Classical Animal Models Research Articles

Animal models of emphysema.

ObjectiveChronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease of human beings characterized by not fully reversible airflow limitation. Emphysema is the main pathological feature of COPD which causes high mortality worldwide every year and consumes a large amount of medical expenses. This paper was to review the establishment and evaluation methods of animal models of emphysema or COPD, and put forward some new ideas on animal selection, method of modeling, and model evaluation.Data sourcesThe author retrieved information from the PubMed database up to July 2019, using various combinations of search terms, including emphysema, model, and animal.Study selectionOriginal articles, reviews, and other articles were searched and reviewed for animal models of emphysema.ResultsThis review summarized animal models of emphysema from the perspectives of animal selection, emphysema mechanism, modeling method and model evaluation, and found that passive smoking is the classic method for developing animal model of emphysema, mice are more suitable for experimental study on emphysema. Compared with pulmonary function indicators, airway inflammation indicators and oxidative stress indicators, pathomorphological indicators of lung tissue are the most important parameters for evaluating the establishment of the animal model of emphysema.ConclusionsMice model induced by passive smoking is the classic animal model of emphysema. Pathomorphological indicators are the most important parameters for evaluating the establishment of the animal model of emphysema.

Single housing-induced effects on cognitive impairment and depression-like behavior in male and female mice involve neuroplasticity-related signaling.

Single-housed stress elicits a range of social isolation-related behavioral and neurobiological abnormalities. To investigate single housing-induced behavioral changes and sex differences on stress outcomes, we examined single-housed stress-induced learning and memory impairment, depression-like behaviors, neuroplasticity abnormalities and underlying mechanism. The results showed that male and female mice socially isolated for 8weeks had significantly decreased memory acquisition, as demonstrated in the learning curve of the Morris water maze task. Memory consolidation and retrieval were also decreased in both the single-housed male and female mice. These findings were corroborated further by the two classical animal models, Y-maze and novel object recognition tests, as demonstrated by reduced spontaneous alternation and recognition index in both sexes of single-housed mice. Subsequent studies suggested that single-housed male mice exhibited increased immobility time in both the forced swim and tail suspension tests, while the female mice only exhibited increased immobility time in the tail suspension test. Moreover, single-housed stress significantly decreased the apical and basal branch points, dendritic length, and spine density in the CA1 of hippocampal neurons in both male and female mice. These effects were consistent with decreased neuroplasticity and neuroprotective-related molecules such as synaptophysin, PSD95, PKA, pCREB and BDNF expression. These findings suggest that loss of neuronal remodeling and neuroprotective mechanisms due to single housing are involved in behavioral changes in both male and female mice. The results provide further evidence that neuroplasticity-related signaling plays a crucial role in isolation-induced effects on neuropsychiatric behavioral deficits in both sexes.

Novel Optogenetic Approaches in Epilepsy Research.

Epilepsy is a major neurological disorder characterized by repeated seizures afflicting 1% of the global population. The emergence of seizures is associated with several comorbidities and severely decreases the quality of life of patients. Unfortunately, around 30% of patients do not respond to first-line treatment using anti-seizure drugs (ASDs). Furthermore, it is still unclear how seizures arise in the healthy brain. Therefore, it is critical to have well developed models where a causal understanding of epilepsy can be investigated. While the development of seizures has been studied in several animal models, using chemical or electrical induction, deciphering the results of such studies has been difficult due to the uncertainty of the cell population being targeted as well as potential confounds such as brain damage from the procedure itself. Here we describe novel approaches using combinations of optical and genetic methods for studying epileptogenesis. These approaches can circumvent some shortcomings associated with the classical animal models and may thus increase the likelihood of developing new treatment options.

Animal models of synucleinopathies and how they could impact future drug discovery and delivery efforts

ABSTRACTIntroduction: Ample efforts have been carried out to develop efficient disease-modifying drugs of Parkinson’s disease and related synucleinopathies. At present, the available animal models appropriate for drug development and delivery for these hitherto incurable disorders are limited.Areas covered: The author, herein, provides their perspectives on classical toxin-based animal models, which have provided some insight into their clinical picture and complex pathogenesis. They also discuss generic and virus-induced models and more recent αSyn transmitter models that reproduce essential clinical and morphological aspects but do not fully replicate the whole spectrum of the human diseases. Yet, these models have, however, provided new insights into the pathogenesis of these disorders.Expert opinion: The recent development of transgenic viral vector-induced αSyn inoculation models and those using induced pluripotent stem cells (iPSCs) in rodents, non-human primates and (rare) primates, reproducing many but not all aspects of the human synucleinopathies and their complex pathogenesis opened the door for the development of successful drugs. Despite these limits, a remarkable amount of work has already been done. However, further attention should be focused on the development of new models to enable better insight into the pathology of these proteinopathies as the basis for the future development of real disease-modifying or even preventive modalities.

Differential impairment of short working and spatial memories in a rat model of progressive Parkinson’s disease onset: A focus on the prodromal stage

Studying the non-motor disorders of the prodromal phase of Parkinson's disease (PD) is of great importance because of their negative impact on patient's quality of life. Classical neurotoxic animal models of PD generally unable the exploration of the progression of the non-motor phase of the prodromal stage of the disease. The aim of this study is to assess the evolution of two types of memory alteration namely; short working and spatial memories at different stages of the prodromal phase of a rat model of PD, using repetitive reserpine administration at low dose. The study was carried out in rat with repeated i.p reserpine administration (0.2 mg/kg/day) during 13 days. Working memory was assessed by the Novel Object Recognition test (NOR) and the T-maze, while spatial memory was assessed by Morris Water maze (MWM) at to stages (7days and 13days) of prodromal phase of the disease. By means of immunohistochemistry, the serotonergic innervation of the Baso-Lateral Amygdala nucleus (BLA) as well as the morphological changes of astroglia within hippocampus (using anti-GFAP marker) were examined at the latest stage (13days) of the disease. Our data show a differential deterioration of short-term working memory without the long-term spatial memory being changed which was accompanied by a significant decrease in serotonin innervation of the BLA and a striking change in both density and morphology of the astrocyte at the level of the hippocampus. The present study has brought evidence of an early deficit of short working memory rather than spatial memory deficit which seems to be intact even at the latest stage of the prodromal phase of PD. Such deficit could arise from the loss of 5-HT innervation in BLA and/or the astroglial morpho-functional changes within the hippocampus leading to possible neurophysiological disturbances of the different neighboring neuronal populations involved in short working memory.

Classic animal models of Parkinson's disease: a historical perspective.

The quest to better understand the pathophysiology of Parkinson's disease (PD) and to find new therapies to provide greater relief to affected patients continues. The use of animal models of PD has been invaluable in the process. Here, we review, through a historical lens, some of the contribution of the 6-hydroxydopamine-lesioned rat and of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned nonhuman primate, in refining our understanding of PD and its treatment-related complications. We examine the mechanisms underlying the toxicity of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and then explore some of the advances at the molecular, pharmacological, electrophysiological and surgical levels made while experimenting on these animal models. We also discuss behavioural testing that can be performed with these animal models and highlight some of their limitations.

The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation

Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD70/30 doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD70/30 doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.

Research Progress on Post-Traumatic Stress Disorder and Its Animal Model

Posttraumatic stress disorder (PTSD) is to a persistently severe mental disorder which is caused by individual exposure to some unusual threatening or catastrophic stressful events. Its essential clinical manifestations refer to repeated playback of traumatic experience, durative avoidance of related clues, mental numbness or affection paralysis, and persistent increase of vigilance level. At present, the pathogenesis of PTSD has not been fully elucidated, and the clinical therapeutic effect has not been ideal. Generally, the classical animal model of PTSD is mouse; the domestic and international researches in the animal model of PTSD in recent years remain active, which are summarized as follows.

The effect of the cholinergic anti-inflammatory pathway on collagen-induced arthritis involves the modulation of dendritic cell differentiation

BackgroundThe cholinergic anti-inflammatory pathway (CAP) has a strong anti-inflammatory effect on collagen-induced arthritis (CIA), a classic animal model of rheumatoid arthritis (RA). However, the underlying immune regulatory mechanism remains unclear. Here, we investigated the effect of the CAP on arthritis development and the involvement of dendritic cells (DCs).MethodsForty DBA/1 mice were randomly divided into five groups: a control group (sham vagotomy+ phosphate-buffered saline; shamVGX+PBS), a CIA group (shamVGX+CIA + PBS), a vagotomy group (VGX + CIA + PBS), a GTS-21 (4 mg/kg) group (shamVGX+CIA + GTS-4), and a GTS-21 (8 mg/kg) group (shamVGX+CIA + GTS-8). The vagotomy group underwent left cervical vagotomy 4 days before arthritis induction, whereas the sham-vagotomy group underwent vagus nerve exposure. Mice were pretreated with GTS-21 by intraperitoneal injection on the day of surgery. The degree of arthritis was measured by using the arthritis score, hematoxylin and eosin staining, and TRAP (tartrate-resistant acid phosphatase) staining. Flow cytometry was used to detect the expression of CD80 and major histocompatibility complex II (MHC II) on CD11c+ DCs in the spleen. Luminex was used to detect the serum concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and IL-10. Immunohistochemistry was used to detect CD11c expression in the synovium. The effects of GTS-21 on DC differentiation and maturation were examined in vitro by treating bone marrow–derived DCs with GTS-21 and assessing differentiation and maturation. Flow cytometry was used to analyze CD80 and MHC II expression on the surface of DCs.ResultsGTS-21 treatment ameliorated clinical arthritis in a mouse model of CIA in vivo, decreasing the secretion of pro-inflammatory cytokines in the serum and downregulating CD80 and MHC II expression on DCs in the spleen of CIA mice. GTS-21 treatment strongly suppressed the infiltration of DCs into the synovium. Vagotomy itself did not exacerbate the severity of arthritis in CIA mice. In vitro, GTS-21 (10 μmol/L) significantly downregulated CD80 and MHC II in bone marrow–derived immature DCs and this effect was blocked by the α7-nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA). However, GTS-21 had no effects on mature DCs.ConclusionsThe present study provides new insight into the mechanism underlying the effects of the CAP on RA and indicates that the immunosuppressive effect of GTS-21 may be mediated by the inhibition of DC differentiation.

Haemostatic bioactivity of novel Schizonepetae Spica Carbonisata-derived carbon dots via platelet counts elevation

Schizonepetae Spica Carbonisata (SSC) has pronounced haemostatic effects for hundreds of years and has been acknowledged in the 2015 Pharmacopoeia of the People’s Republic of China (PPRC) as a haemostatic charcoal drug. However, after years of efforts, the underlying mechanism and the material basis is still less defined. In this research, we developed a novel CDs derived from SSC (SSC-CDs) with an average diameter of 1.29–6.87 nm and a quantum yield of 6.31%. SSC was prepared using a modified pyrolysis method and no further modification and external surface passivation agent is required. With abundant surface groups, SSC-CDs showed distinct solubility and bioactivity. In this study, we innovatively used the Deinagkistrodon acutus (D. acutus) venom model as well as the classical haemorrhagic animal model to evaluate the haemostatic bioactivity of SSC-CDs. The results indicated that SSC-CDs had outstanding haemostatic bioactivity and might inhibit the haemorrhagic activity via PLT elevation. According to the results of this study and our previous work, we discovered that CDs derived from different kinds of charcoal drugs presented similarities and differences in the structural feature, physicochemical property and bioactivity. In order to further explore the self-bioactivities, we first named this kind of CDs as “Chinese Medicine charcoal drug nanoparticles” (CMNP). These results may not only provide evidence for further researches of self-bioactivities of CDs but give new insights into potential biomedical and healthcare applications of CDs, therefore, make contributions to future drug discovery.

Placental insufficiency contributes to fatty acid metabolism alterations in aged female mouse offspring.

Intrauterine growth restriction (IUGR) is an accepted risk factor for metabolic disorders in later life, including obesity and type 2 diabetes. The level of metabolic dysregulation can vary between subjects and is dependent on the severity and the type of IUGR insult. Classical IUGR animal models involve nutritional deprivation of the mother or uterine artery ligation. The latter aims to mimic a placental insufficiency, which is the most frequent cause of IUGR. In this study, we investigated whether IUGR attributable to placental insufficiency impacts the glucose and lipid homeostasis at advanced age. Placental insufficiency was achieved by deletion of the transcription factor AP-2y ( Tfap2c), which serves as one of the major trophoblast differentiation regulators. TdelT-IUGR mice were obtained by crossing mice with a floxed Tfap2c allele and mice with Cre recombinase under the control of the Tpbpa promoter. In advanced adulthood (9-12 mo), female and male IUGR mice are respectively 20% and 12% leaner compared with controls. At this age, IUGR mice have unaffected glucose clearance and lipid parameters (cholesterol, triglycerides, and phospholipids) in the liver. However, female IUGR mice have increased plasma free fatty acids (+87%) compared with controls. This is accompanied by increased mRNA levels of fatty acid synthase and endoplasmic reticulum stress markers in white adipose tissue. Taken together, our results suggest that IUGR by placental insufficiency may lead to higher lipogenesis in female mice in advanced adulthood, at least indicated by greater Fasn expression. This effect was sex specific for the aged IUGR females.

Combined administration on You-Gui Yin and low-dose Raloxifene partially attenuates the bone loss in ovariectomized mice through the proliferation and osteogenic differentiation of bone marrow stromal cells

BackgroundOsteoporosis is a systemic skeletal disease of fragility fractures due to the loss of mass and deterioration of the microarchitecture of bone. PurposeThe aim of the study was to assess the osteogenic effects and the underlying mechanisms of the combined administration of You-Gui Yin (YGY) and Raloxifene hydrochloride (RLX) in ovariectomized (OVX) mice. MethodsFirst, a classic animal model was used to mimic postmenopausal osteoporosis through the removal of the ovary of mice. Second, the OVX mice were administered YGY, RLX, and YGY + RLX for 12 weeks. Next, the bone microtomographic histomorphometry and bone mineral density (BMD) were assessed by micro-CT, and the biochemical markers of procollagen type I N-terminal propeptide (P1NP) and beta-isomerized C-telopeptide (β-CTX) in serum were assessed. Finally, primary bone marrow stromal cells (BMSCs) were isolated from the tibia and cultured to evaluate cell proliferation and osteogenic differentiation. ResultsThe results showed that BMD on the YGY + RLX group was higher than that on the RLX group (p < 0.05) and did not have a significant difference when compared with the sham group. Notably, the YGY + RLX group had a dramatically increased trabecular number (Tb.N) compared with that of the YGY group (p < 0.05). Moreover, the BV/TV (bone volume/total volume) and Tb.N in the YGY + RLX group were higher than that in the RLX group (p < 0.05), and the Tb.Sp (trabecular separation) was lower than that in the RLX group (p < 0.05). Moreover, the serum level of P1NP from the YGY + RLX group dramatically increased when compared with that from the YGY and RLX groups (YGY group: p < 0.05; RLX groups: p < 0.01). Notably, there was no significant difference between the YGY and YGY + RLX groups. In addition, cell proliferation from the co-administration of YGY and RLX was clearly higher than a single use of YGY and RLX (p < 0.01, respectively). The ALP/BCA (alkaline phosphatase/bicinchoninic acid) in the YGY + RLX group was higher than that in the RLX group (p < 0.01). ConclusionOverall, co-administered YGY and RLX could partially attenuate bone loss and were more effective than individually using either one; this outcome might be associated with the proliferation and osteogenic differentiation of BMSCs.

Comparative studies on novel combinations of pregabalin plus venlafaxine with standard diazepam and marketed combination of alprazolam plus sertraline for anxiety disorders

Summary Objective- In present study, eleven novel dose combinations of Pregabalin &amp; Venlafaxine from minimum effective dose to higher anxiolytic dose were taken for assessment of anxiolytic activity in Swiss mice.Method — Classical animal models of anxiety vise: Elevated plus-maze model and Light &amp; Dark Exploration test Apparatus. Diazepam was used as a standard anxiolytic. In addition the combinations were also compared with a fixed dose marketed combination of Alprazolam &amp; Sertraline (Anxit Plus).Result — The results of the study reveal that combinations of Pregabalin &amp; Venlafaxine (serotonin norepinephrine reuptake inhibitor) have better anxiolytic efficacy, which is comparable to Diazepam and Alprazolam-Sertraline combination.Conclusion- Further clinical studies are required for getting better idea about efficacy and clinical utility of Pregabalin-Venlafaxine combination.

Pro-resolving lipid mediators in vascular disease.

Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis - conditions that are responsible for considerable morbidity and mortality. Surgical or catheter-based procedures performed on affected blood vessels induce acute-on-chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall remodeling and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and a return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, to improve tools for clinical measurement, and to better define the potential for "resolution therapeutics" in vascular patients.

Short communication: Genomic prediction using different single-step methods in the Finnish red dairy cattle population

Single-step genomic prediction models utilizing both genotyped and nongenotyped animals are likely to become the prevailing tool in genetic evaluations of livestock. Various single-step prediction models have been proposed, based either on estimation of individual marker effects or on direct prediction via a genomic relationship matrix. In this study, a classical pedigree-based animal model, a regular single-step genomic BLUP (ssGBLUP) model, algorithm for proven and young (APY) with 2 strategies for choosing core animals, and a single-step Bayesian regression (ssBR) model were compared for 305-d production traits (milk, fat, protein) in the Finnish red dairy cattle population. A residual polygenic effect with 10% of total genetic variance was included in the single-step models to reduce inflation of genomic predictions. Validation reliability was calculated as the squared Pearson correlation coefficient between genomically enhanced breeding value (GEBV) and yield deviation for masked records for 2,056 validation cows from the last year in the data set investigated. The results showed that gains of 0.02 to 0.04 on validation reliability were achieved by using single-step methods compared with the classical animal model. The regular ssGBLUP model and ssBR model with an extra polygenic effect yielded the same results. The APY methods yielded similar reliabilities as the regular ssGBLUP and ssBR. Exact prediction error variance of GEBV could be obtained by ssBR to avoid any approximation methods used for ssGBLUP when inversion left-hand side of mixed model equations is computationally infeasible for large data sets.

Genetically induced vs. classical animal models of chronic pancreatitis: a critical comparison.

Chronic pancreatitis (CP) is an utmost complex disease that is pathogenetically linked to pancreas-intrinsic ( e.g., duct obstruction), environmental-toxic ( e.g., alcohol, smoking), and genetic factors. Studying such a complex disease naturally requires validated experimental models. In the past 2 decades, the various animal models of CP usually addressed either the pancreas-intrinsic ( e.g., the caerulein model), the environmental-toxic ( e.g., diet-induced models), or the genetic component of CP. As such, these models were far from mirroring CP in its full spectrum, and the correct choice of models was vital for valid scientific conclusions on CP. The quest for mechanistic, genetic models gave rise to models based on gene modification and transgene insertion, such as the PRSS1 and the IL-1β/IL-1β models. Recently, we witnessed the development of highly exciting models that rely on the importance of autophagy in CP, that is, the murine pancreas-specific Atg5 and LAMP2 knockout models. Today, critical comparison of these several models is more important than ever for guiding research on CP in an efficient direction. The present review outlines the characteristics of the new genetic models in comparison with the well-known classic models for CP, notes the caveats in the choice of models, and also indicates novel directions for model development.-Klauss, S., Schorn, S., Teller, S., Steenfadt, H., Friess, H., Ceyhan, G. O., Demir, I. K. Genetically induced vs. classical animal models of chronic pancreatitis: a critical comparison.

Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression.

Major depressive disorder is one of the most common and debilitating psychiatric disorders. Some of the motivational symptoms of depression, such anergia (lack of self-reported energy) and fatigue are relatively resistant to traditional treatments such as serotonin uptake inhibitors. Thus, new pharmacological targets are being investigated. Epidemiological data suggest that caffeine consumption can have an impact on aspects of depressive symptomatology. Caffeine is a non-selective adenosine antagonist for A1/A2A receptors, and has been demonstrated to modulate behavior in classical animal models of depression. Moreover, selective adenosine receptor antagonists are being assessed for their antidepressant effects in animal studies. This review focuses on how caffeine and selective adenosine antagonists can improve different aspects of depression in humans, as well as in animal models. The effects on motivational symptoms of depression such as anergia, fatigue, and psychomotor slowing receive particular attention. Thus, the ability of adenosine receptor antagonists to reverse the anergia induced by dopamine antagonism or depletion is of special interest. In conclusion, although further studies are needed, it appears that caffeine and selective adenosine receptor antagonists could be therapeutic agents for the treatment of motivational dysfunction in depression.

Antidepressant potential of novel flavonoids derivatives from sweet violet (Viola odorata L): Pharmacological, biochemical and computational evidences for possible involvement of serotonergic mechanism

Plant-derived natural constituents are of great interest in modern drug discovery due to their natural diversity. Viola odorata L has been traditionally used for the treatment of neuropsychiatric disorders. The present study was undertaken to isolate phytoconstituents including three flavonoids 5,7-Dihydroxy-3,6-dimethoxyflavone[1] 5,7,4′-trihydroxy-3′,5’dimethoxyflavone [2] and 5,7,4′-trihydroxy-3′-methoxyflavone [3] from the whole plant of Viola odorata L and to investigate the antidepressant-like effects of these compounds and their possible mechanism of action using antagonists of the serotonergic, dopaminergic and adrenergic system. Classical animal models of depression including tail suspension test (TST) and forced swimming test (FST) using mice were used to evaluate the antidepressant-like effects. Mice were divided into various groups and were administered with either vehicle control, fluoxetine (FLX), or test compounds 1–3 intraperitoneally (i.p.). For experiments involving mechanism determination, mice were pretreated with 5-HT, dopamine and adrenergic antagonists. The brain 5-HT levels were determined following FST. Molecular docking studies were carried out to determine the binding affinity of compounds 1–3 to serotonergic receptors. The results indicated that compounds 1–3 at the dose of 1–30 mg/kg, i.p significantly decreased the immobility time in the FST and TST in mice. The reduction in immobility time was reversed by pre-treating the mice with pCPA (5-HT synthesis inhibitor) 100 mg/kg, i.p. and 5-HT receptor antagonists including WAY100635 (5-HT1a antagonist), ketanserin (a 5-HT2a antagonist) and ondansetron (5-HT3 antagonist) but not with prazosin (α1-adrenergic antagonist) and SCH23390 (D1 dopaminergic antagonist) or haloperidol (D2 dopaminergic antagonist). Moreover, in neurochemical assays, compounds 1–3 caused a significant increase in the 5-HT level in the brain tissue as compared to vehicle. These increases were reversed in the mice groups pretreated with pCPA. Furthermore, molecular docking results also depict that compounds 1–3 can interact with 5HT1A, 5HT2A, and 5HT3 receptors, and are more specific to the 5HT3 receptor subtype. In conclusion, the findings of this study clearly suggest that compounds 1–3 possess antidepressant-like effects which might be mediated via the serotonergic system.

A Novel Murine Chronic Obstructive Pulmonary Disease Model and the Pathogenic Role of MicroRNA-21

Chronic obstructive pulmonary disease (COPD) is a multi-pathogenesis chronic lung disease. The mechanisms underlying COPD have not been adequately illustrated. Many reseachers argue that microRNAs (miRs) could play a crucial role in COPD. The classic animal model of COPD is both time consuming and costly. This study proposes a novel mice COPD model and explores the role of miR-21 in COPD. A total of 50 wide-type (WT) C57BL/6 mice were separated into five euqlly-sized groups—(1) control group (CG), (2) the novel combined method group (NCM, cigarette smoke (CS) exposure for 28 days combined with cigarette smoke extract (CSE) intraperitoneal injection), (3) the short-term CS exposure group (SCSE, CS exposure for 28 days), (4) the CSE intraperitoneal injection group (CSEII, 28 days CSE intraperitoneal injection), and (5) the long-term CS exposure group (LCSE, CS exposure).The body weight gain of mice were recorded and lung function tested once the modeling was done. The pathological changes and the inflammation level by hematoxylin eosin (H&E) staining and immunohistochemical staining (IHS) on the lung tissue sections were also evaluated. The level of miR-21 in the mice lungs of the mice across all groups was detected by RT-qPCR and the effects of miR-21 knock-down in modeled mice were observed. The mice in LCSE and NCM exhibited the most severe inflammation levels and pathological and pathophysiological changes; while the changes for the mice in SCSE and CSEII were less, they remained more severe than the mice in the CG. The level of miR-21 was found to be negatively correlated with lung functions. Moreover, knocking miR-21 down from the modeled mice, ameliorated all those tested COPD-related changes. Our novel modeling method detected virtually the same changes as those detected in the classic method in WT mice, but in less time and cost. Further, it was determined that the level of miR-21 in the lungs could be an indicator of COPD severity and blocking functions of miR-21 could be a potential treatment for early stage COPD.

Concurrent gradients of ribbon volume and AMPA-receptor patch volume in cochlear afferent synapses on gerbil inner hair cells

The Mongolian gerbil is a classic animal model for age-related hearing loss. As a prerequisite for studying age-related changes, we characterized cochlear afferent synaptic morphology in young adult gerbils, using immunolabeling and quantitative analysis of confocal microscopic images. Cochlear wholemounts were triple-labeled with a hair-cell marker, a marker of presynaptic ribbons, and a marker of postsynaptic AMPA-type glutamate receptors. Seven cochlear positions covering an equivalent frequency range from 0.5 – 32 kHz were evaluated. The spatial positions of synapses were determined in a coordinate system with reference to their individual inner hair cell. Synapse numbers confirmed previous reports for gerbils (on average, 20–22 afferents per inner hair cell). The volumes of presynaptic ribbons and postsynaptic glutamate receptor patches were positively correlated: larger ribbons associated with larger receptor patches and smaller ribbons with smaller patches. Furthermore, the volumes of both presynaptic ribbons and postsynaptic receptor patches co-varied along the modiolar-pillar and the longitudinal axes of their hair cell. The gradients in ribbon volume are consistent with previous findings in cat, guinea pig, mouse and rat and further support a role in differentiating the physiological properties of type I afferents. However, the positive correlation between the volumes of pre- and postsynaptic elements in the gerbil is different to the opposing gradients found in the mouse, suggesting species-specific differences in the postsynaptic AMPA receptors that are unrelated to the fundamental classes of type I afferents.