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Quantitative ultrasound (QUS) was used to classify rabbits that were induced to have liver disease by placing them on a fatty diet for a defined duration and/or periodically injecting them with CCl(4). The ground truth of the liver state was based on lipid liver percents estimated via the Folch assay and hydroxyproline concentration to quantify fibrosis. Rabbits were scanned ultrasonically in vivo using a SonixOne scanner and an L9–4/38 linear array. Liver fat percentage was classified based on the ultrasonic backscattered radio-frequency (RF) signals from the livers using either QUS or a 1D convolutional neural network (CNN). Use of QUS parameters with linear regression and canonical correlation analysis (CCA) demonstrated that the QUS parameters could differentiate between livers with lipid levels above or below 5%. However, the QUS parameters were not sensitive to fibrosis. The CNN was implemented by analyzing raw RF ultrasound signals without using separate reference data. The CNN output the classification of liver as either above or below a threshold of 5% fat level in the liver. The CNN outperformed the classification utilizing the QUS parameters combine with a support vector machine (SVM) in differentiating between low and high lipid liver levels, i.e., accuracies of 74% versus 59% on the testing data. Therefore, while the CNN did not provide a physical interpretation of the tissue properties, e.g., attenuation of the medium or scatterer properties, the CNN had much higher accuracy in predicting fatty liver state and did not require an external reference scan.

Purpose The aim of the study was first to examine the heterogeneity of body image and resources, as described by the conservation of resources theory (COR), in a sample of psoriatic patients and explore whether heterogeneity within these variables explains the possible differences in levels of life satisfaction among the participants. Second, we aimed to investigate if life satisfaction level among the observed profiles of psoriatic patients, extracted on the basis of their body image and resources, differed from that of the healthy comparison group. Methods The sample consisted of 735 participants, including 355 adults with a medical diagnosis of psoriasis and 380 healthy adults recruited from a non-clinical general population. Participants filled the Satisfaction with Life Scale, the Multidimensional Body-Self Relations Questionnaire and the COR evaluation questionnaire. Results Latent profile analysis revealed four classes of psoriatic patients with different levels of resources and body image. The group with the highest level of resources and the most positive body image did not differ from the healthy comparison group regarding satisfaction with life. The group with the lowest level of resources and the most negative body image was characterized by the lowest satisfaction with life. Conclusions The results of our study may change the simplifying trend that highlights the traditionally very poor well-being of psoriatic patients. Moreover, the discovery of specific profiles of these patients, which differ with regard to psychological variables, can lead to rethinking contemporary forms of psychological counselling in psoriatic patients.

The chronic unpredictable mild stress (CUMS) model of depression in mice is a model commonly used to investigate stress-induced depressive-like behaviours. The duration of the stress-inducing procedure is variable, thus making it difficult to compare results and draw general conclusions from different protocols. Here, we decided to investigate how the duration of the CUMS procedure affects behavioural changes, body weight as well as the level of plasma corticosterone in stressed and nonstressed C57BL/6J mice subjected to CUMS for 18 or 36 days. We found that 18 days of CUMS induced a robust decrease in grooming time in the splash test and a significant increase in the immobility time in the tail suspension test (TST) and the forced swim test (FST). All of these stress-induced depression-related behavioural effects diminished or even disappeared after 36 days of CUMS. Plasma corticosterone levels were increased in the CUMS mice compared to those in the nonstressed mice. However, this effect was more pronounced in mice stressed for 18 days. On the other hand, a gradual decline in weight loss in the stressed animals was observed as the duration of the CUMS procedure increased. Altogether, the results indicate that 18 days of CUMS did not affect body weight but caused significant behavioural effects as well as a robust increase in corticosterone levels, while 36 days of CUMS induced significant reduction in weight gain but only slight or even non-significant behavioural effects. These results may indicate the presence of adaptive changes to the long-term CUMS procedure in C57BL/6J mice.

Scopolamine, a muscarinic cholinergic receptor antagonist, exerts fast and prolonged antidepressant effects in the clinic. In contrast, the current treatments for major depressive disorder (MDD) require long-term drug administration. On the other hand, the sole use of scopolamine might be related to the high risk of adverse effects. Therefore, it may be preferable to reduce its therapeutic dose. A new approach might include the co-administration of low-dose scopolamine with selected ligands of metabotropic glutamate (mGlu) receptors, which are known to possess antidepressant-like activity in several rodent tests and models of depression. The aim of the present study was to evaluate the potential antidepressant activity of low-dose scopolamine combined with an allosteric agonist of mGlu7 receptors, AMN082 in C57BL/6 mice. It was found that the combination of scopolamine (0.1 mg/kg) and AMN082 (1 mg/kg) exerted significant antidepressant-like effects in the tail suspension test (TST), but these effects were not observed in the mGlu7−/− mice. Furthermore, low-dose AMN082 co-administered with low-doses scopolamine (0.03 and 0.1 mg/kg) induced antidepressant-like activity in the forced swim test (FST) in mice. The tested compounds did not affect locomotor activity and did not impair spatial memory in the Morris water maze (MWM) test or motor coordination in the rotarod test. The results strongly indicated that there is an enhanced antidepressant-like action of scopolamine by AMN082. Co-administration of scopolamine with AMN082 might be a new strategy with better efficacy and a lower risk of adverse effects compared with the sole use of scopolamine or AMN082.

Nowadays cognitive impairments are a growing unresolved medical issue which may accompany many diseases and therapies, furthermore, numerous researchers investigate various neurobiological aspects of human memory to find possible ways to improve it. Until any other method is discovered, in vivo studies remain the only available tool for memory evaluation. At first, researchers need to choose a model of amnesia which may strongly influence observed results. Thereby a deeper insight into a model itself may increase the quality and reliability of results. The most common method to impair memory in rodents is the pretreatment with drugs that disrupt learning and memory. Taking this into consideration, we compared the activity of agents commonly used for this purpose. We investigated effects of phencyclidine (PCP), a non-competitive NMDA receptor antagonist, and scopolamine (SCOP), an antagonist of muscarinic receptors, on short-term spatial memory and classical fear conditioning in mice. PCP (3 mg/kg) and SCOP (1 mg/kg) were administrated intraperitoneally 30 min before behavioral paradigms. To assess the influence of PCP and SCOP on short-term spatial memory, the Barnes maze test in C57BL/J6 mice was used. Effects on classical conditioning were evaluated using contextual fear conditioning test. Additionally, spontaneous locomotor activity of mice was measured. These two tests were performed in CD-1 mice. Our study reports that both tested agents disturbed short-term spatial memory in the Barnes maze test, however, SCOP revealed a higher activity. Surprisingly, learning in contextual fear conditioning test was impaired only by SCOP. Graphical Abstract ᅟ.

Introduction Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies among women at reproductive age, but its pathology remains unknown. From epidemiological studies it is known that endogenous, mainly genetic and exogenous, environmental factors are of importance. Objective The aim of the study was to compare the phenotype of women diagnosed with PCOS from urban and rural areas of Poland. According to the knowledge of the authors, this is first such study. Material and methods The retrospective study included 3,877 PCOS patients: 2511 women living in cities and 1,366 village inhabitants, aged between 18 - 45 years. Clinical data, including medical history, body mass, height and hirsutism severity was obtained from each patient. Hormones were also tested in each patient: follicle stimulating hormone, luteinizing hormone, prolactin, estradiol [E2], testosterone, dehydroepiandrosterone sulphate [DHEAS], thyroid stimulating hormone, free thyroxin, insulin [INS], 17 hydroxyprogesterone, cortisol [CORT]) and metabolic (75g oral glucose tolerance test, Chol - total cholesterol, HDL-C - high density lipoprotein cholesterol, LDL-C low density lipoprotein cholesterol, and the TG (triglicerides) profile. Results PCOS women from urban areas had a higher mean serum concentration of E2 in comparison to the inhabitants of rural areas. Women from cities had a lower mean level of DHEAS, CORT, and INS measured in the morning than rural residents. Insulin-resistance, using homeostasis model assessment, was more pronounced among women from villages. The prevalence of menstrual disorders, in general, was higher in PCOS women living in rural comparing to urban areas. Conclusions The clinical and biochemical indices differed significantly between women diagnosed with PCOS living in cities and villages. In general in Poland, the PCOS phenotype is more severe in women living in rural areas. This study shows that different living conditions significantly affect the PCOS phenotype.

International audience; Normal gonad development assures the fertility of the individual. The properly functioning gonads must contain a sufficient number of the viable germ cells, possess a correct architecture and tissue structure, and assure the proper hormonal regulation. This is achieved by the interplay between the germ cells and different types of somatic cells. N-cadherin coded by the Cdh2 gene plays a critical role in this interplay. To gain an insight into the role of N-cadherin in the development of mouse gonads, we used the Cre-loxP system to knock out N-cadherin separately in two cell lines the SF1 somatic cells and the OCT4 germ cells. We observed that N-cadherin plays a key role in the survival of both female and male germ cells. However, the N-cadherin is not necessary for the differentiation of the Sertoli cells or the initiation of the formation of testis cords or ovigerous cords. In the later stages of gonad development, N-cadherin is important for the maintenance of testis cord structure and is required for the formation of steroidogenic cells. In the ovaries, N-cadherin is necessary for the formation of the ovarian follicles. These results indicate that N-cadherin plays a major role in gonad differentiation, structuralization, and function.

Ketamine produces a rapid antidepressant effect, but its use can be associated with serious side effects. Hence, other therapeutic options that will allow us to obtain a quick and safe antidepressant effect by modulating glutamatergic transmission are needed. Antagonists of mGlu2/3 receptors, which share some mechanisms of action with ketamine, may be good candidates to obtain this effect. Here, we show that the metabotropic glutamate (mGlu) 2/3 receptor antagonist LY341495 induced a dose-dependent antidepressant-like effect in the chronic unpredictable mild stress (CUMS) model of depression in C57BL/6J mice after both single and subchronic (three-day) administration. Furthermore, a noneffective dose of LY341495 (0.3 mg/kg) given jointly with a noneffective dose of ketamine (3 mg/kg) reversed the CUMS-induced behavioral effects, indicating that coadministration of ketamine with an mGlu2/3 receptor antagonist might allow its therapeutically effective dose to be lowered. Western blot results indicate that mTOR pathway activation might be involved in the mechanism of action of this drug combination. Moreover, the combined doses of both substances did not produce undesirable behavioral effects characteristic of a higher dose of ketamine (10 mg/kg) commonly used in rodent studies to induce antidepressant effects. Coadministration of low doses of ketamine and LY341495 did not induce the hyperactivity typical of NMDA channel blockers, did not disturb short-term memory in the novel object recognition (NOR) test, and did not disturb motor coordination in the rotarod test. Our research not only confirmed the earlier data on the rapid antidepressant effect of mGlu2/3 receptor antagonists but also indicated that such compounds can safely lower the effective dose of ketamine.

Ketamine has been shown to induce a rapid antidepressant effect on patients with depression. In many animal models, both rapid and sustained antidepressant activities were also found in response to an antagonist of group II metabotropic glutamate receptors, LY341495, and its mechanism of action seemed to be similar in many ways to the action of ketamine. It has also been found that LY341495 enhanced the antidepressant-like activity of sub-effective doses of ketamine in rats without inducing adverse effects. Here, we investigated the role of AMPA receptor and TrkB receptor activation in the antidepressant-like effects of ketamine (3 mg/kg) co-administered with LY341495 (0.1 mg/kg), in the forced swim test in rats, at three time points (40 min, 3 h and 24 h) after joint administration of the tested compounds. It was found that the AMPA receptor antagonist NBQX (10 mg/kg) reversed the antidepressant effect of ketamine co-administered with LY341495 at all tested time points, whereas the TrkB receptor antagonist ANA-12 contributed to blockade of the effect of ketamine and LY341495 3 h after their joint administration. These results indicate that activation of AMPA receptor and BDNF-related signaling may play a role in the mechanism of antidepressant action of ketamine co-administered with LY341495.

The normal course of gonad development is critical for the sexual development and reproductive capacity of the individual. During development, an incipient bipotential gonad which consists of unorganized aggregate of cells, must differentiate into highly structured testis or ovary. Cell adhesion molecules (CAMs) are a group of proteins crucial for segregation and aggregation of different cell types to form different tissues. E-cadherin (Cdh1) is one of the CAMs expressed in the developing gonads. We used tissue-specific knockout of Cdh1 gene in OCT4+ germ cells and, separately, in SF1+ somatic cells of developing gonads. The knockout of E-cadherin in somatic cells caused decrease in the number of germ cells, while the knockout in the germ cells caused their almost complete loss. Thus, the presence of E-cadherin in both the germ and somatic cells is necessary for the survival of germ cells. Although the lack of E-cadherin did not impair cell proliferation, it enhanced apoptosis, which was a possible cause of germ cell loss. However, the somatic cells of the gonad differentiated normally into Sertoli cells in the testis cords, and into follicular cells in the ovaries. The testis and ovigerous cords maintained their integrity; they were covered by continuous basement membranes. The testicular interstitium with steroidogenic fetal Leydig cells did not show any noticeable changes. However, in the female gonads, because of the lack of germ cells, the ovarian follicles were absent. The sex determination and sexual differentiation of the gonad were not impaired. These results underscore an important role of E-cadherin in germ cell survival and gonad development.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and can often lead to fibrosis, cirrhosis, cancer and complete liver failure. Liver biopsy is the current standard of care to quantify hepatic steatosis, but it comes with increased patient risk and only samples a small portion of the liver. Imaging approaches to assess NAFLD include proton density fat fraction estimated via magnetic resonance imaging (MRI) and shear wave elastography. However, MRI is expensive and shear wave elastography is not proven to be sensitive to fat content of the liver (Kramer et al. 2016). On the other hand, ultrasonic attenuation and the backscatter coefficient (BSC) have been observed to be sensitive to levels of fat in the liver (Lin et al. 2015; Paige et al. 2017). In this study, we assessed the use of attenuation and the BSC to quantify hepatic steatosis in vivo in a rabbit model of fatty liver. Rabbits were maintained on a high-fat diet for 0, 1, 2, 3 or 6 wk, with 3 rabbits per diet group (total N = 15). An array transducer (L9-4) with a center frequency of 4.5 MHz connected to a SonixOne scanner was used to gather radio frequency (RF) backscattered data in vivo from rabbits. The RF signals were used to estimate an average attenuation and BSC for each rabbit. Two approaches were used to parameterize the BSC (i.e., the effective scatterer diameter and effective acoustic concentration using a spherical Gaussian model and a model-free approach using a principal component analysis [PCA]). The 2 major components of the PCA from the BSCs, which captured 96% of the variance of the transformed data, were used to generate input features to a support vector machine for classification. Rabbits were separated into two liver fat-level classes, such that approximately half of the rabbits were in the low-lipid class (≤9% lipid liver level) and half of the rabbits in the high-lipid class (>9% lipid liver level). The slope and the midband fit of the attenuation coefficient provided statistically significant differences (p value = 0.00014 and p value = 0.007, using a two-sample t test) between low and high-lipid fat classes. The proposed model-free and model-based parameterization of the BSC and attenuation coefficient parameters yielded classification accuracies of 84.11 %, 82.93 % and 78.91 % for differentiating low-lipid versus high-lipid classes, respectively. The results suggest that attenuation and BSC analysis can differentiate low-fat versus high-fat livers in a rabbit model of fatty liver disease.

Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or its action. Complications from long-term diabetes consist of numerous biochemical, molecular, and functional tissue alterations, including inflammation, oxidative stress, and neuropathic pain. There is also a link between diabetes mellitus and vascular dementia or Alzheimer's disease. Hence, it is important to treat diabetic complications using drugs which do not aggravate symptoms induced by the disease itself. Pregabalin is widely used for the treatment of diabetic neuropathic pain, but little is known about its impact on cognition or inflammation-related proteins in diabetic patients. Thus, this study aimed to evaluate the effect of intraperitoneal (ip) pregabalin on contextual memory and the expression of inflammatory state-related proteins in the brains of diabetic, streptozotocin (STZ)-treated mice. STZ (200 mg/kg, ip) was used to induce diabetes mellitus. To assess the impact of pregabalin (10 mg/kg) on contextual memory, a passive avoidance task was applied. Locomotor and exploratory activities in pregabalin-treated diabetic mice were assessed by using activity cages. Using Western blot analysis, the expression of cyclooxygenase-2 (COX-2), cytosolic prostaglandin E synthase (cPGES), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-ĸB (NF-ĸB) p50 and p65, aryl hydrocarbon receptor (AhR), as well as glucose transporter type-4 (GLUT4) was assessed in mouse brains after pregabalin treatment. Pregabalin did not aggravate STZ-induced learning deficits in vivo or influence animals' locomotor activity. We observed significantly lower expression of COX-2, cPGES, and NF-κB p50 subunit, and higher expression of AhR and Nrf2 in the brains of pregabalin-treated mice in comparison to STZ-treated controls, which suggested immunomodulatory and anti-inflammatory effects of pregabalin. Antioxidant properties of pregabalin in the brains of diabetic animals were also demonstrated. Pregabalin does not potentiate STZ-induced cognitive decline, and it has antioxidant, immunomodulatory, and anti-inflammatory properties in mice. These results confirm the validity of its use in diabetic patients. Graphical abstract Effect of pregabalin on fear-motivated memory and markers of brain tissue inflammation in diabetic mice.

The results of large randomized trials such as the Women's Health Initiative (WHI), Heart and Estrogen / Progestin Replacement Study (HERS) or Estrogen Replacement and Atherosclerosis Study (ERAS) as well as the Million Women Study (MWS) which does not meet criteria RCT, concerning, among others the impact of HRT on breast cancer risk, thromboembolism, or the aging processes in the central nervous system caused the recent big confusion in the medical community , causing distrust about the safety and advisability of HRT in menopausal women. The paper presents an overview of the available, current literature on HRT. It was found that HRT should not be used in both primary and secondary prevention of coronary heart disease Great expectations was associated with an earlier initiation of therapy, before the advent of atherosclerosis - but there is currently no conclusive data about its role in the primary prevention of coronary disease. Oral HRT increases the risk of thromboembolic events - that is why you should prefer the form of a transdermal. HRT may increase the risk of ischemic stroke (but early initiation of therapy does not increase the risk of stroke) and should not be used in the primary prevention of stroke.

Over the last few decades, depression has become one of the major public health problems in our society. This problem is connected not only with morbidity, but also with treatment, specifically with the effectiveness of the therapy as well as the concomitant side effects of available antidepressants. Major depressive disorder is a complex clinical entity, including different molecular mechanisms and neurological processes. This complexity is a challenge for scientists seeking to discover an innovatory antidepressant drug with multiple and complementary mechanisms of action. In this review, we discuss the role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in depression and antidepressant-like effects.

The maximum detectable velocity of high-frame-rate color flow Doppler ultrasound is limited by the imaging frame rate when using coherent compounding techniques. Traditionally, high quality ultrasonic images are produced at a high frame rate via coherent compounding of steered plane wave reconstructions. However, this compounding operation results in an effective downsampling of the slow-time signal, thereby artificially reducing the frame rate. To alleviate this effect, a new transmit sequence is introduced where each transmit angle is repeated in succession. This transmit sequence allows for direct comparison between low resolution, pre-compounded frames at a short time interval in ways that are resistent to sidelobe motion. Use of this transmit sequence increases the maximum detectable velocity by a scale factor of the transmit sequence length. The performance of this new transmit sequence was evaluated using a rotating cylindrical phantom and compared with traditional methods using a 15-MHz linear array transducer. Axial velocity estimates were recorded for a range of ± 300 mm/s and compared to the known ground truth. Using these new techniques, the root mean square error was reduced from over 400 mm/s to below 50 mm/s in the high-velocity regime compared to traditional techniques. The standard deviation of the velocity estimate in the same velocity range was reduced from 250 mm/s to 30 mm/s. This result demonstrates the viability of the repeated transmit sequence methods in detecting and quantifying high-velocity flow.

International audience; The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-π interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.

In this paper, we describe the latest results involving molecular modeling and pharmacodynamic studies of the selected highly lipophilic compounds acting by human GABA transporter 1 (hGAT1) inhibition. The chemical interaction of 17 GABA analogues with a model of hGAT1 is described using the molecular docking method. The biological role of GAT1 is related to the regulation of GABA level in the central nervous system and GAT1 inhibition plays an important role in the control of seizure threshold. To confirm that GAT1 can be also a molecular target for drugs used to treat other neurological and psychiatric diseases (e.g., pain and anxiety), in the in vivo part of this study, potential antinociceptive and anxiolytic-like properties of tiagabine, a selective GAT1 inhibitor, are described.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and can often lead to fibrosis, cirrhosis, cancer and complete liver failure. Liver biopsy is the current standard of care to quantify hepatic steatosis, but it comes with increased patient risk and only samples a small portion of the liver. Imaging approaches to assess NAFLD include proton density fat fraction (PDFF) estimated via MRI and shear wave elastography. However, MRI is often prohibitively expensive and shear wave elastography is not sensitive to fat content of the liver [1]. On the other hand, ultrasonic attenuation and the backscatter coefficient (BSC) have been observed to be sensitive to levels of fat in the liver. In this study, we explored the use of attenuation and a principal component analysis (PCA) of the BSC to detect and quantify hepatic steatosis in vivo in a rabbit model of fatty liver. Rabbits were maintained on a high fat diet for 0, 1, 2, 3 or 6 weeks with three rabbits per diet group (total N = 15). For analysis, rabbits were separated into three classes based on the total lipid content of the livers estimated using the Folch method: low fat ( 10%). An array transducer L9-4 with center frequency of 4 MHz connected to a SonixOne scanner was used to gather RF backscattered data in vivo from rabbits. The RF signals were used to estimate an average attenuation and BSC for each rabbit. The first five principal components of the PCA from the BSCs were used as input features to a support vector machine (SVM) for classification and comparison to total liver lipid levels. The slope of the attenuation coefficient provided statistically significant differences (p < 0.00058, using two-sample t-test) between low and high lipid fat groups. The proposed PCA-SVM based classification system yielded a classification accuracy of 63.7%, 32.6% and 71.2% for the low, medium and high fat groups, respectively. The results suggest that attenuation and BSC analysis can differentiate low versus high fat livers in a rabbit model. This work was supported by a grant from NIH (R21EB020766).

Depression is a serious global illness, becoming more and more common in developed countries. Because of specific symptoms it is considered as a leading cause of disability all over the world with a high death factor due to suicides. There are many antidepressants used in the therapy, but still more than 30% of patients do not respond to the treatment. The heterogeneous nature of the illness and its complex, unclear aetiology may be responsible for these difficulties. Next to the main monoaminergic hypothesis of depression there are also many other approaches connected with the pathophysiology of the disease, including hypothalamic-pituitary-adrenal axis dysregulation, dopaminergic, cholinergic, glutamatergic or GABA-ergic neurotransmission. Nevertheless, it can be unambiguously stated that serotonergic, noradrenergic and dopaminergic systems are precisely connected with pathogenesis of depression, and should be therefore considered as valuable targets in patients' treatment. Bearing that in mind, this review presents the role of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like effect.

Clinical studies have shown that the muscarinic receptor antagonist scopolamine induces a potent and rapid antidepressant effect relative to conventional antidepressants. However, potential undesirable effects, including memory impairment, partially limit the use of scopolamine in psychiatry. In the present study, we propose to overcome these limitations and enhance the therapeutic effects of scopolamine via administration in combination with the group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. Joint administration of sub-effective doses of scopolamine (0.03 or 0.1 mg/kg, i.p.) with a sub-effective dose of LY341495 (0.1 mg/kg, i.p.) induced a profound antidepressant effect in the tail suspension test (TST) and in the forced swim test (FST) in mice. This drug combination did not impair memory, as measured using the Morris water maze (MWM), and did not influence the locomotor activity of mice. Furthermore, we found that an AMPA receptor antagonist, NBQX (10 mg/kg), completely reversed the antidepressant-like activity of a mixture of scopolamine and LY341495 in the TST. However, this effect was not influenced by para-chlorophenylalanine (PCPA) pre-treatment, indicating a lack of involvement of serotonergic system activation in the antidepressant-like effects of jointly given scopolamine and LY341495. Therefore, the combined administration of low doses of the antimuscarinic drug scopolamine and the group II mGlu receptor antagonist LY341495 might be a new, effective and safe strategy in the therapy of depression.

Introduction Memory disorders accompany numerous diseases and therapies, and this is becoming a growing medical issue worldwide. Currently, various animal models of memory impairments are available; however, many of them require high financial outlay and/or are time-consuming. A simple way to achieve an efficient behavioral model of cognitive disorders is to inject defined drug that has pro-amnesic properties. Since the involvement of cholinergic and glutamatergic neurotransmission in cognition is well established, the utilization of a nonselective muscarinic receptor antagonist, scopolamine (SCOP), a selective M1 muscarinic receptor antagonist, biperiden (BIP), and a non-competitive N-methyl- d -aspartate (NMDA) receptor antagonist, phencyclidine (PCP) seems to be reliable tools to induce amnesia. As the determination of their effective doses remains vague and the active doses vary significantly in laboratory settings and in mouse species being tested, the aim of this study was to compare these three models of amnesia in CD-1 mice. Methods Male Swiss Albino mice were used in passive avoidance (PA) test. All the compounds were administered intraperitoneally (ip) at doses 1 mg/kg, 5 mg/kg, and 10 mg/kg (SCOP and BIP), and 1 mg/kg, 3 mg/kg, and 6 mg/kg (PCP). Results In the retention trial of the PA task, SCOP and PCP led to the reduction of step-through latency at all the tested doses as compared to control, but BIP was effective only at the dose of 10 mg/kg. Conclusion This study revealed the effectiveness of SCOP, PCP, and BIP as tools to induce amnesia, with the PCP model being the most efficacious and SCOP being the only model that demonstrates a clear dose–response relationship.

The chemical interaction of nine antiepileptic drugs (tiagabine, gabapentin, pregabalin, lamotrigine, zonisamide, valproic acid, valpromide, vigabatrin, progabide) and two endogenous metabolites (4-aminobutanoic acid, 4-hydroxybutanoic acid) with a model of human GABA transporter 1 (hGAT1) is described using the molecular docking method. To establish the role of hGAT1 in chronic pain, tiagabine, a selective hGAT1 inhibitor, was assessed in the in vivo experiments for its antiallodynic properties in two mouse models of neuropathic pain. Docking analyses performed in this study provided the complex binding energies, specific hydrogen bond components, and hydrogen bond properties such as energies, distances and angles. The data of the docking studies strongly support the assumption that the antiepileptic and analgesic actions of the studied drugs can be at least in part related to the strength of their chemical interactions with hGAT1. In vivo experiments with tiagabine confirmed the involvement of hGAT1 in the regulation of the mechanical nociceptive threshold in neuropathic pain.

Bmper, which is orthologous to Drosophila melanogaster crossveinless 2, is a secreted factor that regulates Bmp activity in a tissue- and stage-dependent manner. Both pro- and anti-Bmp activities have been postulated for Bmper, although the molecular mechanisms through which Bmper affects Bmp signaling are unclear. In this paper, we demonstrate that as molar concentrations of Bmper exceed Bmp4, Bmper dynamically switches from an activator to an inhibitor of Bmp4 signaling. Inhibition of Bmp4 through a novel endocytic trap-and-sink mechanism leads to the efficient degradation of Bmper and Bmp4 by the lysosome. Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad signaling. We also determined that Noggin and Gremlin, but not Chordin, trigger endocytosis of Bmps. This endocytic transport pathway expands the extracellular roles of selective Bmp modulators to include intracellular regulation. This dosage-dependent molecular switch resolves discordances among studies that examine how Bmper regulates Bmp activity and has broad implications for Bmp signal regulation by secreted mediators.

Background and purpose Since GABAergic dysfunction underlies a variety of neurological and psychiatric disorders, numerous strategies leading to the augmentation of GABAergic neurotransmission have been introduced. One of them is the inhibition of GABA reuptake from the synaptic cleft mediated by four plasma membrane GABA transporters (GAT1-4). GAT1 which is exclusively expressed in the brain is an interesting target for centrally acting drugs. In this research, pharmacological properties of a novel, highly potent and selective inhibitor of GAT1, the guvacine derivative named DDPM-2571, were assessed in vivo. Experimental approach Pharmacological effects and pharmacokinetics of intraperitoneally administered DDPM-2571 were assessed in CD-1 mice. Key results DDPM-2571 was quickly distributed into the brain and was highly effective in the prevention of chemically-induced seizures (pentylenetetrazole and pilocarpine models) and 6-Hz convulsions. It demonstrated significant anxiolytic-like and antidepressant-like properties. DDPM-2571 had antinociceptive properties, both in the hot plate test and in the second phase of the formalin test. Within the dose range tested, it did not impair animals' motor skills, but it impaired cognition and potentiated scopolamine-induced cognitive deficits in the passive avoidance task. Conclusions and implications Due to GAT1 inhibition, DDPM-2571 is effective in mouse models of chemically-induced seizures, anxiety, depression, acute and tonic pain. At biologically active doses, it does not impair animals' motor skills, but it might induce memory deficits. Taken together, DDPM-2571 can be regarded as a promising lead structure in the search for new centrally acting drugs and a potent pharmacological tool to study the biological role of GAT1.

Rationale Numerous preclinical and clinical studies have reported the rapid and sustained antidepressant effects of the NMDA receptor antagonist ketamine. Because ketamine induces several undesirable and dangerous effects, a variety of strategies have been suggested to avoid such effects. Objectives Here, we propose to enhance the sub-effective doses of ketamine by co-administration with the group II metabotropic glutamate (mGlu) receptor antagonist LY341495. This compound potentially acts as an antidepressant via a mechanism similar to that of ketamine. Methods To investigate the rapid and sustained antidepressant-like effects of these drugs, we administered ketamine and LY341495 individually or in combination, 40 min and 24 h before the forced swim test (FST). Results We found that sub-effective doses of ketamine and LY341495, given jointly, induce significant antidepressant-like effects, at both 40 min and 24 h after administration. The results obtained using Western blot technique indicate that mammalian target of rapamycin (mTOR) pathway activation may be involved in the mechanism of this action. The effects of drugs, used at identical ranges of times and doses, on spontaneous locomotor activity in rats were excluded. Furthermore, the results obtained from the rota-rod test and the ketamine-induced hyperlocomotion test suggest a lack of potentially adverse effects from the combined administration of ketamine and LY341495 at doses previously used in the FST. Conclusion Altogether, these data suggest that the joint administration of ketamine and LY341495 might be a noteworthy alternative to the use of solely ketamine in the therapy of depression.

Anxiety-related disorders are among the most common mental illnesses in the world for which benzodiazepines, buspirone and antidepressant drugs remain the first-line treatment. These drugs have good efficacy but they have numerous disadvantages, such as drug abuse potential, delayed onset of action or tolerance. A literature review reveals that a variety of piperazine derivatives may exhibit interesting pharmacological properties, including anxiolytic-like, antidepressant, nootropic and antinociceptive activities demonstrated in animal models, as well as an antioxidant capacity shown in some in vitro tests. Hence, the aim of this study was the synthesis and preliminary pharmacological in vivo evaluation of a novel N-cycloalkyl-N-benzoylpiperazine derivative, compound 9.The test compound 9 was synthesized from a cyclic ketone 6,6-dimethylbicyclo[3.1.0]hexan-3-one (compound 7) and N-benzoylpiperazine. The final product was evaluated in vivo for its anxiolytic-like and antinociceptive activity after intraperitoneal (ip) administration. Its impact on animals' locomotor activity and motor performance was also evaluated.At the dose of 50mg/kg the test compound 9 showed statistically significant (p0.01) anxiolytic-like activity in the four plate test. This effect was completely abolished by pretreatment with naloxone hydrochloride (1mg/kg; ip). Compound 9 did not influence animals' locomotor activity or motor coordination. No antinociceptive effect was demonstrated in the hot plate test.The anxiolytic-like properties of N-bicyclo-[3.1.0]hexyl derivative (9) in the four plate test are mediated by the opioid system. The results obtained make this compound a promising lead structure for further development of anxiolytic drugs.

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.

In this pilot study, focused ultrasound (FUS) was used to produce hyperthermia in cervical lymph nodes of rats having experimental autoimmune encephalomyelitis (EAE) to alleviate symptoms associated with EAE. EAE was induced in dark agouti rats, and EAE scores were recorded over 21 d. At the onset of EAE symptoms, rats were treated with FUS to induce temperatures of 43–44°C for 20 min in the superficial cervical lymph nodes. An EAE remittance score was tallied for all rats, defined as the maximum EAE score observed minus the minimum EAE score observed after the maximum EAE was reached. On average, the peak remittance score for FUS-treated rats was 1.14 ± 0.48 versus 0.33 ± 0.27 for sham-treated rats. These differences were statistically significant ( p = 0.037). Therefore, FUS treatment of cervical lymph nodes in rats with EAE resulted in a significant reduction in EAE score.

Multiple sclerosis (MS) is a prevalent neurological disease among adults worldwide. Disease modifying therapies are only modestly effective for slowing long-term progression of pathological and disability outcomes. One approach to treating MS is to reduce the burden of lymphocytes entering the central nervous system. We hypothesized that using focused ultrasound (FUS) to heat the cervical lymph nodes in rats with EAE, an animal model of MS, would alleviate symptoms of EAE by reducing lymphocyte burden. EAE was induced in rats through injection of myelin oligodendrocyte glycoprotein (MOG) and EAE disability scores were recorded over 21 days post injection. The cervical lymph nodes of rats with EAE were treated at day 9 and day 12 post MOG injection using FUS to elevate the temperature to 43-44 °C for 20 minutes. On average the EAE remittance score for FUS treated rats was 1.14 ± 0.48 versus 0.33 ± 0.27 for sham treated rats. These differences were statistically significant (p = 0.037). Remittance of the EA...