Cyclopentanone Derivative Attenuates Memory Impairment by Inhibiting Amyloid Plaques Formation in the 5xFAD Mice

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder. This study was designed to investigate the effects of cyclopentanone derivative i.e., 2-(hydroxyl-(3-nitrophenyl)methyl)cyclopentanone (3NCP) on behavior, amyloid β (Aβ) plaque deposition, and βAPP cleaving enzyme-1 (BACE-1) expression in the 5xFAD mouse brain. In this study, computational studies were conducted to predict the binding mode of the 3NCP with target sites of the β-secretase. In vivo studies were performed on the 5xFAD mice model of AD using different behavioral test models like light/dark box, elevated plus maze (EPM), and the Barnes maze tests for the assessment of anxiety, spatial learning and memory. The thioflavin-S staining, immunohistochemistry (IHC), and RT-PCR studies were carried out to find the effect of the 3NCP on the β-amyloid plaques formation and BACE-1 expression. The results of the computational studies showed that the 3NCP has excellent binding affinities for beta-secretase. The light/dark box study depicted that the 3NCP does not cause anxiety. The 3NCP treatment effects in the EPM and Barnes maze tests showed a significant effect on learning and memory. Furthermore, the results of the thioflavin staining and IHC revealed that the 3NCP significantly reduced the formation of the beta-amyloid plaques in brain tissues. Moreover, the RT-PCR study showed that 3NCP significantly reduced the BACE-1 expression in the brain. Conclusively, the results of the current study demonstrate that the 3NCP may be a potential candidate for AD treatment in the future.

New 2,3-Benzodiazepine Derivative: Synthesis, Activity on Central Nervous System, and Toxicity Study in Mice

We report the design and synthesis of a new diazepine derivative, 4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-2,3-benzodiazepin-1-one (VBZ102), and the evaluation of its anxiolytic-like profile, memory impairment effect, and toxicity in Swiss mice. VBZ102 was evaluated for central nervous system effects in an open field, light–dark box, and novel object recognition tests under oral administration for acute and sub-acute treatment. We tested the VBZ102 toxicity in mice through a determination of LD50 values and examination of the biochemical and histopathological parameters. The VBZ102 induced an anxiolytic effect at different doses both in the light–dark box and open field tests. Unlike other benzodiazepines (e.g., bromazepam), a sedative effect was noted only after administration of the VBZ102 at 10.0 mg/kg.

Neurotropic properties of new complex compounds of SnCl4 with salicyloyl hydrazones of benzaldehyde and 4-bromobenzaldehyde

Existing data demonstrate that various medicines used for depressive disorders therapy had a number of additional effects such as sedation and mood improvement. In fact, signals from the environmental stress factors such as life-threatening hazards, social stressors and reaction to injury in the organism, firstly transmitted by the sensory nervous system and then this information are processed by the so-called emotional patterns in the brain. Treatment of various diseases that usually accompanied with neuropsychic disorders leads to «polypragmasia» – prescription of many medicines (5 and more) at the same time. Therefore, there is a big of interest to develop complex medicine with broad spectrum of the pharmacological action for the treatment of depressive disorders. Our previous research was focused on the anti-depressive properties of the complex compounds of SnCl4 with salicyloyl hydrazones of benzaldehyde (C-I) and 4-bromobenzaldehyde (C-II) and their functional aspects.The aim of the study is to determine anxiolytic and sedative activity of new complex compounds of SnCl4 with salicyloyl hydrazones of benzaldehyde and 4-bromobenzaldehyde in: «Open-field test» and «Light-dark box».Behaviour of experimental animals (mouse) was analysed by means of the test «light-dark box». It was conducted during 5 min in 1 h, 3 h, 5 and 24 h after the oral administration of substances, registering the following values: residence time in the light box and number of peeps from black to light box. Study of anxiety was conducted by means of «open-field test» during the equal time (1 h, 3 h, 5 h and 24 h). Examination was conducted during 5 min, registering numbers of stands on the hind paws (vertical mobility), numbers of peeps into holes (exploratory activity) and numbers of crossings the boxes(locomotor activity). To determine whether the complexes and functional groups that contained in C-I and C-II demonstrate anxiolytic effect, the anxiolytic action of benzaldehyde, 4-bromobenzaldehyde, salicyloyl hydrazone of benzaldehyde, salicyloyl hydrazones of 4-bromobenzaldehyde have been tested.The results of anxiolytic activity study of the complex compounds of SnCl4 with salicyloyl hydrazones of benzaldehyde and 4-bromobenzaldehyde demonstrated that after oral administration of these compounds the expressive neurotropic effect had observed during the 24 h of the experiment. The study of salicyloyl hydrazones of 4-bromobenzaldehyde indicated its significant contribution into the anxiolytic effect of the C-II. Probably the anxiolytic activity has occurred due to bromine atoms presence in the structure of the complexes.

Comparative Effectiveness of Agmatine and Choline Treatment in Rats with Cognitive Impairment Induced by AlCl3 and Forced Swim Stress

Aim: Endogenous agmatine has a significant role in learning and memory processes as a neurotransmitter. Various studies described the physiological role of endogenous agmatine in learning and memory of multiple cognitive tasks suggesting elevated levels of agmatine during the learning process in the rat brain. Dietary intake of choline showed correlation with cognitive functions in human subjects and treatment with choline supplements validated the ability to diminish learning and cognitive impairment dementias. Methods: 36 Albino rats were equally divided into three groups previously: a) control-water, b) Test I - AlCl3 (100 mg/Kg body weight), and c) Test II - Forced swim stress (FSS) for 14 days. On the next day of AlCl3 and FSS last administration, animals were allocated into further three groups and received the following treatments: a. water was given orally to the control group, b. Agmatine (100 mg/Kg Body Weight) group, and c. Choline (100 mg/Kg Body Weight) group for the next 14 days. Behaviors were assessed in Light/Dark Box, Open Field, Novel Object Recognition Test (NOR), T Maze Test, and Morris Water Maze Test. Results: Animals administered with agmatine demonstrated increased time spent in bright areas of light/dark box and square crossed while improved spatial memory in Morris water maze and T maze test and enhanced discrimination of novel object in NOR were observed in learning and memory paradigms along with choline. Conclusion: The present study determines that agmatine at the dose of (100 mg/kg body weight) attenuates memory and cognitive impairment in comparison with choline supplements.

GC-MS Phytochemical Profiling, Pharmacological Properties, and In Silico Studies of Chukrasia velutina Leaves: A Novel Source for Bioactive Agents

Chukrasia velutina is a local medicinal plant commonly known as chikrassy in Bangladesh, India, China, and other South Asian countries. The leaves, bark, and seeds are vastly used as herbal medicine for fever and diarrhea, and its leaves essential oils are used for antimicrobial purposes. In this study, we discuss the neuropsychiatric properties of C. velutina leaves through several animal models, quantitative and qualitative phytochemical analysis, and computational approaches. Neuropsychiatric effects were performed in rodents on the methanolic extract of C. velutina leaves (MECVL). Antidepressant, anxiolytic, and sedative effects experimented through these rodent models were used such as the force swimming test (FST), tail suspension test (TST), hole board test (HBT), elevated plus maze test (EPMT), light/dark box test (LDBT), open field test (OFT), and hole cross test (HCT). In these rodent models, 200 and 400 mg/kg doses were used which exhibited a significant result in the force swimming and tail suspension test (p < 0.001) for the antidepressant effect. In the anxiolytic study, the results were significant in the hole board, elevated plus maze, and light/dark box test (p < 0.001) for doses of 200 and 400 mg/kg. The result was also significant in the open field and hole cross test (p < 0.001) for sedative action in the sake of similar doses. Moreover, qualitative and quantitative studies were also performed through phytochemical screening and GC-MS analysis, and fifty-seven phytochemical compounds were found. These compounds were analyzed for pharmacokinetics properties using the SwissADME tool and from them, thirty-five compounds were considered for the molecular docking analysis. These phytoconstituents were docking against the human serotonin receptor, potassium channel receptor, and crystal structure of human beta-receptor, where eight of the compounds showed a good binding affinity towards the respective receptors considered to the reference standard drugs. After all of these analyses, it can be said that the secondary metabolite of C. velutina leaves (MECVL) could be a good source for inhibiting the neuropsychiatric disorders which were found on animal models as well as in computational studies.

Anxiolytic Activity and Brain Modulation Pattern of the α-Casozepine-Derived Pentapeptide YLGYL in Mice

α-Casozepine (α-CZP) is an anxiolytic-like bioactive decapeptide derived from bovine αs1-casein. The N-terminal peptide YLGYL was previously identified after proteolysis of the original peptide in an in vitro digestion model. Its putative anxiolytic-like properties were evaluated in a Swiss mice model using a light/dark box (LDB) after an intraperitoneal injection (0.5 mg/kg). The effect of YLGYL on c-Fos expression in brain regions linked to anxiety regulation was afterwards evaluated via immunofluorescence and compared to those of α-CZP and diazepam, a reference anxiolytic benzodiazepine. YLGYL elicited some anxiolytic-like properties in the LDB, similar to α-CZP and diazepam. The two peptides displayed some strong differences compared with diazepam in terms of c-Fos expression modulation in the prefontal cortex, the amygdala, the nucleus of the tractus solitarius, the periaqueductal grey, and the raphe magnus nucleus, implying a potentially different mode of action. Additionally, YLGYL modulated c-Fos expression in the amygdala and in one of the raphe nuclei, displaying a somewhat similar pattern of activation as α-CZP. Nevertheless, some differences were also spotted between the two peptides, making it possible to formulate the hypothesis that these peptides could act differently on anxiety regulation. Taken together, these results showed that YLGYL could contribute to the in vivo overall action of α-CZP.

The Study of the Effect of Sodium Nitroprusside in Anxiety-Like Behavior in Mice in Comparison With Diazepam

Anxiety has become a highly paramount field of research attention in psychopharmacology today. Sundry studies have shown a nitric oxide role in the regulation of anxiety. The goal of the study was to investigate sodium nitroprusside ability to affect anxiety-like behavior in mice and to compare this effect with the standard anxiolytic drug, diazepam, using both plus maze test and light/dark box test. The results revealed that sodium nitroprusside at a dose of 1 mg/kg had a significant effect on the behavior in both of the elevated plus maze test and light/dark test. However, at higher dose (3 mg/kg), it has significantly increased the anxiogenic-like effect in the light/dark box test. Diazepam at a dose of 2 mg/kg increased the time spent in open arms in elevated plus maze test and that in light chambers of light/dark test. These outcomes suggest that a nitric oxide pathway seems to play an important role in anxiety. Furthermore, sodium nitroprusside at a dose of 1 mg/kg showed a nearly anxiolytic ability, when compared with diazepam.

Synergistic Anxiolytic Effect of Curcumin and Zinc on Acute and Chronic Models of Anxiety in Mice

Introduction: Anxiety disorders being ranked at sixth position in the global burden of diseases is affecting over 250 million people. Curcumin, an active phytochemical flavonoid, has shown to induce the monoamine neurotransmitter serotonin, a prominent neurotransmitter in modulating the brain state in anxiety. Also, evidences reveal that zinc plays a key role in human neurodevelopment and supplementation of zinc enhanced the efficacy of antidepressant drugs through synergistic action. Aim: To evaluate the synergistic antianxiety effect of curcumin and zinc on acute and chronic models of anxiety in male swiss albino mice. Materials and Methods: A total of 36 male Swiss Albino mice, weighing 20-30 g, were randomly grouped to six groups, such that each group consisted of six mice. Group 1 served as control. Group 2 received standard drug diazepam 3 mg/kg Intra Peritoneal (IP). Group 3 and 4 received curcumin at doses of 5 and 10 mg/kg, respectively. Group 5 and 6 received curcumin at doses 5 and 10 mg/kg per oral (p.o) along with zinc chloride 10 mg/kg IP, respectively. The anxiolytic effect was studied in two validated models of anxiety such as Elevated Plus Maze (EPM) test and light/dark box test. Each animal was tested initially in the EPM followed by light/dark box test after administration of drug/vehicle one hour prior to the experiment in acute study. Following a washout period of one week, the animals were utilised for the study of chronic anxiolytic effect wherein the drugs were administered once daily for 14 days. Results: Curcumin at doses of 5 mg/kg and 10 mg/kg with zinc chloride 10 mg/kg showed a significant increase in the number of entries and time spent in open arm in EPM both on acute and chronic administration (p<0.001). In the light/dark box test, curcumin at doses of 5 mg/kg and 10 mg/kg when given along with zinc chloride 10 mg/kg significantly increased the number of entries and time spent in the light compartment both in acute and chronic models (p<0.001). Conclusion: The anxiolytic effect of synergistic action of curcumin and zinc was efficacious in both acute and chronic models of anxiety in mice.