Experimental Rodent Models Research Articles

Mice deficient in complement C3 are protected against recognition memory deficits and astrogliosis induced by status epilepticus.

Status epilepticus (SE) can significantly increase the risk of temporal lobe epilepsy (TLE) and cognitive comorbidities. A potential candidate mechanism underlying memory defects in epilepsy may be the immune complement system. The complement cascade, part of the innate immune system, modulates inflammatory and phagocytosis signaling, and has been shown to contribute to learning and memory dysfunctions in neurodegenerative disorders. We previously reported that complement C3 is elevated in brain biopsies from human drug-resistant epilepsy and in experimental rodent models. We also found that SE-induced increases in hippocampal C3 levels paralleled the development of hippocampal-dependent spatial learning and memory deficits in rats. Thus, we hypothesized that SE-induced C3 activation contributes to this pathophysiology in a mouse model of SE and acquired TLE. In this study C3 knockout (KO) and wild type (WT) mice were subjected to one hour of pilocarpine-induced SE or sham conditions (control; C). Following a latent period of two weeks, recognition memory was assessed utilizing the novel object recognition (NOR) test. Western blotting was utilized to determine the protein levels of C3 in hippocampal lysates. In addition, we assessed the protein levels and distribution of the astrocyte marker glial fibrillary acidic protein (GFAP). In the NOR test, control WT + C or C3 KO + C mice spent significantly more time exploring the novel object compared to the familiar object. In contrast, WT+SE mice did not show preference for either object, indicating a memory defect. This deficit was prevented in C3 KO + SE mice, which performed similarly to controls. In addition, we found that SE triggered significant increases in the protein levels of GFAP in hippocampi of WT mice but not in C3 KO mice. These findings suggest that ablation of C3 prevents SE-induced recognition memory deficits and that a C3-astrocyte interplay may play a role. Therefore, it is possible that enhanced C3 signaling contributes to SE-associated cognitive decline during epileptogenesis and may serve as a potential therapeutic target for treating cognitive comorbidities in acquired TLE.

Modeling Taupathies in Zebrafish (<i>Danio rerio</i>)

Taupathies are a group of neurodegenerative diseases characterized by the accumulation of tau-protein in the brain, causing clinical dementia. Tau protein stabilizes microtubules and regulates axonal transport, however, when hyper-phosphorylated, aggregates in the brain. Taupaties can be divided into primary and secondary (e.g., Alzheimer’s disease). Experimental animal models models are an important tool to study taupathies. Here, we discuss molecular mechanisms of taupathies and their existing experimental models in both rodents and novel alternative organisms, zebrafish (Danio rerio), as well as future novel directions of research in this field.

Comparison of Efficacy of Fermented Garlic and Orlistat (Lipase Inhibitor) in Obesity Management Using an Experimental Rodent Model.

Black garlic, also known as fermented garlic, is a useful food that may have therapeutic benefits. The aim of this study was to analyze the impact of fermented garlic and orlistat therapy on obese rats. A total of 40 male albino rats (245-250 g) were fed either an HFD (n = 32) or a normal diet (n = 8) for 6 weeks; therefore we randomly assigned the rats into: group I (normal diet), group II (HFD), groups III and IV (HFD with fermented garlic), and group V (orlistat for) 6 weeks. Two different dosages of fermented garlic (481.2 mg/kg and 963.3 mg/kg) were administered. Afterward, blood was collected, body weight was measured, and tissue was collected for further analysis. Both the orlistat and black garlic groups showed a significant reduction in BMI, lipid profiles, and insulin levels compared with the baseline. The orlistat group showed significant elevation (p < 0.005) in body weight, organ weight, lipids, and liver parameters, with histopathological findings. The administration of black garlic improved the inflammatory markers with all other parameters. The fermented garlic and orlistat reinstated all of the investigated parameters significantly (p < 0.05), especially body weight and lipid profiles, and induced histopathological changes compared to the drug orlistat. Additionally, it showed anti-obesity-related therapeutic impacts compared with the orlistat drug. Black garlic provides a reliable and effective treatment for obesity compared to orlistat.

Disruption of IL-18 signaling via engineered IL-18BP biologics alleviates experimental cholestatic liver disease

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis around intrahepatic and extrahepatic bile ducts leading to severe hepatic cirrhosis and high mortality. Although there is an urgent clinical unmet need for PSC, no effective medical therapy has been developed to delay the disease progression until today. IL-18 binding protein (IL-18BP) is well-known to be a natural negative feedback regulator for IL-18, and we have developed a recombinant long-acting IL-18BP referred to as APB-R3 as a therapeutic agent to treat IL-18-related inflammatory diseases. Here, we aimed to study whether disrupted IL-18 signaling by APB-R3 treatment can inhibit PSC injuries in the experimental DDC diet-induced PSC rodent model. First, we found that the amounts of free IL-18 are augmented under PSC condition with increased expression of biliary IL-18 receptors. Administration of APB-R3 effectively attenuated key diagnostic parameters of PSC such as plasma ALP and GGT levels as well as bile acids levels. We also observed that blockade of IL-18 suppressed ductular reactive and proliferative phenotypes of cholangiocytes. Additionally, APB-R3 significantly ameliorated DDC diet-induced periductal fibrosis and transcriptional expressions of pro-fibrotic marker genes. Enhanced senescence associated secretory phenotype (SASP) markers in cholestatic liver disease were diminished by APB-R3 treatment. Our findings clearly demonstrate that the administration of IL-18BP biologics, APB-R3, effectively alleviates DDC diet-induced biliary injuries in rodent PSC model, implying APB-R3 can be a promising therapeutic reagent which warrants clinical human trials as new therapeutic options.

CD5L Deficiency Protects Mice Against Bleomycin-Induced Pulmonary Fibrosis.

Pulmonary fibrosis (PF), the most common clinical type of irreversible interstitial lung disease with one of the worse prognoses, has a largely unknown molecular mechanisms that underlies its progression. CD5 molecule-like (CD5L) functions in an indispensable role during inflammatory responses; however, whether CD5L functions in regulating bleomycin (BLM)-induced lung fibrosis is less clear. Herein, we describe the engineering of Cd5l knockout mice using CRISPR/Cas9 gene editing technology. The BLM-induced model of acute lung injury represents the most widely used experimental rodent model for PF. Taking advantage of this model, we demonstrated that both CD5L mRNA and protein were enriched in the lungs of mice following BLM-induced pulmonary fibrosis. Inhibition of CD5L prevented mice from BLM-induced lung fibrosis and injury. In particular, a lack of CD5L significantly attenuated inflammatory response and promoted M2 polarization in the lung of this pulmonary fibrosis model as well as suppressing macrophage apoptosis. Collectively, our data support that CD5L deficiency can suppress the development of pulmonary fibrosis, and also provides new molecular targets for the use of immunotherapy to treat lung fibrosis.

Metaphorical investigation of aqueous distillate of Cichorium intybus, Foeniculum vulgare and Solanum nigrum along with atorvastatin and orlistat in experimental rodent models of dyslipidaemia and obesity

BackgroundArq is a traditional Unani liquid formulation. In this study we explored Arq-Makoh, Arq-Badiyan and Arq-Kasni for their pharmacological potential to alleviate the symptoms of hyperlipidaemia and obesity and develop an amalgamation with modern drugs that have clinically well reported antihyperlipidaemic and antiobesity potential. Materials and methodsRats were fed High Fat Diet for 4 weeks. 10 ​ml/kg of each of the three arqs were given alone and along with atorvastatin and orlistat daily for 28 days P.O. During the course of treatment body weight and food intake were carefully observed and after the end of the study, liver weight, heart weight, plasma lipid profile, blood glucose level, insulin and leptin level, serum lipase, lactate dehydrogenase, and antioxidant activity were studied in all treatment groups. ResultBoth Arqs and Atorvastatin and Orlistat significantly reduced body weight, lipid profile in HFD fed rats. Arqs when given along with Atorvastatin and Orlistat produced more significant decrease in the serum lipid profile, serum lipase, atherogenic index, lactate Dehydrogenase and TBARS compared with HFD Control group and elevated the levels of HDL-C and SOD. Apart from antihyperlipidaemic and antiobesity effects the treatment groups showed a significant reduction in elevated fasting blood glucose levels (as a result of HFD model used in the study). The above parameters were further confirmed by histopathological studies. ConclusionThe present study indicates that Arq-Makoh, Arq-Badiyan and Arq-Kasni has lipid lowering potential and could potentiate the antihyperlipidaemic and antiobesity potential of Atorvastatin and Orlistat.

Low-dose inhalation exposure to trichloroethylene induces dopaminergic neurodegeneration in rodents.

Trichloroethylene (TCE) is one of the most pervasive environmental contaminants in the world and is associated with Parkinson disease (PD) risk. Experimental models in rodents show that TCE is selectively toxic to dopaminergic neurons at high doses of ingestion, however, TCE is a highly volatile toxicant, and the primary pathway of human exposure is inhalation. As TCE is a highly lipophilic, volatile organic compound (VOC), inhalation exposure results in rapid diffusion throughout the brain, avoiding first-pass hepatic metabolism that necessitated high doses to recapitulate exposure conditions observed in human populations. We hypothesized that inhalation of TCE would induce significantly more potent neurodegeneration than ingestion and better recapitulate environmental conditions of vapor intrusion or off gassing from liquid TCE. To this end, we developed a novel, whole-body passive exposure inhalation chamber in which we exposed 10-month-old male and female Lewis rats to 50 ppm TCE (time weighted average, TWA) or filtered room air (control) over 8 weeks. In addition, we exposed 12-month-old male and female C57Bl/6 mice to 100 ppm TCE (TWA) or control over 12 weeks. Both rats and mice exposed to chronic TCE inhalation showed significant degeneration of nigrostriatal dopaminergic neurons as well as motor and gait impairments. TCE exposure also induced accumulation of pSer129-αSyn in dopaminergic neurons as well as microglial activation within the substantia nigra of rats. Collectively, these data indicate that TCE inhalation causes highly potent dopaminergic neurodegeneration and recapitulates some of the observed neuropathology associated with PD, providing a future platform for insight into the mechanisms and environmental conditions that influence PD risk from TCE exposure.

Establishment of a Rat Model of Alcoholic Liver Fibrosis with Simulated Human Drinking Patterns and Low-Dose Chemical Stimulation.

Although alcohol is a well-known causal factor associated with liver diseases, challenges remain in inducing liver fibrosis in experimental rodent models. These challenges include rodents' natural aversion to high concentrations of alcohol, rapid alcohol metabolism, the need for a prolonged duration of alcohol administration, and technical difficulties. Therefore, it is crucial to establish an experimental model that can replicate the features of alcoholic liver fibrosis. The objective of this study was to develop a feasible rat model of alcoholic liver fibrosis that emulates human drinking patterns and combines low-dose chemicals within a relatively short time frame. We successfully developed an 8-week rat model of alcoholic liver fibrosis that mimics chronic and heavy drinking patterns. Rats were fed with a control liquid diet, an alcohol liquid diet, or alcohol liquid diet combined with multiple binges via oral gavage. To accelerate the progression of alcoholic liver fibrosis, we introduced low-dose carbon tetrachloride (CCl4) through intraperitoneal injection. This model allows researchers to efficiently evaluate potential therapeutics in preclinical studies of alcoholic liver fibrosis within a reasonable time frame.

The beneficial effects of vortioxetine on BDNF, CREB, S100B, β amyloid, and glutamate NR2b receptors in chronic unpredictable mild stress model of depression.

Depression, one of the most significant mental disorders, is still poorly understood in terms of its pathogenetic mechanisms despite its well-recognized association with stress. The current study's goal was to ascertain how the novel antidepressant drug vortioxetine (VOR) affected the BDNF (brain-derived neurotrophic factor), S100, amyloid β (Aβ), CREB (cAMP response element-binding protein), and NR2B, as well as its impact on depression-like behaviors, and tissue damage in an experimental rodent model of depression caused by chronic unpredictable stress. We employed twenty-eight Wistar albino male rats, and we randomly divided them into four groups, each consisting of 7 rats: control, CUMS (chronic unpredictable mild stress), CUMS+vortioxetine (CUMS+VOR), and CUMS+fluoxetine (CUMS+FLU). Sucrose preference and forced swimming tests (SPT and FST, respectively), PCR, ELISA, and histopathological and immunohistochemical evaluation were made on brains. The behaviors of reduced immobility in the FST and increased sucrose preference were observed in the CUMS group and they improved in the groups treated with VOR and FLU. Compared with the control group, the group exposed to CUMS showed increased Aβ and decreased BDNF, CREB, and S-100 expressions, as well as neuronal degeneration (p<0.001). VOR and FLU treatment ameliorate the findings. This study demonstrated significant ameliorative effects of VOR in an experimental model of chronic unpredictable depression to reduce brain tissue damage and depression-like behaviors in rats. Effects of CUMS on the brain and possible effects of VOR.

Anthocleista vogelii (Planch) stem bark ethanol extract prevents inflammatory and pain phenotypes in experimental rodent models by modulating oxido-inflammatory mediators

Ethnopharmacological relevanceThe Anthocleista species are used to treat pain, inflammation, and stomach disorders, but the mechanism by which Anthocleista vogelii Planch stem bark ethanol extract (AVSBE) elicits its anti-pain activity is not fully understood. AimThis study elucidates the phytochemical signatures of AVSBE along with its anti-nociceptive, anti-inflammatory, and antioxidant activities in animal models of pain and inflammation. MethodsThe Gas Chromatography and Mass Spectrometry (GC-MS) and Lorke's methods were used for the phytochemical characterization and LD50 determination of AVSBE. Male and female Wistar rats and Swiss mice were given oral pre-treatment of AVSBE (100, 200, and 400 mg/kg), indomethacin (10 mg/kg), morphine (10 mg/kg), and vehicle (10 mL/kg). Subsequently, various models were employed to evaluate AVSBE's anti-nociceptive and anti-inflammatory effects. Specifically, the acetic acid-induced mice writhing, formalin-induced paw licking, and hot plate models were used to assess AVSBE's anti-nociceptive activity, while the carrageenan-induced paw edema and air pouch models were used to evaluate AVSBE's anti-inflammatory activity. ResultsAVSBE (100, 200, and 400 mg/kg) reduced writhes, paw licking, and pain reaction time. It also decreased rat paw size and inflammatory exudate volume. AVSBE (200 and 400 mg/kg) lowered oxido-nitrosative stress, inflammatory mediators, and leukocyte counts in the exudate fluid. Animals administered with AVSBE showed no stomach ulceration. The LD50 of AVSBE is over 5000 mg/kg, p.o. GC-MS analysis revealed 19 phytochemical compounds in AVSBE, including eicosanoic, octadecatrienoic, linoleic, palmitoleic, and 9,12-octadecanoic acids, phytol, among others. ConclusionThese findings suggest that AVSBE demonstrated activities that can reduce inflammation and alleviate pain by inhibiting oxido-nitrosative stress and inflammatory mediators, contributing validity to the ethnomedicinal benefit of AVSBE in managing inflammatory and pain-related crisis.

Metabolism effector links in diet-induced and genetically-based obesity: A full-transcriptome study of liver tissue in experimental models in rodents

Background. When developing methods for personalized diet therapy of obesity, an urgent task is to study the molecular genetics features of the obesity pathogenesis using in vivo experimental models in laboratory animals.The aim. To determine metabolism effector links in obesity based on a comparative analysis of full-transcriptome profiles of the liver tissue of mice and rats of various strains.Materials and methods. We carried out a comparative analysis of the changes in liver transcriptome in rats and mice fed with diets of excessive energy value and exerting lipogenic effect. Data of full-transcriptome profiling using DNA microarray technology have been presented previously in 8 publications. Results. In three strains of mice treated with a high-carbohydrate high-fat diet (HCHFD), a significant differential expression (DE) of 1849 genes was revealed, of which 74 genes responded jointly in at least two groups of animals. In Wistar and Zuckerfa rats, 2109 genes responded to the consumption of HCHFD, of which 242 genes responded jointly in two groups of animals. For rodents different in genetic predisposition to the development of diet-induced obesity, the groups of genes that responded with the opposite sign of DE (depending on the genotype) in reaction to the consumption of HCHFD were identified. Bioinformatical analysis allowed establishing the presence of 43 metabolic pathways, which are targeted for the applied experimental diets exposure, in rats and 77 pathways – in mice. Four of these pathways – the pathway of retinoid metabolism, PPAR signaling pathway associated with it the previous one, xenobiotics metabolism and drugs metabolism mediated by cytochrome P450 system – responded in all groups of animals (except for female mice). The importance of the expression of Tat gene encoding tyrosine aminotransferase in the modulation of biogenic amines synthesis in diet-induced obesity was shown, which may represent a new neurometabolic regulatory function of the liver in response to the consumption of high-calorie diets. Conclusion. The analysis of the results of full-transcriptome studies showed that within each studied species (Rattus rattus and Mus domesticus) and animal sex, a number of genetic variants with a greater or lesser predisposition to the development of diet-induced obesity phenotype can be identified; and at the same time, within these variants, there is a largely similar pattern in the response of metabolism effector links to hypercaloric dietary intake. This pattern creates new prospects for translating the results of transcriptomic and metabolomic studies of laboratory animals into clinical practice in order to substantiate new approaches to personalized diet therapy of alimentary dependent diseases in patients with different genetic predisposition to obesity.

Contextual modifiers of healthspan, lifespan, and epigenome in mice under chronic social stress

Sustained life stress and low socioeconomic status are among the major causes of aging-related diseases and decreased life expectancy. Experimental rodent models can help to identify the underlying mechanisms, yet very few studies address the long-term consequences of social stress on aging. We conducted a randomized study involving more than 300 male mice of commonly used laboratory strains (C57BL/6J, CD1, and Sv129Ev) chosen for the spontaneous aggression gradient and stress-vulnerability. Mice were exposed to a lifelong chronic psychosocial stress protocol to model social gradients in aging and disease vulnerability. Low social rank, inferred based on a discretized aggression index, was found to negatively impact lifespan in our study population. However, social rank interacted with genetic background in that low-ranking C57BL/6J, high-ranking Sv129Ev, and middle-ranking CD1 mice had lower survival, respectively, implying a cost of maintaining a given social rank that varies across strains. Machine learning linear discriminant analysis identified baseline fat-free mass as the most important predictor of mouse genetic background and social rank in the present dataset. Finally, strain and social rank differences were significantly associated with epigenetic changes, most significantly in Sv129Ev mice and in high-ranking compared to lower ranking subjects. Overall, we identified genetic background and social rank as critical contextual modifiers of aging and lifespan in an ethologically relevant rodent model of social stress, thereby providing a preclinical experimental paradigm to study the impact of social determinants of health disparities and accelerated aging.

The epithelial sodium channel in inflammation and blood pressure modulation.

A major regulator of blood pressure and volume homeostasis in the kidney is the epithelial sodium channel (ENaC). ENaC is composed of alpha(α)/beta(β)/gamma(γ) or delta(δ)/beta(β)/gamma(γ) subunits. The δ subunit is functional in the guinea pig, but not in routinely used experimental rodent models including rat or mouse, and thus remains the least understood of the four subunits. While the δ subunit is poorly expressed in the human kidney, we recently found that its gene variants are associated with blood pressure and kidney function. The δ subunit is expressed in the human vasculature where it may influence vascular function. Moreover, we recently found that the δ subunit is also expressed human antigen presenting cells (APCs). Our studies indicate that extracellular Na+ enters APCs via ENaC leading to inflammation and salt-induced hypertension. In this review, we highlight recent findings on the role of extra-renal ENaC in inflammation, vascular dysfunction, and blood pressure modulation. Targeting extra-renal ENaC may provide new drug therapies for salt-induced hypertension.

Renal control of life-threatening malarial anemia.

Iron recycling prevents the development of anemia under homeostatic conditions. Whether iron recycling was co-opted as a defense strategy to prevent the development of anemia in response to infection is unclear. We find that in severe Plasmodium falciparum malaria, the onset of life-threatening anemia is associated with acute kidney injury (AKI), irrespective of parasite load. Using a well-established experimental rodent model of malaria anemia, we identify a transcriptional response that endows renal proximal tubule epithelial cells (RPTECs) with the capacity to store and recycle iron during P. chabaudi chabaudi (Pcc) infection. This response encompasses the induction of ferroportin 1/SLC40A1, which exports iron from RPTECs and counteracts AKI while supporting compensatory erythropoiesis and preventing the onset of life-threatening malarial anemia. Iron recycling by myeloid cells is dispensable to this protective response, suggesting that RPTECs provide an iron-recycling salvage pathway that prevents the pathogenesis of life-threatening malarial anemia.

Intra-Peritoneal Transplantation for Generating Acute Myeloid Leukemia in Mice.

There is an unmet need for novel therapies to treat acute myeloid leukemia (AML) and the associated relapse that involves persistent leukemia stem cells (LSCs). An experimental AML rodent model to test therapies based on successfully transplanting these cells via retro-orbital injections in recipient mice is fraught with challenges. The aim of this study was to develop an easy, reliable, and consistent method to generate a robust murine model of AML using an intra-peritoneal route. In the present protocol, bone marrow cells were transduced with a retrovirus expressing human MLL-AF9 fusion oncoprotein. The efficiency of lineage negative (Lin-) and Lin-Sca-1+c-Kit+ (LSK) populations as donor LSCs in the development of primary AML was tested, and intra-peritoneal injection was adopted as a new method to generate AML. Comparison between intra-peritoneal and retro-orbital injections was done in serial transplantations to compare and contrast the two methods. Both Lin- and LSKcells transduced with human MLL-AF9 virus engrafted well in the bone marrow and spleen of recipients, leading to a full-blown AML. The intra-peritoneal injection of donor cells established AML in recipients upon serial transplantation, and the infiltration of AML cells was detected in the blood, bone marrow, spleen, and liver of recipients by flow cytometry, qPCR, and histological analyses. Thus, intra-peritoneal injection is an efficient method of AML induction using serial transplantation of donor leukemic cells.

Nanodelivery of histamine H3 receptor inverse agonist BF-2649 with H3 receptor antagonist and H4 receptor agonist clobenpropit induced neuroprotection is potentiated by antioxidant compound H-290/51 in spinal cord injury.

Military personnel are often victims of spinal cord injury resulting in lifetime disability and decrease in quality of life. However, no suitable therapeutic measures are still available to restore functional disability or arresting the pathophysiological progression of disease in victims for leading a better quality of life. Thus, further research in spinal cord injury using novel strategies or combination of available neuroprotective drugs is urgently needed for superior neuroprotection. In this regard, our laboratory is engaged in developing TiO2 nanowired delivery of drugs, antibodies and enzymes in combination to attenuate spinal cord injury induced pathophysiology and functional disability in experimental rodent model. Previous observations show that histamine antagonists or antioxidant compounds when given alone in spinal cord injury are able to induce neuroprotection for short periods after trauma. In this investigation we used a combination of histaminergic drugs with antioxidant compound H-290/51 using their nanowired delivery for neuroprotection in spinal cord injury of longer duration. Our observations show that a combination of H3 receptor inverse agonist BF-2549 with H3 receptor antagonist and H4 receptor agonist clobenpropit induced neuroprotection is potentiated by antioxidant compound H-290/51 in spinal cord injury. These observations suggests that histamine receptors are involved in the pathophysiology of spinal cord injury and induce superior neuroprotection in combination with an inhibitor of lipid peroxidation H-290/51, not reported earlier. The possible mechanisms and significance of our findings in relation to future clinical approaches in spinal cord injury is discussed.

An Experimental Model of Chromoblastomycosis Caused by Fonsecaea sp. Species.

The experimental rodent models for the fungal disease are a handy tool for understanding host-fungus interactions. To Fonsecaea sp., one of the causative agents of chromoblastomycosis, there is an extra challenge because the animals preferably used show a spontaneous cure; so until now, there is no model to reproduce the long-term disease similar to human chronic disease. In this chapter, we described an experimental model using rats and mice with a subcutaneous route, with the checkpoints of acute-like and chronic-like lesion analysis comparable with human lesions, the fungal burden, and the lymphocytes investigation.

Chemical characterization, anti-nociceptive and anti-inflammatory activities of Plukenetia conophora seed oil in experimental rodent models

Ethnopharmacological relevanceThe seed of the African walnut, Plukenetia conophora Mull.-Arg is well-known for its nutritional and medicinal values. The seed oil is widely used in massages to relieve pain, as nerve tonic and to enhance sexual performance. ObjectiveThe study aimed at investigating the chemical profile, antinociceptive and anti-inflammatory activities of P. conophora oil (PCO). MethodsSeed oil of P. conophora was characterized using Gas-Liquid Chromatographic method (GC-MS) and oral acute toxicity evaluated at 2000 mg/kg. Antinociceptive effects were evaluated in hot plate, acetic acid and formalin-induced paw licking tests. The anti-inflammatory effects were investigated in egg albumin and carrageenan-, formalin and complete Freund adjuvant (CFA)-induced paw oedema models. The levels of pro-inflammatory cytokines in the fluid exudates were also evaluated in carrageenan air pouch model. ResultsPCO exhibited high content of alpha linolenic acid (ALA). No toxicity was observed at 2000 mg/kg of PCO. PCO (50–200 mg/kg) demonstrated significant anti-nociceptive activity in pain models. PCO exhibited anti-inflammatory activity against oedema formation by phlogistic agents. The increased inflammatory oedema and oxidative stress in CFA-treated rats were also attenuated by PCO. The PCO (100 and 200 mg/kg) significantly reduced the levels of TNF-α (59.3% and 85.2%) and IL-6 (27.5% and 72.5%) in carrageenan-induced air pouch model. ConclusionThe results of this study suggest that ALA-rich seed oil of Plukenetia conophora demonstrated anti-nociceptive and anti-inflammatory activities via inhibition of pro-inflammatory cytokines and oxidative stress, lending supportive evidences for its use in painful inflammatory conditions.

Contribution of intraocular pressure‐dependent and pressure‐independent glaucoma models to neuroprotection

AbstractGlaucoma is considered a heterogeneous group of degenerative optic neuropathies characterized mainly by an ongoing loss of retinal ganglion cells (RGCs) which causes progressive deterioration of the visual field and irreversible blindness. The aetiology and pathophysiology of glaucoma are not known in detail and are a matter of debate. Although the most significant risk factor in the development and progression of glaucoma correlates with elevated intraocular pressure (IOP), at present the only treatment available to prevent or delay its development is to reduce IOP by medication or surgery to slow its detrimental effects. But reducing IOP alone does not stop the progression of the disease. Therefore, IOP may not be the only motive for glaucomatous retinopathy and optic neuropathy, and there could be other hidden mechanisms contributing to the loss of RGCs.A suitable animal model of neurodegenerative disease, such as glaucoma, should be easy to induce and reproduce, feasible and predictable, and allow detection and quantification at the biochemical, morphological and functional levels of the induced pathological changes. However, no model emulates all aspects of a pathology such as glaucoma, which is likely to have more than one aetiology and manifest itself through different pathological mechanisms. Hence, the interest and need to establish and use different experimental models in rodents to improve our understanding of the pathophysiology of glaucoma and to investigate possible neuroprotective agents. In general, experimental models of glaucoma established in rodents involve a transient or chronic increase in IOP above normal values, which allows us to study the pathological changes associated with ocular hypertension. However, elevated IOP may not be the only cause of glaucomatous retinopathy and optic neuropathy, hence the need for models that do not involve an increase in intraocular pressure to deal with specific issues of the evolution of this pathology, such as optic nerve injury, retinal ischaemia/reperfusion, intravitreal injection of excitatory amino acids or endothelin‐induced optic neuropathy.Results obtained in different experimental models of glaucoma mimicking ocular hypertension or optic nerve damage have confirmed the existence of morphofunctional differences in the time course of RGC loss, both between different types of RGCs and between different lesions. As well as the effects on other retinal cell populations. In this regard, in the outer retina, there is a significant contrast between damage caused by ocular hypertension and optic nerve injury. Both axotomy and ocular hypertension induce a selective loss of RGCs, but ocular hypertension also promotes a loss of photoreceptors.Thanks to the different glaucoma models studied, the findings obtained have contributed to improving our knowledge of glaucomatous pathology and to the development of future neuroprotective therapies.

Evaluation of the Effect of Cariprazine on Memory and Cognition in Experimental Rodent Models.

The main symptoms of schizophrenia are categorized as positive, negative, and cognitive. Cognitive impairments do not generally respond to antipsychotics. Cariprazine is a novel antipsychotic conceived with the idea that high affinity for D3 receptors may elicit a favorable response in the management of cognitive deficits. We evaluated the pro-cognitive properties of 14-day long pre-treatment with cariprazine (0.25, 0.5, and 1 mg/kg b.w. intraperitoneally) in experimental rodent models with scopolamine-induced memory impairment employing novel object recognition test (NORT), T-maze, Y-maze, and passive avoidance tasks (step-through and step-down). Statistical analysis was performed with One Way ANOVA. In NORT cariprazine increased the recognition index. In T-maze and Y-maze cariprazine increased the working memory index as well as the percentage of spontaneous alternation. Cariprazine improved learning and memory in both short-term and long-term memory retention tests in step-down and step-through tasks. Cariprazine improves learning, recognition, and spatial memory in rats with scopolamine-induced memory impairment. Cariprazine's beneficial effect on cognition is likely due to its affinity for D3 receptors, as well as agonism at 5-HT1A receptors. Most probably, the cognitive-enhancing properties of cariprazine are the result of integrated modulation in the amygdala, hippocampus, and prefrontal cortex.