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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.

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.

γ-Aminobutyric acid (GABA) neurotransmission has a significant impact on the proper functioning of the central nervous system. Numerous studies have indicated that inhibitors of the GABA transporters mGAT1-4 offer a promising strategy for the treatment of several neurological disorders, including epilepsy, neuropathic pain, and depression. Following our previous results, herein, we report the synthesis, biological evaluation, and structure-activity relationship studies supported by molecular docking and molecular dynamics of a new series of N-benzyl-4-hydroxybutanamide derivatives regarding their inhibitory potency toward mGAT1-4. This study allowed us to identify compound 23a (N-benzyl-4-hydroxybutanamide bearing a dibenzocycloheptatriene moiety), a nonselective GAT inhibitor with a slight preference toward mGAT4 (pIC50 = 5.02 ± 0.11), and compound 24e (4-hydroxy-N-[(4-methylphenyl)-methyl]butanamide bearing a dibenzocycloheptadiene moiety) with relatively high inhibitory activity toward mGAT2 (pIC50 = 5.34 ± 0.09). In a set of in vivo experiments, compound 24e successively showed predominant anticonvulsant activity and antinociception in the formalin model of tonic pain. In contrast, compound 23a showed significant antidepressant-like properties in mice. These results were consistent with the available literature data, which indicates that, apart from seizure control, GABAergic neurotransmission is also involved in the pathophysiology of several psychiatric diseases, however alternative mechanisms underlying this action cannot be excluded. Finally, it is worth noting that the selected compounds showed unimpaired locomotor skills that have been indicated to give reliable results in behavioral assays.

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.

Six series of 2-substituted 4-aminobutanamide derivatives were synthesized and evaluated for their ability to inhibit GABA transport proteins mGAT1−4 stably expressed in HEK-293 cell lines. The pIC50 values determined were in the range 4.23–5.23. Two compounds (15b and 15c) were selected for further in vitro studies. These compounds were also subjected to preliminary behavioral studies to evaluate their anticonvulsant, antidepressant-like, and antinociceptive activities in mice. Their influence on motor coordination was also assessed. We report that, among a spectrum of in vivo activities, both 15b and 15c displayed significant activity against pentylenetetrazole (PTZ)-induced seizures.

Bone Morphogenetic Proteins (BMPs) are crucial for many aspects of the development and differentiation of the nervous system and are important in controlling cytoskeletal remodeling during neuronal morphogenesis. BMPs are TGFβ superfamily members that signal through a heteromeric complex of type I and type II BMP receptors. The BMPRII receptor is particularly important in mediating remodeling of the neuronal cytoskeleton through the activation of BMPRII-bound cytoskeletal regulators, such as LIM Kinase (LIMK). Here, we show that PAK1, a key regulator of diverse neuronal processes and an upstream activator of LIMK, binds to the BMP type I receptor, ALK2. Although, PAK1 is dispensable for activation of the Smad transcriptional mediators, abrogation of PAK1 expression or inhibition of PAK1 activity prevents BMP-induced neurite outgrowth in cultured neuroblastoma cell lines. Moreover, in primary murine embryonic cortical neurons, inhibition of PAK activity blocks BMP7-induced cofilin phosphorylation, prevents remodeling of the actin cytoskeleton and thereby blocks BMP7-induced dendrite formation. Thus, we propose a model in which BMP7 signaling leads to the recruitment of ALK2-bound PAK1 to BMPRII, which binds a downstream regulator of the actin cytoskeleton, LIMK1, and that the BMP receptor complex thereby acts as a scaffold to localize and coordinate actin cytoskeletal remodeling. We propose that this scaffold plays a key role in mediating BMP7-dependent dendritogenesis in primary cortical neurons.