bioactives compound of lemon are preventing radical-mediated diseases like cancer, diabetes, neurodegenerative disorders but no one reported that effect of Citrus limon juice on scopolamine induced amnesia model in animal. Rats were divided into five groups. Group 1 rats (normal control) received 1 ml/kg normal saline for 14 days intraperitoneally (i.p.). Group 2 rats received scopolamine (3 mg/kg, i.p.) 30 min prior to the trial on the 14th day. Group 3 rats received 3 mg/kg/day of donepezil as pre-treatment for 14 days and scopolamine (3 mg/kg, i.p.) 30 min prior to the trial on the 14th day. Group 4 and 5 rats received Citrus limon juice (0.6, 1.2 ml/kg/day) for 14 days and scopolamine (3 mg/kg, i.p) 30 min prior to the trial on 14th day respectively. On the day 14, working memory and long-term memory in rats were tested by experimental paradigms and Morris Water Maze (MWM) task. On day 15, 6 rats of each group were sacrificed and brain tissue of these rats was isolated for the estimation of biochemical parameters, histopathological examination and western blot analysis. Scopolamine treated rats showed significantly increased escape latency (p<0.0001), Acetylcholinesterase (AchE) activity (P < 0.001), lipid peroxidation (p<0.001) and significantly decreased GSH level (p< 0.001) in the hippocampus compared to the control group. These parameters were significantly recovered in the rats pretreated with Citrus limon juice and donepezil. Histopathological examination showed that Citrus limon juice and donepezil provided significant protection against pyramidal cell degeneration, neuronophagia, and thickened endothelium of blood vessels with perivascular and moderately inflammatory cells like eosinophils in scopolamine treated rats. Furthermore, Citrus limon juice was found to significantly upregulate the expression levels of ERK and beta-actin proteins in rat hippocampus. The findings of this study demonstrated that Citrus limon juice and their constituents have potential to improve the cognitive performance in scopolamine induced amnesia in Wistar rats. Further extensive studies are needed to explore the efficacy of Citrus limon juice and its constituents for treatment of various neurodegenerative diseases such as Alzheimer's disease.

Synthesis, docking, and biological evaluation of novel 1-benzyl-4-(4-(R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidin-2-ones as potential nootropic agents

In order to search for innovative nootropic agents, new 1-benzyl-4- (4- (R)-5-sulfonylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl) pyrrolidine-2-ones was synthesized by reacting benzylamine with itaconic acid to 1-benzyl-5-oxopyrrolidine-3-carboxylic acid, which was then subjected to hydrazinolysis followed by the addition of substituted isothiacyanate followed by cyclization of intermediate thiosemicarbazides. The structure and purity of the obtained substances were confirmed by elemental analysis, 1H NMR spectroscopy, 13C NMR spectroscopy and LC/MS. Docking studies were performed for the substances synthesized using Autodock 4.2 software. Approximate values of LD50 (in silico determination) are around 870–1000 mg/kg. All synthesized substances were tested for nootropic activity by the passive avoidance test on the scopolamine amnesia model in doses that are about 1/10 of the estimated LD50. Based on the results of docking and pharmacological experiment, the most promising substances 7a, as well as 7e, 7f were identified. The results of molecular docking (hit compound 7a) indicate a positive correlation between the obtained values of docking studies and experimental data.

Genistein suppresses microglial activation and inhibits apoptosis in different brain regions of hypoxia-exposed mice model of amnesia.

Genistein (GE) or 4',5,7-trihydroxyflavone, a plant derived isoflavone, is a biologically active compound having several beneficial properties. Studies showed that GE possesses anti-neoplastic, anti-tumor, anti-helminthic, anti-oxidant, and anti-inflammatory activities. Herein, we investigated the neuroprotective effects of GE in a mouse model of hypoxia-induced amnesia. Mice were exposed to hypoxic conditions (10% O2) in a designated hypoxia chamber and co-treated with GE (10, 20, or 30mg/kg) for 4weeks. Following this, behavioral tests were performed to evaluate memory performance. We assessed microglial activation in the hippocampus, amygdala, and pre-frontal cortex (PFC) regions by evaluating the Iba-1 and GFAP transcript levels, and MIP-1β, Cox-2, and IL6 protein levels. Apoptosis was assessed by evaluating Bax, BAD, and Bcl-2 mRNA levels, and caspase-3 activity. To uncover the underlying molecular mechanism, we evaluated the levels of Nrf2, HO-1, and NQO1 in different brain regions of mice from all groups. Results showed that hypoxia-exposed mice have reduced performance in the behavioral tests and GE treatment enhanced the memory performance in hypoxia-exposed mice. Moreover, hypoxia-exposed mice showed increased expression of microglial activation markers and enhanced apoptosis in the hippocampus, amygdala, and PFC. GE treatment suppressed microglial activation and prevented apoptosis in the brain of hypoxia-exposed mice. Furthermore, hypoxia-exposure reduced the expression of Nrf2, NQO1, and HO-1 while GE treatment ameliorated this decrease in different regions of hypoxia-exposed mice brain. In conclusion, GE prevents cognitive dysfunction by suppressing microglial activation and inhibiting apoptosis in the hypoxia-exposed mice brain.

Effect of chlorogenic acid plus donepezil on critical neurocortical enzyme activities, inflammatory markers, and synaptophysin immunoreactivity in scopolamine-assaulted rats, supported by multiple ligand simultaneous docking.

The effect of chlorogenic acid (a natural phenolic acid ubiquitous in plant foods) on selected therapeutic properties of donepezil (DON) in a scopolamine (SCOP)-induced rat model of amnesia was the focus of this study. Adult albino (Wister strain) rats were allocated into five groups (n=11) consisting of control, SCOP, SCOP + chlorogenic acid (CGA), SCOP + DON, and SCOP + CGA + DON for 7 days. Post-treatment, the rat brain cerebral cortex homogenate was assayed for cholinesterase and monoamine oxidase activities. Also, the reactive oxygen species, total thiol and nitric oxide contents, alongside catalase, and superoxide dismutase activities were determined. Routine histology for neuronal and glial cells as well as synaptophysin immunoreactivity was also carried out on the cerebral cortex. Thereafter, multiple ligand simultaneous docking was carried out for DON and CGA at the active sites of AChE and BChE. The results revealed that the biochemical parameters, glial cells, and synaptophysin immunoreactivity were significantly impaired in the cerebral cortex of scopolamine-treated rats. However, impaired butyrylcholinesterase and monoamine oxidase activity, together with antioxidant, glial cells, and synaptophysin levels were significantly ameliorated in scopolamine-treated rats administered DON + CGA compared to donepezil alone. The docking of both DON and CGA at the active sites of AChE or BChE showed higher binding energy to both enzymes compared to individual interactions of either DON or CGA. Hence, this study has been able to show that CGA could improve some of the therapeutic effects of DON, which could broaden the therapeutic spectrum of this drug. PRACTICAL APPLICATIONS: This study showed that chlorogenic acid (a major phenolic acid found in plant foods such as coffee) modulated some of the therapeutic properties of donepezil (an anticholinesterase drug used in the treatment of mild-to-moderate Alzheimer's disease). The combinations elicited better anti-butyrylcholinesterase, antimonoamine oxidase, and antioxidant properties, thus presenting this food-drug interaction as potentially able to offer better therapeutic properties.

Flavonoid Derivatives as Potential Cholinesterase Inhibitors in Scopolamine-Induced Amnesic Mice: An In Vitro, In Vivo and Integrated Computational Approach.

Flavonoids are one of the most exciting types of phenolic compounds with a wide range of bioactive benefits. A series of flavone derivatives (F1–F5) were previously synthesized from substituted O-hydroxy acetophenone and substituted chloro-benzaldehydes. The titled compounds F1–F5 in the present study were evaluated for their anticholinesterase potential (against AChE and BuChE). The obtained results were then validated through a molecular docking approach. Compound F5 was found to be the most potent inhibitor of AChE (IC50 = 98.42 ± 0.97 µg/mL) followed by compound F4, whereas compound F2 was found to be the most promising inhibitor of BuChE (IC50 = 105.20 ± 1.43 µg/mL) among the tested compounds. The molecular docking analysis revealed a similar trend in the binding affinity of compounds with the targeted enzymes and found them to be capable of forming highly stable complexes with both receptors. The selected compounds were further subjected to in vivo assessment of cognitive function in a scopolamine-induced amnesic animal model, in which almost all compounds F1–F5 significantly attenuated the amnesic effects as evaluated through Y-Maze Paradigm and novel object discrimination (NOD) tasks, findings that were further supported by ex vivo experimental results. Among (F1–F5), F5 showed significant anti-amnesic effects in scopolamine-induced amnesic models and ameliorated the memory loss in behavioral model studies as compared to counterparts. In ex vivo study, noteworthy protection from oxidative stress in the brains of scopolamine-induced amnesic mice was also recorded for F5. These findings also confirmed that there were no significant differences among the in vivo and ex vivo results after administration of F1–F5 (7.5 or 15 mg/kg) or donepezil (2 mg/kg). These synthesized flavonoids could serve as potential candidates for new neuroprotective and nootropic drugs. However, further studies are needed to validate their observed potential in other animal models as well.

Vitamin B12 as a cholinergic system modulator and blood brain barrier integrity restorer in Alzheimer's disease

So far, the cholinergic hypothesis of Alzheimer's disease (AD) remains the fundamental explanation for the complex etiopathology of AD. However, therapeutics raising synaptic acetylcholine (Ach) or having cholinergic receptors agonistic activity had shown limited clinical efficacy, possibly, due to lacking capability to aggregate cholinergic receptors within the degenerated cholinergic neurons. Vitamin-B12 (B12) is an epigenetic modifier. It has a specific CNS transport system via the cubam receptors. The later enclose a cholinergic aggregator; agrin protein, suggesting that B12 administration may cause cholinergic receptors aggregation. Further, B12 involvement in homocysteine (Hcy) metabolism may restore blood brain barrier (BBB) integrity disrupted by elevated Hcy levels in AD. Here in, using a pharmacological model of cholinergic amnesia, three different B12 doses were compared to the standard of care; donepezil (DON) regarding cholinergic system modulation, and their effect on Hcy metabolic pathways. Further, AD-associated cerebro-vascular pathology was assessed by morphometric analyses of cerebro-vasculature morphology and ultrastructure using scanning and transmission electron-microscopes, respectively. Consequent effect on key AD-hallmarks and behavioral cognitive tests was also examined. The highest B12-tested dose (B12-HD) showed the greatest hippocampal cholinergic modulation with dose-dependent preferential upregulation of one cholinergic receptor over the other. Altered Hcy metabolism was proved to be a consequence of cholinergic disruption that was variably reversed by different B12 doses. In spite of equipotent effect of DON and B12-HD therapies in decreasing β-amyloid synthesis, B12-HD-treated group revealed the greatest restoration of BBB integrity indicating superior capability of β-amyloid clearance. Therefore, B12-HD therapy may represent a promising AD-modifying agent with extra-ability over conventional cholinergic modulators to aggregate cholinergic receptors.

Design, Synthesis and Evaluation of Benzimidazole Hybrids to Inhibit Acetylcholinesterase and COX for Treatment of Alzheimer's Disease.

A simultaneous administration of an acetylcholinesterase (AChE) inhibitor and a NSAID as a drug cocktail has been documented to exhibit significantly protective effects in AD patients. But it suffers from poor patent compliance, pharmacodynamics and pharmacokinetic issues. The present study is aimed to design and synthesize a hybrid molecule capable of exhibiting both AChE inhibition and anti-inflammatory activities for de-accelerating the progression of AD. The synthesized molecules will be evaluated for in vitro and in vivo models. The present study involves the coupling of ibuprofen or naproxen to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05. The synthesized compounds were characterized using FTIR, 1H-NMR, 13C-NMR and MS. All compounds were evaluated for in vitro AChE inhibitory and COX inhibitory activities. The most active compound was taken for in vivo evaluation. Compounds of series IB01-IB05 are found more potent as compared to NP01-NP05. The maximally potent compound IB04 in in vitro evaluation is selected for in vivo evaluation of memory restoration activity using scopolamine-induced amnesia model in mice. It significantly reverses the scopolamine-induced changes (i.e., escape latency time, mean time spent in target quadrant, brain AChE activity and oxidative stress) in a dose-dependent manner. IB04 at 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil. The findings indicate that Benzimidazole hybrids utilizing ibuprofen and pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.

Advancing combination treatment with cilostazol and caffeine for Alzheimer's disease in high fat-high fructose-STZ induced model of amnesia

Several studies have suggested that phosphodiesterase (PDE) inhibitors may be a disease-modifying for Alzheimer’s disease (AD). Cilostazol (CSZ) has been shown to be a new treatment for cognitive impairment with limited efficacy. Our aim was to investigate the effect of caffeine on the efficacy of CSZ against STZ-induced type 2 diabetes (T2D)-related cognitive impairment in high fat/high fructose fed rats. The efficacy of low doses of caffeine, CSZ, and CSZ plus caffeine against abnormal behavioral, biochemical, histological, or genetic changes of animal models of AD was examined. Eight weeks treatment with CSZ plus caffeine was more effective than CSZ or caffeine in improving impaired behavioral tests for cognition and memory. Histological examination exhibited a significant augmentation in the efficacy of CSZ by caffeine in protecting neurons from damage in T2D rats. Importantly, CSZ and caffeine normalized the accumulation of Amyloid beta (Aβ-42) and phosphorylated tau protein (p-tau) positive cells in the brain of T2D rats. CSZ or CSZ plus caffeine reversed low glutamate gene expression, elevated cholinesterase level, and elevated caspase-3 activity in T2D rats. Furthermore, CSZ plus caffeine was significantly more effective than CSZ or caffeine in inhibiting the increase in malondialdehyde (MDA) level, total oxidative stress, pro-inflammatory cytokines and glucogen synthase kinase-3 beta (GSK-3β) in the hippocampus of T2D rats. Also, CSZ plus caffeine was more effective than CSZ or caffeine in alleviating insulin resistance and hypercholesterolemia in T2D rats. Our findings suggest the possibility of effective treatment of AD by enhancing the therapeutic potential of CSZ through combined treatment with lower doses of caffeine. The enhancement of CSZ effect by caffeine is attributed to the increased inhibitory effect of CSZ on insulin resistance, GSK-3β activity, hypercholesterolemia, oxidative stress and pro-inflammatory cytokines.

Design, molecular Docking, synthesis and evaluation of xanthoxylin hybrids as dual inhibitors of IL-6 and acetylcholinesterase for Alzheimer's disease

Interleukin-6 (IL-6) and acetylcholinesterase (AChE) are two important targets implicated in progression of Alzheimer's Disease (AD). Simultaneous inhibition of both IL-6 and AChE by a molecule presents an effective strategy for the treatment of AD. In this study, the pharmacophores for inhibition of IL-6 and AChE are identified, and coupled to design novel molecules capable of acting as dual inhibitors of IL-6 and AChE. Literature review reveals that xanthoxylin and a disubstituted or a carbamoyl amine are pharmacophore for IL-6 and AChE inhibition, respectively. Therefore, xanthoxylin is coupled with various disubstituted amines or carbamoyl amines through alkyl linkers of different lengths (1–4 carbon atoms) to design two series of 80 compounds. All designed compounds are docked in AChE. Based on their docking score, 15 compounds are selected for synthesis and evaluation of AChE inhibitory activity. The compounds showing > 45% inhibition of EeAChE are selected for evaluation of IL-6 and butyrylcholinesterase (BuChE) inhibitory activities. Compound Y13g is found to be the most potent inhibitor of EeAChE, BuChE and IL-6. It is further evaluated in vivo using STZ-induced amnesia model in mice at three doses (0.2, 0.4 and 0.8 mg/kg), wherein it shows dose-dependent effects. At 0.8 mg/kg, it reverses the STZ-induced memory deficit, and shows histopathology similarly as in normal animals. The findings suggest that compounds derived from coupling of xanthoxylin with piperazine through a 3-carbon chain provides a useful template for the development of new chemical entities effective against AD.

Effect of Whey-Derived Lactopeptide \u03b2-Lactolin on Memory in Healthy Adults: An Integrated Analysis of Data from Randomized Controlled Trials

ContextEpidemiological studies have shown that consumption of dairy products reduces the risk of dementia and cognitive decline in older individuals. Tryptophan-tyrosine-related β-lactopeptides and their representative β-lactolin of glycine-threonine-tryptophan-tyrosine tetra-peptide have been identified as agents in dairy products, which improve cognitive function as well as memory function via the activation of the dopaminergic system in a mouse model of amnesia. Previous clinical trials have shown that supplementation with β-lactolin improves memory retrieval in healthy older adults. Specifically, β-lactolin improved the scores in some neuropsychological tests. However, the effects of β-lactolin on memory function have not been clarified.ObjectivesThe aim of this study was to evaluate the effect of β-lactolin on memory function using statistical methods.Data SourcesWe searched the Web of Science, Cochrane Library, and JDream III until November 2021 to identify relevant randomized controlled trials for integrated analysis.Data SynthesisThree randomized controlled trials evaluating the effect of β-lactolin on memory in healthy adults were selected for the integrated analysis. The results showed that the score of cued recall among the neuropsychological tests in the β-lactolin group was significantly higher than that in the placebo group (g=0.33; 95% CI: 0.10, 0.55). In addition, the total memory score was higher but this difference was not significant (g=0.17; 95% CI: −0.09, 0.43).ConclusionsTaken together, these results suggest that supplementation with β-lactolin improves cued recall in healthy older adults.

Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia.

Prolyl oligopeptidase (POP) is a large cytosolic serine peptidase that is altered in patients with Alzheimer’s disease, Parkinsonian syndrome, muscular dystrophies, and other denervating diseases. Thus, POP may represent a relevant therapeutic target for treatment of neuropsychiatric disorders and neurodegenerative diseases. Here, we report the characterization of five novel cyanopyrrolidine-based compounds (BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN) and show that they are potent inhibitors of POP and are predicted to penetrate the blood-brain barrier (BBB). Indeed, we show that CbzMetPrdN penetrates the rat BBB and effectively inhibits POP in the brain when administered intraperitoneally. Furthermore, molecular modeling confirmed these compounds likely inhibit POP via interaction with the POP catalytic site. We evaluated protective effects of the cyanopyrrolidine-based POP inhibitors using scopolamine- and maximal electroshock-induced models of amnesia in rats and showed that BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, and CbzGlnPrdN significantly prolonged conditioned passive avoidance reflex (CPAR) retention time when administered intraperitoneally (1 and 2 mg/kg) before evaluation in both models of amnesia, although CbzAlaPrdN was not effective in scopolamine-induced amnesia. Our data support previous reports on the antiamnesic effects of prolinal-based POP inhibitors and indicate an important role of POP in the regulation of learning and memory processes in the CNS.

P.0541 Comparison the effects of donepezil and memantine on learning and memory in rats with a model of scopolamine-induced amnesia

P.0541 Comparison the effects of donepezil and memantine on learning and memory in rats with a model of scopolamine-induced amnesia

A standardized black pepper seed extract containing β-caryophyllene improves cognitive function in scopolamine-induced amnesia model mice via regulation of brain-derived neurotrophic factor and MAPK proteins.

β-caryophyllene (BCP), a natural sesquiterpene present in plants, is a selective agonist of cannabinoid receptor type-2 (CB2) of the endocannabinoid system. In this study, we have prepared an extract from Piper nigrum (black pepper) seeds using supercritical fluid extraction, standardized to contain 30% BCP (ViphyllinTM ). The beneficial effects of prophylactic treatment with Viphyllin on cognitive functions were demonstrated in Scopolamine-induced dementia model mice. Male Swiss albino mice (25-30g) were administered with Viphyllin (50mg and 100mg/kg body weight p.o.) or donepezil (1.60mg/kg) for 14days. Subsequently, cognitive deficits were induced by treating the animals intraperitoneally with Scopolamine (0.75mg/kg). The cognitive behavior of mice was evaluated using a novel object recognition test (NORT) and Morris water maze (MWM) test. The brain homogenates were studied for biochemical parameters including cholinesterase activities and antioxidant status. Western blot analysis was performed to investigate the mechanism of action. Viphyllin dose dependently improved the recognition and spatial memory and cholinergic functions in Scop-treated mice. The extract was found protective against Scop-induced oxidative damage and histopathologic changes in the brain. At 100mg/kg Viphyllin markedly reduced the proBDNF/mBDNF ratio (p<.05) and augmented the TrkB expression (p<.01). Viphyllin (100mg/kg) was found to be neuroprotective by reducing the Scop-induced upregulation of p-JNK and p-p38 MAPK proteins, Bax/Bcl-2 ratio, and caspase activation in the brain. Viphyllin also exerted anti-inflammatory effects by downregulating Cox-2, TNF-α, and NOS-2 in Scop-induced mice (p<.05). To summarize, our data encourage Viphyllin as a functional ingredient/dietary supplement for brain health and cognition. PRACTICAL APPLICATIONS: Black pepper is a culinary spice having several medicinal attributes. Essential oils in the seeds of the plant give aroma and flavor to it. Here we have prepared an extract from the seeds of black pepper using supercritical fluid extraction, characterized for the presence of β-caryophyllene (not <30%). This research work further validates the neuroprotective mechanism of the extract in Scopolamine-induced cognitive impairment model mice. The findings from this study strongly suggest the beneficial neuroactive properties of black pepper seed extract having the presence of BCP, a CB2 receptor agonist. It can thus be used potentially as a functional food ingredient for cognition and brain function.

Anti- Alzheimer’s and Anti- Oxidant Activity of Cyamopsis tetragonoloba Fruit Extract in Mice

The present study was designed to investigate the anti-alzheimer’s activity of Cyamopsis tetragonoloba fruit in mice. The two exteroceptive models, scopolamine (1mg/kg) and diazepam (1mg/kg) induced amnesia were used to study the anti-alzheimer’s effect of ethanolic fruit extract of Cyamopsis tetragoloba (CTFE) at the oral dose of 200mg/kg and 400mg/kg in Wistar albino mice. Piracetam (400mg/kg) was used as a standard drug. After completion of the 10 days respective treatments, scopolamine induced amnesia model showed the better activity in all the three; Elevated plus maze, Radial arm maze and Y maze parameters. The CFE at a dose of 200mg/kg and 400mg/kg, improved memory in a dose dependent manner. In scopolamine and diazepam induced amnesia model, biochemical parameters like lipid hydroperoxide (P&lt;0.05) and malondialdehyde (P&lt;0.01) levels were significantly decreased with administration of CFE (400mg/kg) when compared to scopolamine control. Whereas, acetylcholinesterase (P&lt;0.01) level was significantly increased when compared to scopolamine control on administration of CFE (400mg/kg). In-vivo antioxidants like superoxide dismutase, reduced glutathione and catalase were decreased on inducing amnesia by scopolamine and diazepam when compared to normal group. Treatment with 400mg/kg of CFE significantly increased the levels of superoxide dismutase (P&lt;0.05), reduced glutathione (P&lt;0.05) and catalase (P&lt;0.05) when compared to negative controls. From the results it was concluded that the ethanolic fruit extract of Cyamopsis tetragonoloba elicits anti-alzheimer’s activity in experimental animal models.

Antiamnestic effect of new nicotinic acid derivatives

Introduction: The search for new drugs for the prevention and treatment of vascular cognitive disorders continues to be a relevant task of pharmacology. In this regard, the aim of this work is to study the antiamnestic effect of five new nicotinic acid derivatives in comparison with the well-known drug mexidol (ethylmethylhydroxypyridine succinate) in animals.&#x0D; Materials and methods: The experiments were carried out on white male mice using conditioned passive avoidance reflex (CPAR). Electroconvulsive shock (ECS), scopolamine administration, and acute hypoxia in a hermetic chamber were used as amnesic effects. Testing for the safety of CPAR was performed 24 h after amnesic exposure. The new substances, reference drug mexidol, and a 0.9% sodium chloride solution (control group) were administered once intraperitoneally 60 min before mice training.&#x0D; Results and discussion: Three of the five new nicotinic acid derivatives, LKhT 4-19 (100 mg/kg), LKhT 6-19 (25, 50, and 100 mg/kg), and LKhT 7-19 (100 mg/kg), have antiamnestic properties on models of amnesia in mice induced by ESC, scopolamine, and acute hypoxia in a hermetic chamber. At the same time, the most efficient substance – LKhT 6-19 – exceeds the reference drug mexidol on all three models used. In addition, this compound is also more efficient than two other new compounds, LKhT 4-19 and LKhT 7-19, on the model of ESC-induced amnesia and LKhT 7-19 on the scopolamine-induced amnesia model.&#x0D; Conclusion: Compound LKhT 6-19 is promising for further advanced preclinical studies as a potential drug with antiamnestic activity.

A comparative in vivo Evaluation of Anti-Alzheimer Activity of Bacopa Extract and its Solid Lipid Nanoparticles

Background: Bacopa monnieri (Brahmi; family Scrophulariaceae) is a well-known plant known for its nootropic activity. Delivery of Bacosides (an active constituent) is limited at the site of action owing to the existence of the Blood-Brain Barrier (BBB). In order to take the Bacoside- Rich Extract (BRE) across BBB, formulated solid lipid nanoparticles (SLNs) were used. Objective: The objective of this work was to evaluate the pharmacokinetic and pharmacodynamic behavior (in vivo potential) of the prepared SLNs containing BRE in comparison to BRE alone for the treatment of Alzheimer’s disease. Methods: Swiss albino male mice (25-30 gm) were used for the study. The pharmacokinetic, as well as pharmacodynamic evaluation of formulated SLNs, were performed in comparison to BRE in a scopolamine-induced amnesia model. Results: BRE-loaded SLNs were found to be significantly more effective than BRE in alleviating neurodegeneration. The pharmacokinetic study revealed the improved bioavailability of prepared SLNs with the potential of sustaining the drug release in mice for an extended period of time. Conclusion: The results demonstrated that the SLNs can be considered as a potential delivery system for taking BRE across the BBB to treat Alzheimer’s disease.

High ethanol preference and dissociated memory are co-occurring phenotypes associated with hippocampal GABAAR-δ receptor levels

Alcohol use disorder (AUD) frequently co-occurs with dissociative disorders and disorders with dissociative symptoms, suggesting a common neurobiological basis. It has been proposed that facilitated information processing under the influence of alcohol, resulting in the formation of dissociated memories, might be an important factor controlling alcohol use. Access to such memories is facilitated under the effect of alcohol, thus further reinforcing alcohol use. To interrogate possible mechanisms associated with these phenotypes, we used a mouse model of dissociative amnesia, combined with a high-alcohol preferring (HAP) model of AUD. Dissociated memory was induced by activation of hippocampal extrasynaptic GABA type A receptor delta subunits (GABAAR-δ), which control tonic inhibition and to which ethanol binds with high affinity. Increased ethanol preference was associated with increased propensity to form dissociated memories dependent on GABAAR-δ in the dorsal hippocampus (DH). Furthermore, the DH level of GABAAR-δ protein, but not mRNA, was increased in HAP mice, and was inversely correlated to the level of miR-365-3p, suggesting an miRNA-mediated post-transcriptional mechanism contributing to elevated GABAAR-δ. The observed changes of DH GABAAR-δ were associated with a severe reduction of excitatory projections stemming from GABAAR-δ-containing pyramidal neurons in the subiculum and terminating in the mammillary body. These results suggest that both molecular and circuit dysfunction involving hippocampal GABAAR-δ receptors might contribute to the co-occurrence of ethanol preference and dissociated information processing.

Mitigating Effect of Lindera obtusiloba Blume Extract on Neuroinflammation in Microglial Cells and Scopolamine-Induced Amnesia in Mice.

Lindera obtusiloba Blume (family, Lauraceae), native to Northeast Asia, has been used traditionally in the treatment of trauma and neuralgia. In this study, we investigated the neuroinflammatory effect of methanol extract of L. obtusiloba stem (LOS-ME) in a scopolamine-induced amnesia model and lipopolysaccharide (LPS)-stimulated BV2 microglia cells. LOS-ME downregulated the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, inflammatory cytokines, and inhibited the phosphorylation of nuclear factor kappa-B (NF-ĸB) and extracellular signal-regulated kinase (ERK) in LPS-stimulated BV2 cells. Male C57/BL6 mice were orally administered 20 and 200 mg/kg of LOS-ME for one week, and 2 mg/kg of scopolamine was administered intraperitoneally on the 8th day. In vivo behavioral experiments (Y-maze and Morris water maze test) confirmed that LOS-ME alleviated cognitive impairments induced by scopolamine and the amount of iNOS expression decreased in the hippocampus of the mouse brain. Microglial hyper-activation was also reduced by LOS-ME pretreatment. These findings suggest that LOS-ME might have potential in the treatment for cognitive improvement by regulating neuroinflammation.

Скринінгове дослідження антиамнестичної активності нових похідних 4-амінобутанової кислоти

The purpose of the study is to conduct screening of newly synthesized derivatives of 4-aminobutanoic acid (BC) for the presence of antiamnestic activity and to identify the most active compounds that are promising for further study.The study included 11 new compounds ‒ derivatives of 4-aminobutanoic acid, which were synthesized at the National University of Pharmacy. The of the test compounds on mnestic functions was assessed in mice by the passive avoidance conditional reflex (PACR) test in a model of anterograde amnesia caused by scopolamine (1,5 mg/kg, intraperitoneally).As a result of pharmacological screening of 11 new derivatives of 4-aminobutanoic acid for the presence of antiamnestic activity, compounds were found that showed activity: KGM-2, KGM-5, KGM-6. Analysis of the «structure-antiamnestic effect» relationship for the synthesized series of compounds showed that the most active are 4-aminobutanoic acid derivatives containing a hydroxymethyl radical (KGM-1 and KGM-2). Introduction of methyl radical to the molecule KGM-2 leads to a decrease in antiamnestic activity (KGM-3). It was found that the replacement of one of the hydroxymethyl radicals in the molecule KGM-2 also helps to reduce the antiamnestic effect. Methylation of the basic compound (4-aminobutanoic acid, BC) contributed to the increase of activity only in cases when methyl and benzyl radicals (compounds KGM-5 and KGM-6) were present in the molecule. The introduction of methyl radicals only (compounds KGM-9; KGM-10 and KGM-11) enhances the antiamnestic activity compared to BC, and in the studied series of compounds they show high antiamnestic activity only at the highest dose of 50 mg / kg. It was found that the compounds KGM-1, KGM-2, KGM-5 show dose-dependent antiamnestic activity.Thus, among 11 derivatives of 4-aminobutanoic acid three compounds (KGM-2, KGM-5, KGM-6) with pronounced antiamnestic were selected as promising for further pharmacological study. The dependence of structure-antiamnestic effect has been proven: the introduction of hydroxymethyl radical enhances antiamnestic activity. The combination in the structure of both benzyl and methyl radicals provides a high antiamnestic effect.

Genistein Prevents Hypoxia-Induced Cognitive Dysfunctions by Ameliorating Oxidative Stress and Inflammation in the Hippocampus.

Genistein (GE), a plant-derived isoflavone, is a polyphenolic non-steroidal compound. Studies showed that GE possesses anti-cancer, anti-inflammatory, anti-microbial, anti-oxidant, and anti-apoptotic activities. However, the neuroprotective role of GE in amnesia has not been studied. This study aimed to evaluate the anti-amnesic potential of GE in a mice model of hypoxia-induced amnesia and to understand the underlying mechanism. Mice were exposed to hypoxia (10% O2) and administered vehicle or GE (10, 20, 30mg/kg) orally for 28days. Thereafter, Morris water maze (MWM), novel object recognition (NOR), and passive avoidance task (PAT) were performed to evaluate cognitive behavior. Next, we performed biochemical tests and gene expression analysis to uncover the mechanism underlying GE mode of action. Our results showed that GE-treatment ameliorated hypoxia-induced cognitive dysfunctions in mice. Further, GE-treatment suppressed the oxidative stress in the hippocampus of amnesic mice as evidenced by reduced lipid peroxidation, reduced nitrite and ROS levels, and increased levels of reduced glutathione (GSH) and increased total antioxidant capacity. GE treatment reduced the expression of pro-inflammatory cytokines TNFα, IL1β, IL6, and MCP-1 and increased the expression of anti-inflammatory cytokine IL10 in the hippocampus of amnesic mice. Finally, GE treatment enhanced the expression of neuroprotective genes including BDNF, CREB, CBP, and IGF1 in the hippocampus of amnesic mice. Altogether, our results showed that GE treatment prevents hypoxia-induced cognitive dysfunction in mice by reducing oxidative stress and suppressing neuroinflammation while increasing the expression of neuroprotective genes in the hippocampus.