Ketamine is a versatile agent primarily utilized as a dissociative anesthetic, which acts by blocking the excitatory receptor
-methyl-d-aspartate receptor (NMDA). It functions to inhibit the current ...of both Na
and K
voltage-gated channels, thus preventing serotonin and dopamine reuptake. Studies have indicated that administering a single subanesthetic dose of ketamine relieves depression rapidly and that the effect is sustained. For decades antidepressant agents were based on the monoamine theory. Although ketamine may not be the golden antidepressant, it has opened new avenues toward mechanisms involved in the pathology of treatment-resistant depression and achieving rapid antidepressant effects. Thus, preclinical studies focusing on deciphering the molecular mechanisms involved in the antidepressant action of ketamine will assist in the development of a new antidepressant. This review was conducted to elucidate the emerging pathways that can explain the complex dose-dependent mechanisms achieved by administering ketamine to treat major depressive disorders. Special attention was paid to reviewing the literature on hydroxynorketamines, which are ketamine metabolites that have recently attracted attention in the context of depression.
Although there is a sex bias in the pathological mechanisms exhibited by brain disorders, investigation of the female brain in biomedical science has long been neglected. Use of the male model has ...generally been the preferred option as the female animal model exhibits both biological variability and hormonal fluctuations. Existing studies that compare behavioral and/or molecular alterations in animal models of brain diseases are generally underrepresented, and most utilize the male model. Nevertheless, in recent years there has been a trend toward the increased inclusion of females in brain studies. However, current knowledge regarding sex-based differences in depression and stress-related disorders is limited. This can be improved by reviewing preclinical studies that highlight sex differences in depression. This paper therefore presents a review of sex-based preclinical studies of depression. These shed light on the discrepancies between males and females regarding the biological mechanisms that underpin mechanistic alterations in the diseased brain. This review also highlights the conclusions drawn by preclinical studies to advance our understanding of mood disorders, encouraging researchers to promote ways of investigating and managing sexually dimorphic disorders.
•Existing studies on behavioral and molecular alterations in female animal models of brain diseases are underrepresented.•Current knowledge regarding sex-based differences in depression and stress-related disorders is limited.•The discrepancies between genders in the depressed brain will help in developing new therapeutic strategies.
Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. This study examined the therapeutic effects of sitagliptin, a dipeptidyl peptidase inhibitor, on DN and explored the ...underlying mechanism. Male Wistar albino rats (
= 12) were intraperitoneally administered a single dose of streptozotocin (30 mg/kg) to induce diabetes. Streptozotocin-treated and untreated rats (
= 12) were further divided into normal control, normal sitagliptin-treated control, diabetic control, and sitagliptin-treated diabetic groups (
= 6 in each). The normal and diabetic control groups received normal saline, whereas the sitagliptin-treated control and diabetic groups received sitagliptin (100 mg/kg, p.o.). We assessed the serum levels of DN and inflammatory biomarkers. Protein tyrosine phosphatase 1 B (PTP1B), phosphorylated Janus kinase 2 (P-JAK2), and phosphorylated signal transducer activator of transcription (P-STAT3) levels in kidney tissues were assessed using Western blotting, and kidney sections were examined histologically. Sitagliptin reduced DN and inflammatory biomarkers and the expression of PTP1B, p-JAK2, and p-STAT3 (
< 0.001) and improved streptozotocin-induced histological changes in the kidney. These results demonstrate that sitagliptin ameliorates inflammation by inhibiting DPP-4 and consequently modulating the PTP1B-related JAK/STAT axis, leading to the alleviation of DN.
The mechanism underlying depression, anxiety, and stress-related psychiatric disorders is far from understood. The utilization of animal models of anxiety and stress can improve our knowledge of the ...pathology of these disorders as well as aiding in the identification of pharmacological therapeutic targets. The involvement of inflammation in the pathology of stress-related disorders is widely acknowledged. This study was therefore undertaken to assess depressive and anxiety-like behavior as well as neuroinflammation in acute-isolated rats. The study design comprised two main groups:1) rats in acute isolation (one rat per cage) and 2) standard housing (two rats per cage). Within ten days of acute isolation, we carried behavioral tests including Sucrose Neophobia (SNP), Sucrose Preference Test (SPT), Open field (OPF), and a Forced swim test (FST). In a separate set of experiments, we examined the molecular changes after five days of isolations, we examined the mRNA expression of Toll-like receptors (TLRs) and inflammatory markers in the hippocampal brain region. We found that acute social isolation did not have profound functional effects and the behavioral analysis revealed similarities between the isolated and standard housed rats. However, the molecular studies showed a significant increase in TLRs. An increase in Interleukin 6 (IL-6) and Tumor necrosis factor-alpha (TNF-alpha) was observed in the hippocampus of isolated rats but not the control rats. The results suggest that acute environmental isolation does not significantly affect depressive and anxiety-like behavior but does contribute to upregulations in neuroinflammatory responses. This indicates the initiation of neuronal insults following exposure to short-term isolation.
This paper investigates the effect of dwell time and heat treatment on the modified friction stir clinched (MFSC) joint of AA2024-T3/AA6061-T6 Al alloys. The precipitation-hardening heat treatment ...method involves the combination of solution heat treatment (at 520 °C for 1 h) and aging (at 165 °C for 18 h) processes. The microstructure, failure load, hardness, and fracture behavior of the as-welded and heat-treated MFSC joints were investigated. TEM images show that re-precipitation of strengthening Al2CuMg and MgZn2 phases, dislocation density, and tangles are more pronounced in the heat-treated MFSC joint. A rise in dwell time increases the average grain sizes (1.39–6.65 μm), tensile-shear strength (101–133 MPa), and cross tension strength (59–88 MPa) of the MFSC welded 2024-T3/6061-T6 joints due to an upsurge in the in-process exposure time-induced heat input and inter-material flow. An increase in dwell time beyond 15 s is undesirable. It induces the formation of nugget cracks and micro-voids in the joints and an impaired joint failure load consequently ensues. Heat treatment processing further causes grain coarsening (2.48–9.15 μm) and improves the hardness (at the weld center), tensile-shear (146 MPa), and cross tension (102 MPa) failure strengths of the MFSC joints due to the re-precipitated strengthening phases.
Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One ...possible theory is the alteration of the microvascular and macrovascular environment of the blood–brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Leprdb/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Leprdb/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Leprdb/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Leprdb/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Leprdb/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research.
An overview of freshwater fish variety worldwide and the variables influencing trends in variation between and within river basins are given in this review. Continental freshwater ecosystems are ...highly diverse and species-rich, housing nearly 18,000 species of fish (>50% of all fish species) in <0.5% of the total land area and providing a negligible (<0.01%) share of the planet’s water supply. Large lowland tropical river basins such as the Amazon, Congo, and Mekong basins are home to the greatest freshwater fish diversity. Freshwater species of fish depth variation at the global mag¬nitude is correlated with the total amount and variation of aquatic habitats and the environment’s equilibrium overtime during the evolution of scales. The river continuum concept states that there is a predictable shift in fish species depth, diversity of species, and functional characteristics along gradients of environment from headwater to estuary. The ongoing trade of minerals and organic matter related to nearby floodplains is a strong factor in the number and variety of riverine fishes in most parts of the world (the flood pulse concept). Without coordinated conservation efforts, freshwater fishes will suffer significant losses in abundance and diversity due to the numerous threats they currently face worldwide. However, further development, adaptation, training, and guidance are needed. New technologies based on water conservation, suitable species, and local traditions are needed. Waste materials and local feed additives can also be used. Farmers should be provided with the necessary training and information.
The coronavirus disease 2019 (COVID-19) infection has emerged lately, leading to a serious public health threat. The clinical features associated with COVID-19 are yet to be conclusively documented. ...Caution is needed when interpreting the severity of the symptoms as most of the diagnosed patients are those attending clinical assessments. Features of COVID-19 are far from understood. There is a suggested increased risk of COVID-19 infection among people with mental health disorders, which is primarily attributable to the challenges associated with limited resources. There are a variety of reasons why individuals with mental health disorders are more susceptible to infectious diseases. There is currently no specific recommended antiviral treatment. The interventions now used are supportive treatments to alleviate the symptoms and invasive mechanical ventilation. In this review, we discuss the adverse events associated with COVID-19 vaccinations. We further highlight the need to develop guidelines and recommendations for managing patients with mental health. It is evident from this review, there is a need to provide training programs with interprofessional, multidisciplinary communication channels.
Depression is a common psychiatric disorder that has been poorly understood. Consequently, current antidepressant agents have clinical limitations. Until today, most have exhibited the slow onset of ...therapeutic action and, more importantly, their effect on remission has been minimal. Thus, the need to find new forms of therapeutic intervention is urgent. The inflammation hypothesis of depression is widely acknowledged and is one that theories the relationship between the function of the immune system and its contribution to the neurobiology of depression. In this research, we utilized an environmental isolation (EI) approach as a valid animal model of depression, employing biochemical, molecular, and behavioral studies. The aim was to investigate the anti-inflammatory effect of etanercept, a tumor necrosis factor-α inhibitor on a toll-like receptor 7 (TLR 7) signaling pathway in a depressive rat model, and compare these actions to fluoxetine, a standard antidepressant agent. The behavioral analysis indicates that depression-related symptoms are reduced after acute administration of fluoxetine and, to a lesser extent, etanercept, and are prevented by enriched environment (EE) housing conditions. Experimental studies were conducted by evaluating immobility time in the force swim test and pleasant feeling in the sucrose preference test. The mRNA expression of the TLR 7 pathway in the hippocampus showed that TLR 7, MYD88, and TRAF6 were elevated in isolated rats compared to the standard group, and that acute treatment with an antidepressant and anti-inflammatory drugs reversed these effects. This research indicates that stressful events have an impact on behavioral well-being, TLR7 gene expression, and the TLR7 pathway. We also found that peripheral administration of etanercept reduces depressive-like behaviour in isolated rats: this could be due to the indirect modulation of the TLR7 pathway and other TLRs in the brain. Furthermore, fluoxetine treatment reversed depressive-like behaviour and molecularly modulated the expression of TLR7, suggesting that fluoxetine exerts antidepressant effects partially by modulating the TLR7 signaling pathway.
The axonal initial segment (AIS) is the subcellular compartment required for initiation of the action potential in neurons. Scaffolding and regulatory proteins at the AIS cluster with ion channels ...ensuring the integrity of electrical signaling. Interference with the configuration of this protein network can lead to profound effects on neuronal polarity, excitability, cell-to-cell connectivity and brain circuit plasticity. As such, the ability to visualize AIS components with precision provides an invaluable opportunity for parsing out key molecular determinants of neuronal function. Fluorescence-based immunolabeling is a sensitive method for morphological and molecular characterization of fine structures in neurons. Yet, even when combined with confocal microscopy, detection of AIS elements with immunofluorescence has been limited by the loss of antigenicity caused by fixative materials. This technical barrier has posed significant limitations in detecting AIS components alone or in combination with other markers. Here, we designed improved protocols targeted to confocal immunofluorescence detection of the AIS marker fibroblast growth factor 14 (FGF14) in combination with the cytoskeletal-associated protein Ankyrin-G, the scaffolding protein βIV-spectrin, voltage-gated Na(+) (Nav) channels (especially the Nav1.6 isoform) and critical cell type-specific neuronal markers such as parvalbumin, calbindin, and NeuN in the mouse brain. Notably, we demonstrate that intracardiac perfusion of animals with a commercially available solution containing 1% formaldehyde and 0.5% methanol, followed by brief fixation with cold acetone is an optimal and sensitive protocol for FGF14 and other AIS marker detection that guarantees excellent tissue integrity. With variations in the procedure, we also significantly improved the detection of Nav1.6, a Nav isoform known for its fixative-sensitivity. Overall, this study provides an ensemble of immunohistochemical recipes that permit excellent staining of otherwise invisible molecules within well-preserved tissue architecture. While improving the specific investigation of AIS physiology and cell biology, our thorough study can also serve as a roadmap for optimizing immunodetection of other fixative-sensitive proteins expanding the repertoire of enabling methods for brain studies.
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