Spontaneous Partial Recovery of Striatal Dopaminergic Uptake Despite Nigral Cell Loss in Asymptomatic MPTP-Lesioned Minipigs

2021 ◽  
Author(s):  
Anne M. Landau ◽  
Thea P. Lillethorup ◽  
Ove Noer ◽  
Aage Kristian Olsen Alstrup ◽  
Kathrine Stokholm ◽  
...  
Keyword(s):  
Animal Model ◽  
Spontaneous Recovery ◽  
Ethical Issues ◽  
Cell Loss ◽  
Large Animal Model ◽  
Large Animal ◽  
Partial Recovery ◽  
Behavioral Deficits ◽  
Large Animal Models ◽  
Human Primate

Abstract The gold standard animal model of Parkinson’s disease is the non-human primate rendered parkinsonian with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin. Low availability, ethical issues, and primate-specific biohazards make alternative large animal models necessary. Here, we investigate the temporal evolution of presynaptic dopaminergic function after MPTP in another large animal model, the Göttingen minipig. We subcutaneously injected seven sedated minipigs with 1–2 mg/kg of MPTP, and two minipigs with saline, three times a week over 4 weeks. We monitored behavioral deficits using a validated motor scale and a Gait4Dog® walking mat. Minipig brains were imaged with (+)-⍺-[11C]-dihydrotetrabenazine ([11C]-DTBZ) and [18F]-fluorodopa ([18F]-FDOPA) PET at baseline and 1, 3, 9 and 12 months after the final MPTP injection. Immunohistochemical tyrosine hydroxylase (TH) staining was used to assay nigral TH + area loss post-mortem. The minipigs showed only mild bradykinesia and impaired coordination at early timepoints after MPTP. PET revealed decreases of striatal [11C]-DTBZ and [18F]-FDOPA uptake post-MPTP with a partial spontaneous recovery of [18F]-FDOPA after 9 months. Postmortem histological analysis showed a loss of 71% TH-immunopositive area in the substantia nigra. When testing the efficacy of putative neuroprotective agents, partial spontaneous recovery of dopamine terminal function must be taken into account in the MPTP minipig model of parkinsonism.

Method used to establish a large animal model of drug-induced acute kidney injury

2021 ◽  
pp. 153537022098175
Author(s):  
Si-Yang Wang ◽  
Chao-Yang Zhang ◽  
Guang-Yan Cai ◽  
Xiang-Mei Chen
Keyword(s):  
Acute Kidney Injury ◽  
Animal Model ◽  
Health Hazard ◽  
Kidney Injury ◽  
Basic Research ◽  
Large Animal Model ◽  
Large Animal ◽  
Drug Induced ◽  
Large Animal Models ◽  
New Treatments

Acute kidney injury is a serious health hazard disease due to its complex etiology and lack of effective treatments, resulting in high medical costs and high mortality. At present, a large number of basic research studies on acute kidney injury have been carried out. However, acute kidney injury models established in rodents sometimes do not simulate the course of human disease well. Research in large animal models of acute kidney injury is relatively rare, and methods to build a mature model of acute kidney injury have failed. Because its kidney anatomy and morphology are very similar to those in humans, the mini pig is an ideal animal in which to model kidney disease. Nephrotoxic drug-induced acute kidney injury has a high incidence. In this study, we established models of acute kidney injury induced by two drugs (gentamicin and cisplatin). Finally, the model of cisplatin-induced acute kidney injury was developed successfully, but we found the model of gentamycin-induced acute kidney injury was not reproducible. Compared to other models, these models better represent acute kidney injury caused by antibiotics and chemotherapeutic drugs and provide a basis for the study of new treatments for acute kidney injury in a large animal model.

scholarly journals Safety and Tolerability of the Adeno-Associated Virus Vector, AAV6.2FF, Expressing a Monoclonal Antibody in Murine and Ovine Animal Models

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1186
Author(s):  
Amira D. Rghei ◽  
Laura P. van Lieshout ◽  
Benjamin M. McLeod ◽  
Yanlong Pei ◽  
Jordyn A. Lopes ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Animal Model ◽  
Animal Models ◽  
Human Monoclonal Antibody ◽  
Scale Up ◽  
Large Animal Model ◽  
Large Animal ◽  
Aav Vector ◽  
Adeno Associated Virus ◽  
Large Animal Models

Adeno-associated virus (AAV) vector mediated expression of therapeutic monoclonal antibodies is an alternative strategy to traditional vaccination to generate immunity in immunosuppressed or immunosenescent individuals. In this study, we vectorized a human monoclonal antibody (31C2) directed against the spike protein of SARS-CoV-2 and determined the safety profile of this AAV vector in mice and sheep as a large animal model. In both studies, plasma biochemical parameters and hematology were comparable to untreated controls. Except for mild myositis at the site of injection, none of the major organs revealed any signs of toxicity. AAV-mediated human IgG expression increased steadily throughout the 28-day study in sheep, resulting in peak concentrations of 21.4–46.7 µg/ mL, demonstrating practical scale up from rodent to large animal models. This alternative approach to immunity is worth further exploration after this demonstration of safety, tolerability, and scalability in a large animal model.

DEVELOPMENT OF A LARGE ANIMAL MODEL OF OPIATE ADDICTION TO EVALUATE CARDIOVASCULAR FUNCTION.

Analgesia ◽  
1995 ◽  
Vol 1 (4) ◽  
pp. 598-602 ◽  
Author(s):  
L.D. Napier ◽  
Z. Mateo ◽  
D.A. Yoshishige ◽  
B.A. Barron ◽  
J.L. Caffrey
Keyword(s):  
Animal Model ◽  
Cardiovascular Function ◽  
Large Animal Model ◽  
Opiate Addiction ◽  
Large Animal

scholarly journals A novel large animal model of smoke inhalation-induced acute respiratory distress syndrome

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Premila D. Leiphrakpam ◽  
Hannah R. Weber ◽  
Andrea McCain ◽  
Roser Romaguera Matas ◽  
Ernesto Martinez Duarte ◽  
...  
Keyword(s):  
Animal Model ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Distress Syndrome ◽  
Inhalation Injury ◽  
Smoke Inhalation ◽  
Large Animal Model ◽  
Large Animal ◽  
X Ray ◽  
Chest X Ray

Abstract Background Acute respiratory distress syndrome (ARDS) is multifactorial and can result from sepsis, trauma, or pneumonia, amongst other primary pathologies. It is one of the major causes of death in critically ill patients with a reported mortality rate up to 45%. The present study focuses on the development of a large animal model of smoke inhalation-induced ARDS in an effort to provide the scientific community with a reliable, reproducible large animal model of isolated toxic inhalation injury-induced ARDS. Methods Animals (n = 21) were exposed to smoke under general anesthesia for 1 to 2 h (median smoke exposure = 0.5 to 1 L of oak wood smoke) after the ultrasound-guided placement of carotid, pulmonary, and femoral artery catheters. Peripheral oxygen saturation (SpO2), vital signs, and ventilator parameters were monitored throughout the procedure. Chest x-ray, carotid, femoral and pulmonary artery blood samples were collected before, during, and after smoke exposure. Animals were euthanized and lung tissue collected for analysis 48 h after smoke inhalation. Results Animals developed ARDS 48 h after smoke inhalation as reflected by a decrease in SpO2 by approximately 31%, PaO2/FiO2 ratio by approximately 208 (50%), and development of bilateral, diffuse infiltrates on chest x-ray. Study animals also demonstrated a significant increase in IL-6 level, lung tissue injury score and wet/dry ratio, as well as changes in other arterial blood gas (ABG) parameters. Conclusions This study reports, for the first time, a novel large animal model of isolated smoke inhalation-induced ARDS without confounding variables such as cutaneous burn injury. Use of this unique model may be of benefit in studying the pathophysiology of inhalation injury or for development of novel therapeutics.

scholarly journals Impella RP versus pharmacologic vasoactive treatment in profound cardiogenic shock due to right ventricular failure: Unloading and end-organ perfusion in a large animal model

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
J Josiassen ◽  
OKL Helgestad ◽  
NLJ Udesen ◽  
A Banke ◽  
PH Frederiksen ◽  
...  
Keyword(s):  
Animal Model ◽  
Cardiogenic Shock ◽  
Oxygen Saturation ◽  
Treatment Strategies ◽  
Large Animal Model ◽  
Similar Degree ◽  
Large Animal ◽  
Organ Perfusion ◽  
Venous Oxygen Saturation ◽  
Cerebral Venous Oxygen Saturation

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation Unrestricted research grant from Abiomed Background No strong evidence exists regarding the treatment of cardiogenic shock (CS) caused by acute right ventricular (RV) failure which has mainly consisted of vasoactive drugs. There is expert agreement that treatment with the recently developed Impella RP is feasible, but no previous studies have compared vasoactive treatment strategies with the Impella RP in terms of cardiac unloading and end-organ perfusion. Hypothesis Treatment with the Impella RP device will be associated with lower RV myocardial workload (pressure-volume area) compared to vasoactive treatment strategies and can furthermore be achieved without compromising organ perfusion. Methods CS was induced by a stepwise injection of polyvinyl alcohol microspheres into the right coronary artery in twenty adult female Danish landrace pigs weighing 75-80 kg. After induction of CS, the pigs were allocated to one of the two interventions for 180 minutes: 1) vasoactive therapy comprised a continuous infusion of norepinephrine (0.1 µg/kg/min) for the first 30 minutes, supplemented by an infusion of milrinone (0.4 µg/kg/min) for the remaining 150 minutes or 2) immediate insertion of and treatment with the Impella RP.  The results are presented as median [Q1;Q3]. Results Treatment with the Impella RP was associated with a lower RV workload compared to the vasoactive group, while no difference was observed with regards to left ventricular workload among intervention groups, Figure 1. Renal venous oxygen saturation increased to a similar degree following both interventions compared to the state of CS. A trend towards a higher cerebral venous oxygen saturation was observed with norepinephrine compared to Impella RP (Impella RP 51 [47;61] % vs Norepinephrine 62 [57;71] % ; p = 0.07), which became significantly higher with the addition of milrinone (Impella RP 45 [32;63] % vs Norepinephrine +Milrinone 73 [66;81] %; p = 0.002). Conclusion In this large animal model of profound CS caused by predominantly RV failure the Impella RP unloaded the failing RV. The vasoactive treatment, however, caused a higher cerebral venous oxygen saturation, while both interventions increased renal venous oxygen saturation to a similar degree. Abstract Figure 1

DEMONSTRATION OF THE EFFICIENCY OF A BIOARTIFICIAL LIVER IN A POTENTIALLY REVERSIBLE LARGE ANIMAL MODEL OF ACUTE LIVER FAILURE.

2000 ◽  
Vol 69 (Supplement) ◽  
pp. S405
Author(s):  
I. Fourneau ◽  
S. H. Yap ◽  
T. Roskams ◽  
L. Flendrig ◽  
R. Chamuleau ◽  
...  
Keyword(s):  
Animal Model ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Bioartificial Liver ◽  
Large Animal Model ◽  
Large Animal
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