Rodent models of AKI and AKI-CKD transition: an update in 2024.

Despite known drawbacks, rodent models are essential tools in the research of renal development, physiology, and pathogenesis. In the past decade, rodent models have been developed and used to mimic different etiologies of acute kidney injury (AKI), AKI to chronic kidney disease (CKD) transition or progression, and AKI with comorbidities. These models have been applied for both mechanistic research and preclinical drug development. However, current rodent models have their limitations, especially since they often do not fully recapitulate the pathophysiology of AKI in human patients, and thus need further refinement. Here, we discuss the present status of these rodent models, including the pathophysiologic compatibility, clinical translational significance, key factors affecting model consistency, and their main limitations. Future efforts should focus on establishing robust models that simulate the major clinical and molecular phenotypes of human AKI and its progression.

Environmental enrichment improves cognitive function, learning, memory and anxiety-related behaviours in rodent models of dementia: Implications for future study.

Environmental enrichment (EE) is a process of brain stimulation by modifying the surroundings, for example, by changing the sensory, social, or physical conditions. Rodents have been used in such experimental strategies through exposure to diverse physical, social, and exploration conditions. The present study conducted an extensive analysis of the existing literature surrounding the impact of EE on dementia rodent models. The review emphasised the two principal aspects that are very closely related to dementia: cognitive function (learning and memory) as well as psychological factors (anxiety-related behaviours such as phobias and unrealistic worries). Also highlighted were the mechanisms involved in the rodent models of dementia showing EE effects. Two search engines, PubMed and Science Direct, were used for data collection using the following keywords: environmental enrichment, dementia, rodent model, cognitive performance, and anxiety-related behaviour. Fifty-five articles were chosen depending on the criteria for inclusion and exclusion. The rodent models with dementia demonstrated improved learning and memory in the form of hampered inflammatory responses, enhanced neuronal plasticity, and sustained neuronal activity. EE housing also prevented memory impairment through the prevention of amyloid beta (Aß) seeding formation, an early stage of Aß plaque formation. The rodents subjected to EE were observed to present increased exploratory activity and exert less anxiety-related behaviour, compared to those in standard housing. However, some studies have proposed that EE intervention through exercise would be too mild to counteract the anxiety-related behaviour and risk assessment behaviour deficits in the Alzheimer's disease rodent model. Future studies should be conducted on old-aged rodents and the duration of EE exposure that would elicit the greatest benefits since the existing studies have been conducted on a range of ages and EE durations. In summary, EE had a considerable effect on dementia rodent models, with the most evident being improved cognitive function.

A Guide to Preclinical Models of Zoster-Associated Pain and Postherpetic Neuralgia.

Reactivation of latent varicella-zoster virus (VZV) causes herpes zoster (HZ), which is commonly accompanied by acute pain and pruritus over the time course of a zosteriform rash. Although the rash and associated pain are self-limiting, a considerable fraction of HZ cases will subsequently develop debilitating chronic pain states termed postherpetic neuralgia (PHN). How VZV causes acute pain and the mechanisms underlying the transition to PHN are far from clear. The human-specific nature of VZV has made in vivo modeling of pain following reactivation difficult to study because no single animal can reproduce reactivated VZV disease as observed in the clinic. Investigations of VZV pathogenesis following primary infection have benefited greatly from human tissues harbored in immune-deficient mice, but modeling of acute and chronic pain requires an intact nervous system with the capability of transmitting ascending and descending sensory signals. Several groups have found that subcutaneous VZV inoculation of the rat induces prolonged and measurable changes in nociceptive behavior, indicating sensitivity that partially mimics the development of mechanical allodynia and thermal hyperalgesia seen in HZ and PHN patients. Although it is not a model of reactivation, the rat is beginning to inform how VZV infection can evoke a pain response and induce long-lasting alterations to nociception. In this review, we will summarize the rat pain models from a practical perspective and discuss avenues that have opened for testing of novel treatments for both zoster-associated pain and chronic PHN conditions, which remain in critical need of effective therapies.

NIR-II nanoprobes for investigating the glymphatic system function under anesthesia and stroke injury.

The glymphatic system plays an important role in the transportation of cerebrospinal fluid (CSF) and the clearance of metabolite waste in brain. However, current imaging modalities for studying the glymphatic system are limited. Herein, we apply NIR-II nanoprobes with non-invasive and high-contrast advantages to comprehensively explore the function of glymphatic system in mice under anesthesia and cerebral ischemia-reperfusion injury conditions. Our results show that the supplement drug dexmedetomidine (Dex) enhances CSF influx in the brain, decreases its outflow to mandibular lymph nodes, and leads to significant differences in CSF accumulation pattern in the spine compared to isoflurane (ISO) alone, while both ISO and Dex do not affect the clearance of tracer-filled CSF into blood circulation. Notably, we confirm the compromised glymphatic function after cerebral ischemia-reperfusion injury, leading to impaired glymphatic influx and reduced glymphatic efflux. This technique has great potential to elucidate the underlying mechanisms between the glymphatic system and central nervous system diseases.

Short-term behavioral and histological findings following a single concussive and repeated subconcussive brain injury in a rodent model.

PRIMARY OBJECTIVE: It is unclear of the correlation between a mild traumatic brain injury (mTBI) and repeated subconcussive (RSC) impacts with respect to injury biomechanics. Thus, the present study was designed to determine the behavioral and histological differences between a single mTBI impact and RSC impacts with subdivided cumulative kinetic energies of the single mTBI impact. RESEARCH DESIGN: Adult male Sprague-Dawley rats were randomly assigned to a single mTBI impact, RSC impact, sham, or repeated sham groups. METHODS AND PROCEDURES: Following a weight drop injury, anxiety-like behavior and general locomotive activity and were assessed using the open field test, while motor coordination was evaluated using a rotarod unit. Neuronal loss, astrogliosis, and microgliosis were assessed using NeuN, GFAP and Iba-1 immunohistochemistry. All assessments were undertaken at 3- and 7-days post impact. MAIN OUTCOMES AND RESULTS: No behavioral disturbances were observed in injury groups, however, both injury groups did lead to microgliosis following 3-days post-impact. CONCLUSIONS: No pathophysiological differences were observed between a single mTBI impact and RSC impacts of the same energy input. Even though a cumulative injury threshold for RSC impacts was not determined, a threshold still may exist where no pathodynamic shift occurs.

A Novel Model of Staphylococcus aureus-Induced Lymphoplasmacytic Rhinosinusitis in Rats.

Chronic rhinosinusitis (CRS) is characterized by sinonasal mucosal inflammation. Staphylococcus aureus (S. aureus) is associated with severe CRS phenotypes. Different animal models have been proposed to study the association of CRS and S. aureus. However, current animal models are expensive due to the use of large animals, have high barriers to ethics approval, or require invasive surgical intervention, necessitating a need for a model that can overcome these limitations. This study aimed at establishing a reliable and efficient rat lymphoplasmacytic inflammatory model for rhinosinusitis. Sprague Dawley rats received a daily intranasal application of 20 µL of saline, S. aureus CI-182 exoprotein (250 µg/mL), or exoprotein CI-182 in combination with S. aureus clinical isolate (CI-908 or CI-913) 108 colony-forming unit (CFU)/mL. The rats' sinuses were harvested at 1 and 2 weeks post-intervention. The CFU and histopathologic examination of inflammation were evaluated. S. aureus clinical isolates CI-908 or CI-913 in combination with the exoprotein (CI-182) had higher CFUs and caused persistently higher inflammation at both the 1 and 2-week post-intervention compared to the exoprotein and saline group. The observed inflammatory cell type was lymphoplasmacytic. This study provided evidence that the combination of a S. aureus exoprotein with S. aureus induces inflammation that persists for a minimum of two weeks post-intervention. This model is the first known animal model to create the lymphoplasmacytic inflammation subtype seen in CRS patients. This offers a cost-effective, accessible, non-invasive, and easy-to-replicate model to study the causes and treatment of such inflammation.

Dense dopaminergic innervation of the peri-infarct cortex despite dopaminergic cell loss after a pure motor-cortical stroke in rats.

After ischemic stroke, the cortex directly adjacent to the ischemic core (i.e., the peri-infarct cortex, PIC) undergoes plastic changes that facilitate motor recovery. Dopaminergic signaling is thought to support this process. However, ischemic stroke also leads to the remote degeneration of dopaminergic midbrain neurons, possibly interfering with this beneficial effect. In this study, we assessed the reorganization of dopaminergic innervation of the PIC in a rat model of focal cortical stroke. Adult Sprague-Dawley rats either received a photothrombotic stroke (PTS) in the primary motor cortex (M1) or a sham operation. 30 days after PTS or sham procedure, the retrograde tracer Micro Ruby (MR) was injected into the PIC of stroke animals or into homotopic cortical areas of matched sham rats. Thus, dopaminergic midbrain neurons projecting into the PIC were identified based on MR signal and immunoreactivity against tyrosine hydroxylase (TH), a marker for dopaminergic neurons. The density of dopaminergic innervation within the PIC was assessed by quantification of dopaminergic boutons indicated by TH-immunoreactivity. Regarding postsynaptic processes, expression of dopamine receptors (D1- and D2) and a marker of the functional signal cascade (DARPP-32) were visualized histologically. Despite a 25% ipsilesional loss of dopaminergic midbrain neurons after PTS, the number and spatial distribution of dopaminergic neurons projecting to the PIC was not different compared to sham controls. Moreover, the density of dopaminergic innervation in the PIC was significantly higher than in homotopic cortical areas of the sham group. Within the PIC, D1-receptors were expressed in neurons, whereas D2-receptors were confined to astrocytes. The intensity of D1- and DARPP-32 expression appeared to be higher in the PIC compared to the contralesional homotopic cortex. Our data suggest a sprouting of dopaminergic fibers into the PIC and point to a role for dopaminergic signaling in reparative mechanisms post-stroke, potentially related to recovery.

Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats.

Malformations of cortical development represent a major cause of epilepsy in childhood. However, the pathological substrate and dynamic changes leading to the development and progression of epilepsy remain unclear. Here, we characterized an etiology-relevant rat model of subcortical band heterotopia (SBH), a diffuse type of cortical malformation associated with drug-resistant seizures in humans. We used longitudinal electrographic recordings to monitor the age-dependent evolution of epileptiform discharges during the course of epileptogenesis in this model. We found both quantitative and qualitative age-related changes in seizures properties and patterns, accompanying a gradual progression towards a fully developed seizure pattern seen in adulthood. We also dissected the relative contribution of the band heterotopia and the overlying cortex to the development and age-dependent progression of epilepsy using timed and spatially targeted manipulation of neuronal excitability. We found that an early suppression of neuronal excitability in SBH slows down epileptogenesis in juvenile rats, whereas epileptogenesis is paradoxically exacerbated when excitability is suppressed in the overlying cortex. However, in rats with active epilepsy, similar manipulations of excitability have no effect on chronic spontaneous seizures. Together, our data support the notion that complex developmental alterations occurring in both the SBH and the overlying cortex concur to creating pathogenic circuits prone to generate seizures. Our study also suggests that early and targeted interventions could potentially influence the course of these altered developmental trajectories, and favorably modify epileptogenesis in malformations of cortical development.

Targeting proteostasis of the HEV replicase to combat infection in preclinical models.

BACKGROUND & AIMS: Appropriate treatment options are lacking for hepatitis E virus (HEV)-infected pregnant women and immunocompromised individuals. Thus, we aimed to identify efficient anti-HEV drugs through high-throughput screening, validate them in vitro and in vivo (in a preclinical animal study), and elucidate their underlying antiviral mechanism of action. METHODS: Using appropriate cellular and rodent HEV infection models, we studied a critical pathway for host-HEV interactions and performed a preclinical study of the corresponding antivirals, which target proteostasis of the HEV replicase. RESULTS: We found 17 inhibitors that target HEV-HSP90 interactions by unbiased compound library screening on human hepatocytes harboring an HEV replicon. Inhibitors of HSP90 (iHSP90) markedly suppressed HEV replication with efficacy exceeding that of conventional antivirals (IFNα and ribavirin) in vitro. Mechanistically, iHSP90 treatment released the viral replicase ORF1 protein from the ORF1-HSP90 complex and triggered rapid ubiquitin/proteasome-mediated degradation of ORF1, resulting in abrogated HEV replication. Furthermore, a preclinical trial in a Mongolian gerbil HEV infection model showed this novel anti-HEV strategy to be safe, efficient, and able to prevent HEV-induced liver damage. CONCLUSIONS: In this study, we uncover a proteostatic pathway that is critical for host-HEV interactions and we provide a foundation from which to translate this new understanding of the HEV life cycle into clinically promising antivirals. IMPACT AND IMPLICATIONS: Appropriate treatment options for hepatitis E virus (HEV)-infected pregnant women and immunocompromised patients are lacking; hence, there is an urgent need for safe and effective HEV-specific therapies. This study identified new antivirals (inhibitors of HSP90) that significantly limit HEV infection by targeting the viral replicase for degradation. Moreover, these anti-HEV drugs were validated in an HEV rodent model and were found to be safe and efficient for prevention of HEV-induced liver injury in preclinical experiments. Our findings substantially promote the understanding of HEV pathobiology and pave the way for antiviral development.

How animal models can be utilized to find new biomarkers for cardiovascular diseases.

It has been more than 60 years since the colonized genetic model of hypertension was first established. Model animals contribute greatly to the advance of understanding of the pathophysiology and development of effective therapy. In this review, the author focuses on two points: gene-related biomarkers and the use of humanized mice to search for biomarkers. First, the author provides an overview of the history of the establishment of hypertension and salt-sensitivity model rats, as well as advances in genetic analysis of causative genes of hypertension and the theory of renal causes of salt-sensitive hypertension. The recent animal model analysis adds the notion of the importance of epigenetic alterations in addition to the genetic causes of hypertension. Both germline mutations and epigenetic analysis of congenic animal models are complementary and should carry out furtherly. Among epigenetic factors, non-coding RNA is a promising new 'liquid biopsy' which is originally applied to diagnose cancers by detecting cancer cell-derived DNA, RNA, or other molecules in a person's body fluid and now it can be applied to any pathophysiological conditions. Then, the author reviews the usefulness of humanized mice. Few studies have used such mice in cardiovascular research, but the present study highlights a study of immune-related disease and the search for biomarkers in such mice. Perspectives on using humanized mice in cardiovascular research are discussed.

Rodent Models of Spinal Cord Injury: From Pathology to Application.

Spinal cord injury (SCI) often has devastating consequences for the patient's physical, mental and occupational health. At present, there is no effective treatment for SCI, and appropriate animal models are very important for studying the pathological manifestations, injury mechanisms, and corresponding treatment. However, the pathological changes in each injury model are different, which creates difficulties in selecting appropriate models for different research purposes. In this article, we analyze various SCI models and introduce their pathological features, including inflammation, glial scar formation, axon regeneration, ischemia-reperfusion injury, and oxidative stress, and evaluate the advantages and disadvantages of each model, which is convenient for selecting suitable models for different injury mechanisms to study therapeutic methods.

γδ T-cell-mediated immune responses to malaria.

Malaria is one of the deadliest infectious diseases. Licensed vaccine have demonstrated just over 30% efficacy, and therefore, developing new vaccine candidates and understanding immune responses to Plasmodium have become necessary. γδ T cells have been suggested to be associated with immune responses to malaria due to the observation of their expansion in patients with malaria and experimental models of malaria. γδ T cells act as both "innate-like" and "adaptive-like" cells during immune response to malaria. Studies have found that γδ T cells can recognize Plasmodium phosphoantigen, present the antigen, and initiate adaptive immune response during blood-stage Plasmodium infection. Recent reports also suggested the phagocytic and cytotoxic potential of γδ T cells. Furthermore, γδ T cells can provide protection upon immunization with whole parasite. In addition, γδ T cells during the liver-stage infection were able to prevent experimental cerebral malaria. Despite these new findings, questions related to γδ T-cell response during Plasmodium infection remain to be answered. However, investigating these cells in humans remains difficult in many ways; in this regard, rodent models of malarial infection enable us to study these cells in more detail. Insights from experimental malaria models give rise to new cues for development of malarial vaccine and adjunctive therapy for severe malaria. Here, we review our current knowledge of γδ T-cell immune function in human and experimental mouse malarial infection models; especially, we focus on the mechanisms underlying γδ T cells that are associated with protective immunity during malarial infection.

Satralizumab, Novel Interleukine-6 Inhibitor for Preventing Descending Thoracic Aorta Aneurysm Development.

BACKGROUND: Descending thoracic aorta aneurysm (dTAA) has increasing incidence and, if left untreated, could lead to death. There is not any study of satralizumab treatment for preventing dTAA formation and progression. MATERIALS AND METHODS: Forty male 10-week-old Rattus norvegicus were enrolled in the experiment. They were divided into four equal groups: dTAA treated with saline (dTAA-P) and dTAA treated with satralizumab (dTAA-S). One of the control groups was treated with saline (C-P), and the other was treated with satralizumab (C-S). Satralizumab and saline were used once every 2 weeks, subcutaneously 120 mg for 4 weeks. dTA diameter was measured at days 0, 3, 7, 14, 21, and 28. RESULTS: IL-6 level was measured on the 7th day that showed significantly increased IL-6 serum level in dTAA-P rats compared to C-P. Maximal dTA diameter (%MAD) was obtained at day 14, which was scientifically matched to the aorta aneurysm definition (>50% increase in diameter). From the seventh day, a significant difference in %MAD was observed between dTAA-P and dTAA-S groups. However, the %MAD of these two groups was significantly higher than control groups till the end of the 28th day. CONCLUSION: Using an IL-6 inhibitor agent to prevent dTAA formation and progression showed promising results. It suggests that using the IL-6 inhibitors in susceptible persons can be considered a lifesaving therapeutic approach.

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery.

Even with modern therapy, patients with heart failure only have a 50% five-year survival rate. To improve the development of new therapeutic strategies, preclinical models of disease are needed to properly emulate the human condition. Determining the most appropriate model represents the first key step for reliable and translatable experimental research. Rodent models of heart failure provide a strategic compromise between human in vivo similarity and the ability to perform a larger number of experiments and explore many therapeutic candidates. We herein review the currently available rodent models of heart failure, summarizing their physiopathological basis, the timeline of the development of ventricular failure, and their specific clinical features. In order to facilitate the future planning of investigations in the field of heart failure, a detailed overview of the advantages and possible drawbacks of each model is provided.

System Biology Investigation Revealed Lipopolysaccharide and Alcohol-Induced Hepatocellular Carcinoma Resembled Hepatitis B Virus Immunobiology and Pathogenesis.

Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV.

Changes in Plasma Metabolomic Profile Following Bariatric Surgery, Lifestyle Intervention or Diet Restriction-Insights from Human and Rat Studies.

Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled Würzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI -34.3% (OP) vs. -1.2% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss.

Dysregulated UPR and ER Stress Related to a Mutation in the Sdf2l1 Gene Are Involved in the Pathophysiology of Diet-Induced Diabetes in the Cohen Diabetic Rat.

The Cohen Diabetic rat is a model of type 2 diabetes mellitus that consists of the susceptible (CDs/y) and resistant (CDr/y) strains. Diabetes develops in CDs/y provided diabetogenic diet (DD) but not when fed regular diet (RD) nor in CDr/y given either diet. We recently identified in CDs/y a deletion in Sdf2l1, a gene that has been attributed a role in the unfolded protein response (UPR) and in the prevention of endoplasmic reticulum (ER) stress. We hypothesized that this deletion prevents expression of SDF2L1 and contributes to the pathophysiology of diabetes in CDs/y by impairing UPR, enhancing ER stress, and preventing CDs/y from secreting sufficient insulin upon demand. We studied SDF2L1 expression in CDs/y and CDr/y. We evaluated UPR by examining expression of key proteins involved in both strains fed either RD or DD. We assessed the ability of all groups of animals to secrete insulin during an oral glucose tolerance test (OGTT) over 4 weeks, and after overnight feeding (postprandial) over 4 months. We found that SDF2L1 was expressed in CDr/y but not in CDs/y. The pattern of expression of proteins involved in UPR, namely the PERK (EIF2α, ATF4 and CHOP) and IRE1 (XBP-1) pathways, was different in CDs/y DD from all other groups, with consistently lower levels of expression at 4 weeks after initiation of DD and coinciding with the development of diabetes. In CDs/y RD, insulin secretion was mildly impaired, whereas in CDs/y DD, the ability to secrete insulin decreased over time, leading to the development of the diabetic phenotype. We conclude that in CDs/y DD, UPR participating proteins were dysregulated and under-expressed at the time point when the diabetic phenotype became overt. In parallel, insulin secretion in CDs/y DD became markedly impaired. Our findings suggest that under conditions of metabolic load with DD and increased demand for insulin secretion, the lack of SDF2L1 expression in CDs/y is associated with UPR dysregulation and ER stress which, combined with oxidative stress previously attributed to the concurrent Ndufa4 mutation, are highly likely to contribute to the pathophysiology of diabetes in this model.

Cirrhotic Cardiomyopathy Following Bile Duct Ligation in Rats-A Matter of Time?

Cirrhotic patients often suffer from cirrhotic cardiomyopathy (CCM). Previous animal models of CCM were inconsistent concerning the time and mechanism of injury; thus, the temporal dynamics and cardiac vulnerability were studied in more detail. Rats underwent bile duct ligation (BDL) and a second surgery 28 days later. Cardiac function was assessed by conductance catheter and echocardiography. Histology, gene expression, and serum parameters were analyzed. A chronotropic incompetence (Pd31 < 0.001) and impaired contractility at rest and a reduced contractile reserve (Pd31 = 0.03, Pdob-d31 < 0.001) were seen 31 days after BDL with increased creatine (Pd35, Pd42, and Pd56 < 0.05) and transaminases (Pd31 < 0.001). A total of 56 days after BDL, myocardial fibrosis was seen (Pd56 < 0.001) accompanied by macrophage infiltration (CD68: Pgroup < 0.001) and systemic inflammation (TNFα: Pgroup < 0.001, white blood cell count: Pgroup < 0.001). Myocardial expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was increased after 31 (Pd31 < 0.001) and decreased after 42 (Pd42 < 0.001) and 56 days (Pd56 < 0.001). Caspase-3 expression was increased 31 and 56 days after BDL (Pd31 = 0.005; Pd56 = 0.005). Structural changes in the myocardium were seen after 8 weeks. After the second surgery (second hit), transient myocardial insufficiency with secondary organ dysfunction was seen, characterized by reduced contractility and contractile reserve.

Tibolone Improves Locomotor Function in a Rat Model of Spinal Cord Injury by Modulating Apoptosis and Autophagy.

Spinal cord injury (SCI) harms patients' health and social and economic well-being. Unfortunately, fully effective therapeutic strategies have yet to be developed to treat this disease, affecting millions worldwide. Apoptosis and autophagy are critical cell death signaling pathways after SCI that should be targeted for early therapeutic interventions to mitigate their adverse effects and promote functional recovery. Tibolone (TIB) is a selective tissue estrogen activity regulator (STEAR) with neuroprotective properties demonstrated in some experimental models. This study aimed to investigate the effect of TIB on apoptotic cell death and autophagy after SCI and verify whether TIB promotes motor function recovery. A moderate contusion SCI was produced at thoracic level 9 (T9) in male Sprague Dawley rats. Subsequently, animals received a daily dose of TIB orally and were sacrificed at 1, 3, 14 or 30 days post-injury. Tissue samples were collected for morphometric and immunofluorescence analysis to identify tissue damage and the percentage of neurons at the injury site. Autophagic (Beclin-1, LC3-I/LC3-II, p62) and apoptotic (Caspase 3) markers were also analyzed via Western blot. Finally, motor function was assessed using the BBB scale. TIB administration significantly increased the amount of preserved tissue (p < 0.05), improved the recovery of motor function (p < 0.001) and modulated the expression of autophagy markers in a time-dependent manner while consistently inhibiting apoptosis (p < 0.05). Therefore, TIB could be a therapeutic alternative for the recovery of motor function after SCI.

Synaptic loss in a mouse model of euthyroid Hashimoto's thyroiditis: possible involvement of the microglia.

BACKGROUND: Hashimoto's thyroiditis (HT) is an autoimmune illness that renders individuals vulnerable to neuropsychopathology even in the euthyroid state, the mechanisms involved remain unclear. We hypothesized that activated microglia might disrupt synapses, resulting in cognitive disturbance in the context of euthyroid HT, and designed the present study to test this hypothesis. METHODS: Experimental HT model was induced by immunizing NOD mice with thyroglobulin and adjuvant twice. Morris Water Maze was measured to determine mice spatial learning and memory. The synaptic parameters such as the synaptic density, synaptic ultrastructure and synaptic-markers (SYN and PSD95) as well as the interactions of microglia with synapses were also determined. RESULTS: HT mice had poorer performance in Morris Water Maze than controls. Concurrently, HT resulted in a significant reduction in synapse density and ultrastructure damage, along with decreased synaptic puncta visualized by immunostaining with synaptophysin and PSD-95. In parallel, frontal activated microglia in euthyroid HT mice showed increased engulfment of PSD95 and EM revealed that the synaptic structures were visible within the microglia. These functional alterations in microglia corresponded to structural increases in their attachment to neuronal perikarya and a reduction in presynaptic terminals covering the neurons. CONCLUSION: Our results provide initial evidence that HT can induce synaptic loss in the euthyroid state with deficits might be attributable to activated microglia, which may underlie the deleterious effects of HT on spatial learning and memory.