IU Indianapolis ScholarWorks :: Browsing by Subject "animal models"

Browsing by Subject "animal models"

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Alendronate treatment results in similar levels of trabecular bone remodeling in the femoral neck and vertebra
(2009-04) Diab, Tamim; Allen, Matthew R.; Burr, David B.
Introduction Bone turnover suppression in sites that already have a low surface-based remodeling rate may lead to oversuppression that could have negative effects on the biomechanical properties of bone. The goal was to determine how alendronate suppresses bone turnover at sites with different surface-based remodeling rates. Methods Dynamic histomorphometric parameters were assessed in trabecular bone of the femoral neck and lumbar vertebrae obtained from skeletally mature beagles treated with saline (1 ml/kg/day) or alendronate (ALN 0.2 or 1.0 mg/kg/day). The ALN0.2 and ALN1.0 doses approximate, on a milligram per kilogram basis, the clinical doses used for the treatment of postmenopausal osteoporosis and Paget’s disease, respectively. Results Alendronate treatment resulted in similar absolute levels of bone turnover in the femoral neck and vertebrae, although the femoral neck had 33% lower pre-treatment surface-based remodeling rate than the vertebra (p < 0.05). Additionally, the high dose of alendronate (ALN 1.0) suppressed bone turnover to similar absolute levels as the low dose of alendronate (ALN 0.2) in both sites. Conclusions Alendronate treatment may result in a lower limit of trabecular bone turnover suppression, suggesting that sites of low pre-treatment remodeling rate are not more susceptible to oversuppression than those of high pre-treatment remodeling rate.
Changes in non-enzymatic glycation and its association with altered mechanical properties following 1-year treatment with risedronate or alendronate
(2009-06) Tang, SY; Allen, Matthew R.; Phipps, R; Burr, David B.; Vashishth, Deepak
Summary One year of high-dose bisphosphonate (BPs) therapy in dogs allowed the increased accumulation of advanced glycation end-products (AGEs) and reduced postyield work-to-fracture of the cortical bone matrix. The increased accumulation of AGEs in these tissues may help explain altered bone matrix quality due to the administration of BPs in animal models Introduction Non-enzymatic glycation (NEG) is a posttranslational modification of the organic matrix that results in the formation of advanced glycation end-products (AGEs). In bone, the accumulation of AGEs play an important role in determining fracture resistance, and elevated levels of AGEs have been shown to adversely affect the bone’s propensity to brittle fracture. It was thus hypothesized that the suppression of tissue turnover in cortical bone due to the administration of bisphosphonates would cause increased accumulation of AGEs and result in a more brittle bone matrix. Methods Using a canine animal model (n = 12), we administered daily doses of a saline vehicle (VEH), alendronate (ALN 0.20, 1.00 mg/kg) or risedronate (RIS 0.10, 0.50 mg/kg). After a 1-year treatment, the mechanical properties, intracortical bone turnover, and the degree of nonenzymatic cross-linking of the organic matrix were measured from the tibial cortical bone tissue of these animals. Results There was a significant accumulation of AGEs at high treatment doses (+49 to + 86%; p < 0.001), but not at doses equivalent to those used for the treatment of postmenopausal osteoporosis, compared to vehicle. Likewise, postyield work-to-fracture of the tissue was significantly reduced at these high doses (−28% to −51%; p < 0.001) compared to VEH. AGE accumulation inversely correlated with postyield work-to-fracture (r 2 = 0.45; p < 0.001), suggesting that increased AGEs may contribute to a more brittle bone matrix. Conclusion High doses of bisphosphonates result in the accumulation of AGEs and a reduction in energy absorption of cortical bone. The increased accumulation of AGEs in these tissues may help explain altered bone matrix quality due to the administration of BPs in animal models.
Changes in vertebral strength-density and energy absorption-density relationships following bisphosphonate treatment in beagle dogs
(2008-01) Allen, Matthew R.; Burr, David B.
We aimed to determine the effects of bisphosphonates on mechanical properties independent of changes in bone density. Our results show that at equivalent bone densities, vertebrae from beagles treated with bisphosphonate have equivalent bone strength and reduced bone energy absorption compared to those from untreated animals. INTRODUCTION: Assessing the relationship between mechanical properties and bone density allows a biomechanical evaluation of bone quality, with differences at a given density indicative of altered quality. The purpose of this study was to evaluate the strength-density and energy absorption-density relationships in vertebral bone following a one-year treatment with clinical doses of two different bisphosphonates in beagle dogs. METHODS: Areal bone mineral density (aBMD) and compressive mechanical properties (ultimate load and energy absorption) were assessed on lumbar vertebrae from skeletally mature beagle dogs treated with vehicle (VEH), alendronate (ALN), or risedronate (RIS). Relationships among properties were assessed using analyses of covariance. RESULTS: Neither treatment altered the strength-density relationship compared to VEH, suggesting increases in vertebral strength with bisphosphonate-treatment are explained by increased density. The energy absorption-density relationship was altered by ALN, resulting in significantly lower energy absorption capacity at a given aBMD compared to both VEH (-22%) and RIS (-14%). CONCLUSIONS: These data document that after adjusting for increased aBMD, vertebrae from animals treated with bisphosphonates have similar strength as those from untreated animals. Conversely, when adjusted for increased aBMD, alendronate treatment, but not risedronate treatment, significantly reduces the energy required for vertebral fracture, indicative of an alteration in bone quality.
Genetic Background and Sex: Impact on Generalizability of Research Findings in Pharmacology Studies
(Springer, 2020) Sukoff Rizzo, Stacey J.; McTighe, Stephanie; McKinzie, David L.; Pharmacology and Toxicology, School of Medicine
Animal models consisting of inbred laboratory rodent strains have been a powerful tool for decades, helping to unravel the underpinnings of biological problems and employed to evaluate potential therapeutic treatments in drug discovery. While inbred strains demonstrate relatively reliable and predictable responses, using a single inbred strain alone or as a background to a mutation is analogous to running a clinical trial in a single individual and their identical twins. Indeed, complex etiologies drive the most common human diseases, and a single inbred strain that is a surrogate of a single genome, or data generated from a single sex, is not representative of the genetically diverse patient populations. Further, pharmacological and toxicology data generated in otherwise healthy animals may not translate to disease states where physiology, metabolism, and general health are compromised. The purpose of this chapter is to provide guidance for improving generalizability of preclinical studies by providing insight into necessary considerations for introducing systematic variation within the study design, such as genetic diversity, the use of both sexes, and selection of appropriate age and disease model. The outcome of implementing these considerations should be that reproducibility and generalizability of significant results are significantly enhanced leading to improved clinical translation.
Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth
(2011-09) Fishel, Melissa L.; Jiang, Yanlin; Rajeshkumar, NV.; Scandura, Glenda; Sinn, Anthony L.; He, Ying; Shen, Changyu; Jones, David R.; Pollok, Karen E.; Ivan, Mircea; Maitra, Anirban; Kelley, Mark R.
Pancreatic cancer is especially a deadly form of cancer with a survival rate less than 2%. Pancreatic cancers respond poorly to existing chemotherapeutic agents and radiation, and progress for the treatment of pancreatic cancer remains elusive. To address this unmet medical need, a better understanding of critical pathways and molecular mechanisms involved in pancreatic tumor development, progression, and resistance to traditional therapy is therefore critical. Reduction–oxidation (redox) signaling systems are emerging as important targets in pancreatic cancer. AP endonuclease1/Redox effector factor 1 (APE1/Ref-1) is upregulated in human pancreatic cancer cells and modulation of its redox activity blocks the proliferation and migration of pancreatic cancer cells and pancreatic cancer-associated endothelial cells in vitro. Modulation of APE1/Ref-1 using a specific inhibitor of APE1/Ref-1′s redox function, E3330, leads to a decrease in transcription factor activity for NFκB, AP-1, and HIF1α in vitro. This study aims to further establish the redox signaling protein APE1/Ref-1 as a molecular target in pancreatic cancer. Here, we show that inhibition of APE1/Ref-1 via E3330 results in tumor growth inhibition in cell lines and pancreatic cancer xenograft models in mice. Pharmacokinetic studies also show that E3330 attains more than10 μmol/L blood concentrations and is detectable in tumor xenografts. Through inhibition of APE1/Ref-1, the activity of NFκB, AP-1, and HIF1α that are key transcriptional regulators involved in survival, invasion, and metastasis is blocked. These data indicate that E3330, inhibitor of APE1/Ref-1, has potential in pancreatic cancer and clinical investigation of APE1/Ref-1 molecular target is warranted. Mol Cancer Ther; 10(9); 1698–708. ©2011 AACR.
The individual and combined effects of exercise and collagenase on the rodent Achilles tendon
(2014-07-11) Dirks, Rachel Candace; Warden, Stuart J.; Allen, Matthew R.; Fuchs, Robyn K.; Robling, Alexander G.
Tendinopathy is a common degenerative pathology that is characterized by activity related pain, focal tendon tenderness, intratendinous imaging changes, and typically results in changes in the histological, mechanical, and molecular properties of the tendon. Tendinopathy is difficult to study in humans, which has contributed to limited knowledge of the pathology, and thus a lack of appropriate treatment options. However, most believe that the pathology is degenerative as a result of a combination of both extrinsic and intrinsic factors. In order to gain understanding of this pathology, animal models are required. Because each tendon is naturally exposed to different conditions, a universal model is not feasible; therefore, an appropriate animal model must be established for each tendon susceptible to degenerative changes. While acceptable models have been developed for several tendons, a reliable model for the Achilles tendon remains elusive. The purpose of this dissertation was to develop an animal model of Achilles tendinopathy by investigating the individual and combined effects of an intrinsic and extrinsic factor on the rodent Achilles tendon. Rats selectively bred for high capacity running and Sprague Dawley rats underwent uphill treadmill running (an extrinsic factor) to mechanically overload the Achilles tendon or served as cage controls. Collagenase (intrinsic factor) was injected into one Achilles tendon in each animal to intrinsically break down the tendon. There were no interactions between uphill running and collagenase injection, indicating that the influence of the two factors was independent. Uphill treadmill running alone failed to produce any pathological changes in the histological or mechanical characteristics of the Achilles tendon, but did modify molecular activity. Intratendinous collagenase injection had negative effects on the histological, mechanical, and molecular properties of the tendon. The results of this dissertation demonstrated that the combined introduction of uphill treadmill running and collagenase injection did not lead to degenerative changes consistent with human Achilles tendinopathy. Intratendiouns collagenase injection negatively influenced the tendon; however, these changes were generally transient and not influenced by mechanical overload. Future studies should consider combinations of other intrinsic and extrinsic factors in an effort to develop an animal model that replicates human Achilles tendinopathy.
Molecular targets of alcohol action: translational research for pharmacotherapy development and screening.
(Elsevier, 2011) Gorini, Giorgio; Bell, Richard L.; Mayfield, R. Dayne; Department of Psychology, School of Science
Alcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented.
Pathological and Transcriptome Changes in the ReninAAV db/db uNx Model of Advanced Diabetic Kidney Disease Exhibit Features of Human Disease
(Sage, 2018-12) Harlan, Shannon M.; Heinz-Taheny, Kathleen M.; Overstreet, Jessica M.; Breyer, Matthew D.; Harris, Raymond C.; Heuer, Josef G.; Medicine, School of Medicine
The ReninAAV db/db uNx model of diabetic kidney disease (DKD) exhibits hallmarks of advanced human disease, including progressive elevations in albuminuria and serum creatinine, loss of glomerular filtration rate, and pathological changes. Microarray analysis of renal transcriptome changes were more similar to human DKD when compared to db/db eNOS−/− model. The model responds to treatment with arterial pressure lowering (lisinopril) or glycemic control (rosiglitazone) at early stages of disease. We hypothesized the ReninAAV db/db uNx model with advanced disease would have residual disease after treatment with lisinopril, rosiglitazone, or combination of both. To test this, ReninAAV db/db uNx mice with advanced disease were treated with lisinopril, rosiglitazone, or combination of both for 10 weeks. All treatment groups showed significant lowering of urinary albumin to creatinine ratio compared to baseline; however, only combination group exhibited lowering of serum creatinine. Treatment improved renal pathological scores compared to baseline values with residual disease evident in all treatment groups when compared to db/m controls. Gene expression analysis by TaqMan supported pathological changes with increased fibrotic and inflammatory markers. The results further validate this model of DKD in which residual disease is present when treated with agents to lower arterial pressure and glycemic control.
Skeletal loading in animals
(2001) Robling, Alexander G; Burr, David B.; Turner, Charles H
A number of in vivo skeletal loading models have been developed to test specific hypotheses addressing the key mechanical and biochemical signals involved in bone’s adaptive response to loading. Exercise protocols, osteotomy procedures, loading of surgically implanted pins, and force application through the soft tissues are common approaches to alter the mechanical environment of a bone. Although each animal overload model has a number of assets and limitations, models employing extrinsic forces allow greater control of the mechanical environment. Sham controls, for both surgical intervention (when performed) and loading, are required to unequivocally demonstrate that responses to loading are mechanically adaptive. Collectively, extrinsic loading models have fostered a greater understanding of the mechanical signals important for stimulating bone cells, and highlighted the roles of key signaling molecules in the adaptive response.
A soluble guanylate cyclase stimulator, BAY 41-8543, preserves pulmonary artery endothelial function in experimental pulmonary embolism
(European Respiratory Journal, 2013-09) Watts, John; Gellar, Michael; Fulkerson, Mary-Beth; Quach, Hugh; Kline, Jeffrey A.
Background: BAY 41-8543 reduces pulmonary vascular resistance and right ventricle injury in experimental PE. Objective: Test if BAY 41-8543 protects pulmonary artery (PA) endothelial function in PE. Methods: PE was induced (anesthetized, Sprague-Dawley rats, 25 µm polystyrene microspheres, 1.95 million/100g, IV) with BAY 41-8543 (50 ug/kg, IV) or solvent treatment. Controls had vehicle for microspheres. Rings isolated from primary PA branches (5hr. PE) were contracted (phenylephrine, 10-6M) and dilation was endothelium-dependent (acetylcholine, 10-7M – 10-5M) or with BAY 41-8543 (10-8M – 10-6M). Oxidant stress was assessed: PA tissue 4-hydroxynoneal (4-HNE) immunohistochemistry; plasma malondialdehyde (MDA). Other Control rings received red blood cell (RBC) lysate. Results: PE inhibited dilation to acetylcholine vs. Control (dose x group interaction p=0.001), while dilation to BAY 41-8543 was minimally changed. PE raised plasma hemoglobin (30-fold, p=0.003), 4-HNE stain and plasma MDA (2.2-fold, p=0.009). Treating PE rats with BAY 41-8543 reduced plasma hemoglobin, 4-HNE and MDA to levels not different from Control. Dilation to acetylcholine significantly improved in PE + BAY 41-8543 rats vs. PE (dose x group interaction p=0.04). Addition of RBC lysate to Control rings reduced dilation to acetylcholine, while BAY 41-8543 responses remained strong. Conclusion: PE caused PA endothelial dysfunction, elevated plasma hemoglobin and oxidant stress. Treating rats with BAY 41-8543 lowered plasma hemoglobin, oxidant stress and endothelial dysfunction in PE. Treating isolated rings with BAY 41-8543 bypassed endothelial dysfunction with PE or RBC lysate.

Browsing by Subject "animal models"

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