Non-treated Hamsters Research Articles

Radotinib Decreases Prion Propagation and Prolongs Survival Times in Models of Prion Disease.

The conversion of cellular prion protein (PrPC) into pathogenic prion isoforms (PrPSc) and the mutation of PRNP are definite causes of prion diseases. Unfortunately, without exception, prion diseases are untreatable and fatal neurodegenerative disorders; therefore, one area of research focuses on identifying medicines that can delay the progression of these diseases. According to the concept of drug repositioning, we investigated the efficacy of the c-Abl tyrosine kinase inhibitor radotinib, which is a drug that is approved for the treatment of chronic myeloid leukemia, in the treatment of disease progression in prion models, including prion-infected cell models, Tga20 and hamster cerebellar slice culture models, and 263K scrapie-infected hamster models. Radotinib inhibited PrPSc deposition in neuronal ZW13-2 cells that were infected with the 22L or 139A scrapie strains and in cerebellar slice cultures that were infected with the 22L or 263K scrapie strains. Interestingly, hamsters that were intraperitoneally injected with the 263K scrapie strain and intragastrically treated with radotinib (100 mg/kg) exhibited prolonged survival times (159 ± 28.6 days) compared to nontreated hamsters (135 ± 9.9 days) as well as reduced PrPSc deposition and ameliorated pathology. However, intraperitoneal injection of radotinib exerted a smaller effect on the survival rate of the hamsters. Additionally, we found that different concentrations of radotinib (60, 100, and 200 mg/kg) had similar effects on survival time, but this effect was not observed after treatment with a low dose (30 mg/kg) of radotinib. Interestingly, when radotinib was administered 4 or 8 weeks after prion inoculation, the treated hamsters survived longer than the vehicle-treated hamsters. Additionally, a pharmacokinetic assay revealed that radotinib effectively crossed the blood-brain barrier. Based on our findings, we suggest that radotinib is a new candidate anti-prion drug that could possibly be used to treat prion diseases and promote the remission of symptoms.

Effect of Motexafin lutetium-mediated ultrasound-guided red laser photodynamic therapy on endothelial dysfunction using a new automatic ultrasound image processing software

Abstract Background As is well recognized, the majority of atherosclerosis start with an inflammatory process, resulting in endothelial dysfunction. Purpose In this study, we developed an experimental photosensitizer Motexafin lutetium (Lu-Tex)-mediated photodynamic therapy system, and investigated its effectiveness on endothelial dysfunction improvement in an animal model of balloon dilation injury, using a new automatic ultrasound image processing software. Methods Briefly, Golden Syrian hamsters' femoral artery underwent balloon dilatation injury. After four weeks, femoral arteries of the treatment group at the lesion region, treated using Motexafin lutetium - mediated fiber optic catheter-based red low level laser (742 nm, 150 J/cm2) photodynamic therapy. In order to evaluate endothelial-dependent relaxation, acetylcholine-mediated dilation (AMD) was measured during the infusion of acetylcholine at a rate of 0.5 μg/kg/min and endothelial independent relaxation was evaluated by measuring nitroglycerin mediated dilation (NMD) during the infusion of nitroglycerin at a rate of 5μg/kg/min. For off-line analysis, a computerized analysis method for evaluating instantaneous changes in the wall of the hamster femoral artery was used. For automatic measurement of the mean wall thickness and the lumen diameter from longitudinal B-mode ultrasound images, two algorithms, i.e., maximum gradient and dynamic programming were composed and implemented. Reference points and cost function were based on dynamic programming and maximum gradient, respectively. Results Results from computerized B-mode ultrasound image processing software showed significant differences in AMD between the treated and the non-treated hamsters (p<0.05), whereas there were no significant differences in NMD between the treatment and normal groups (p>0.05). Conclusion Cytotoxic and anti-inflammatory effect of Motexafin lutetium, induced by red laser photodynamic therapy accompanied by photobiomodulation effect of red laser, can cause to reduce the immune cells in intimal layer and improve the endothelial dysfunction via increasing the endothelial nitric oxide synthase function. Furthermore, it is concluded that the new automatic method enables accurate and repeated evaluation of the endothelial dysfunction using photodynamic therapy in this model. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab

A novel carbohydrate antigen expression during development of Opisthorchis viverrini- associated cholangiocarcinoma in golden hamster: A potential marker for early diagnosis

Poor prognosis of cholangiocarcinoma (CCA) is primarily due to delayed diagnosis because of the lack of appropriate tumor marker(s) to detect cancer development at an early stage. We have recently established a S121 monoclonal antibody (mAb) which recognizes an unidentified glycan epitope on MUC5AC, designated as CCA-associated carbohydrate antigen (CCA-CA). This antigen is expressed in human CCA cells but not in normal biliary epithelia. Detection of CCA-CA effectively distinguished CCA patients' sera from normal control sera with high specificity and sensitivity. In the present study, we examined a time profile of the expression of CCA-CA by immunohistochemical methods in the liver tissues of Opisthorchis viverrini (Ov)-associated CCA in a hamster model. Hamsters were divided into four groups; non-treated, Ov infected, NDMA (N-nitrosodimethamine) treated and Ov + NDMA treated groups, and animals from each group were euthanized at 1, 3 and 6 months post-treatment. CCA-CA was not detected in normal biliary cells of non-treated hamsters throughout the course of experiment. CCA-CA became detectable in the cytoplasm and apical surface of biliary cells of the NDMA and Ov + NDMA groups at early stage (1 month) of tumor development and increased with tumor progression. In contrast, CCA-CA was detected as nuclear staining at the 1 month post Ov infection and declined thereafter. These results suggest the possibility of CCA-CA as an early marker for CCA.

In vivo method for sister chromatid exchanges in Chinese hamster foetal and bone marrow cells.

An in vivo BrdU labelling method for sister chromatid staining in Chinese hamster foetal and bone marrow cells is reported. The mitotic index in bone marrow cells was many times higher than that in foetal cells (2.7 to 11.3 and 0.1 to 2.1, respectively) whereas both tissues produced metaphases of high quality. Sister chromatid exchanges (SCE) in the foetal cells of 3 non-treated hamsters varied from 5.4 to 7.4, and in the bone marrow cells of 11 non-treated hamsters, from 2.9 to 5.4.

Administration of insulin?like growth factor?1 (IGF?1) improves both structure and function of delta?sarcoglycan deficient cardiac muscle in the hamster

Dilated cardiomyopathies (DCM) are due to progressive dilatation of the cardiac cavities and thinning of the ventricular walls and lead unavoidably to heart failure. They represent a major cause for heart transplantation and, therefore, defining an efficient symptomatic treatment for DCM remains a challenge. We have taken advantage of the hamster strain CHF147 that displays progressive cardiomyopathy leading to heart failure to test whether stimulation of a hypertrophic pathway could delay the process of dilatation.Six month old CHF147 hamsters were treated with IGF-1 so that we could compare the efficacy of systemic administration of human recombinant IGF-1 protein (rh IGF-1) at low dose to that of direct myocardial injections of a plasmid DNA containing IGF-1 cDNA (pCMV-IGF1).IGF-1 treatment did not induce a significant variation of ventricle mass, but preserved left ventricular (LV) wall thickness and delayed dilatation of cardiac cavities when compared to non-treated hamsters. Together with this reduction of dilatation, we also noted a reduction in the amount of interstitial collagen. Furthermore, IGF-1 treatment induced beneficial effects on cardiac function since treated hamsters presented improved cardiac output and stroke volume, decreased end diastolic pressure when compared to nontreated hamsters and also showed a trend towards increased contractility (dP/dt(max)).This study provides evidence that IGF-1 treatment induces beneficial structural and functional effects on DCM of CHF147 hamsters, hence making this molecule a promising candidate for future gene therapy of heart failure due to DCM.

Simvastatin enhances the regeneration of endothelial cells via VEGF secretion in injured arteries.

The search for a novel therapy for endothelial regenerating is an area of intensive investigation. Recent experimental and clinical evidence strongly suggests that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have several physiological effects independent of low-density lipoprotein cholesterol reduction. We here report that the carotid arterial blood flow after endothelial injury in hamsters treated with simvastatin was restored, in contrast to the situation in nontreated hamsters. Histologic observations showed a prompt recovery of endothelial cells with a much higher DNA synthesis index in repaired endothelium of hamsters treated with simvastatin. The amount of secreted vascular endothelial cell growth factor (VEGF) by cultured vascular smooth muscle cells from hamsters treated with simvastatin was significantly increased. Mevalonate reduced the amount of VEGF secretion by simvastatin in vitro. Finally, an injection of either an anti-VEGF antibody or an anti-VEGF receptor-1 (Flt-1) antibody, but not anti-VEGF receptor-2 (Flk-1), reduced the prompt endothelial healing. Simvastatin regulates endothelial regenerating by an over-release of VEGF and by this may result in prompt endothelial healing after vascular injury. Our results provide new insights into the role of statin and VEGF in the pathogenesis of vascular diseases.

Liver function tests during amoebic liver abscess formation in indomethacin-treated hamsters.

Establishment of Entamoeba histolytica infection is facilitated through macrophage effector disruption by a prostaglandin E2 (PGE2)-mediated mechanism. Infection severity may be measured by weight of abscess formed. Indomethacin (Indo) treatment of infected hamsters reduced abscess weight by 30% at 7 days post-infection presumably by inhibition of PGE2. To explain reductions in abscess development by Indo treatment, we determined liver functionality in Indo-treated or untreated animals, either healthy or infected. Determinations of serum glutamic oxaloacetic (SGOT) and glutamic pyruvic (SGPT) transaminases, serum alkaline phosphatase (SAP), total serum protein (TSP), and bilirubinemia were done. SGOT, SGPT, and SAP activities showed a significant increase in their values by 600% at seven days post-infection in infected animals in both conditions; nonstatistical differences were found between animals treated or not. This increase did not correlate with the percentage of damage. Infected nontreated hamsters showed TSP levels 30% below normal group (P < 0.05). Infected Indo-treated hamsters had no significant differences compared to normal values. Infected nontreated animals showed an increase in bilirubin, particularly in indirect bilirubin, whereas infected Indo-treated hamsters showed total bilirubin values lower than normals (P < 0.05), with a decrease in direct bilirubin levels. Our results demonstrated that E. histolytica infection in hamsters produces similar abnormalities in liver function as it does in humans, and that the beneficial effect of Indo treatment on amoebic abscess development is not related with an improvement of liver functionality.

Retinal ganglion cells expressing the FOS protein after light stimulation in the Syrian hamster are relatively insensitive to neonatal treatment with monosodium glutamate

In nocturnal rodents, the c-fos gene is directly involved in the light mechanism of resetting of the suprachiasmatic nucleus (circadian clock). Light also induces c-fos expression in the retinal ganglion cell layer (GCL), but no attempt has been made to study the retinal responses to the phase-shifting effects of light. The expression of the Fos protein in each of the two populations of the GCL (displaced amacrine cells [DACs] and ganglion cells [GCs]) was analyzed in hamsters after light stimulation delivered early (circadian time [CT13]) and in the middle (CT18) of the subjective night. To evaluate as accurately as possible the number of GCs able to phase shift the locomotor activity rhythm (LAR), neonatal hamsters treated with monosodium glutamate (MSG) were also used, an in vivo model which displays retinal degeneration and LAR normally entrained by light. In nontreated hamsters, the number of Fos-immunoreactive (Fos-ir+) nuclei in the GCL was significantly higher at CT18 than at CT13. In MSG-treated hamsters, the number of Fos-ir+ nuclei was the same at both CTs and nonsignificantly different as those of nontreated hamsters at CT13. MSG treatment destroyed as many Fos-ir+ DACs as Fos-ir- DACs or Fos-ir+ GCs. Fos-ir+ GCs were less sensitive to neurotoxic than other GCs, as only 37% of them were destroyed by treatment versus 92% for Fos-ir- GCs. At CT18, a maximum of 3,500 GCs expressed Fos protein in nontreated hamsters versus only 2,200 in MSG-treated hamsters. This minor subgroup was sufficiently potent to normally synchronize the circadian rhythms to the Light/dark cycle in treated hamsters. J. Comp. Neurol. 392:458–467, 1998. © 1998 Wiley-Liss, Inc.

Retinal ganglion cells expressing the FOS protein after light stimulation in the Syrian hamster are relatively insensitive to neonatal treatment with monosodium glutamate

In nocturnal rodents, the c-fos gene is directly involved in the light mechanism of resetting of the suprachiasmatic nucleus (circadian clock). Light also induces c-fos expression in the retinal ganglion cell layer (GCL), but no attempt has been made to study the retinal responses to the phase-shifting effects of light. The expression of the Fos protein in each of the two populations of the GCL (displaced amacrine cells [DACs] and ganglion cells [GCs]) was analyzed in hamsters after light stimulation delivered early (circadian time [CT13]) and in the middle (CT18) of the subjective night. To evaluate as accurately as possible the number of GCs able to phase shift the locomotor activity rhythm (LAR), neonatal hamsters treated with monosodium glutamate (MSG) were also used, an in vivo model which displays retinal degeneration and LAR normally entrained by light. In nontreated hamsters, the number of Fos-immunoreactive (Fos-ir+) nuclei in the GCL was significantly higher at CT18 than at CT13. In MSG-treated hamsters, the number of Fos-ir+ nuclei was the same at both CTs and nonsignificantly different as those of nontreated hamsters at CT13. MSG treatment destroyed as many Fos-ir+ DACs as Fos-ir- DACs or Fos-ir+ GCs. Fos-ir+ GCs were less sensitive to neurotoxic than other GCs, as only 37% of them were destroyed by treatment versus 92% for Fos-ir- GCs. At CT18, a maximum of 3,500 GCs expressed Fos protein in nontreated hamsters versus only 2,200 in MSG-treated hamsters. This minor subgroup was sufficiently potent to normally synchronize the circadian rhythms to the Light/dark cycle in treated hamsters.

GR144053, a fibrinogen receptor antagonist, enhances the suppression of neointima formation by losartan, an angiotensin II receptor antagonist, in the injured carotid artery of hamster.

1. The present study investigated the inhibitory effect of losartan, a type 1 angiotensin II (AT1) antagonist, and of combined treatment with losartan and GR144053, a fibrinogen receptor (GPIIb/IIIa) antagonist, on neointima formation subsequent to vascular injury in the hamster carotid artery. Vascular injury was achieved by a roughened-tip 2F catheter and the neointimal area was measured up to 2 weeks inducing the injury. 2. Compared to non-treated hamsters (intimal area (IA/internal elastic laminal area (IELA) ratio = 60.3 +/- 5.9%, n = 12), losartan dissolved in drinking water (1, 3 and 10 mg kg-1 per day, n = 8 each) reduced neointimal area dose-dependently, a significant decrease (IA/IELA = 39.7 +/- 5.6%) being attained with the highest dose when it was administered from 1 day before injury. However, neointima formation was not prevented even with the highest dose of losartan when the administration was started after injury. 3. When the administration of GR144053 (1.0 mg kg-1 per hour) via an implanted osmotic pump was started 30 min before the injury and continued for the next 2 weeks, no suppression of neointima formation was observed, although platelet aggregation evoked ex vivo by adenosine diphosphate (ADP) at the end of treatment period was efficiently inhibited. 4. In separate experiments in which 5-bromo-2-deoxy-Uridine (BrdU) was used to test smooth muscle cell (SMC) proliferation 1 and 7 days after injury, the ratio of SMC proliferation in the injured area was only slightly decreased by losartan when its administration was started after the injury, despite the marked reduction of SMC proliferation when treatment was started before the injury. Treatment with GR144053 as indicated above also significantly decreased the SMC proliferating index 1 day after the injury. 5. To examine the potential benefit of the coadministration of the GPIIb/IIIa antagonist with the AT1 receptor antagonist, GR144053 (1.0 mg kg-1 per hour) was combined with post-injury treatment with losartan (10 mg kg-1 per day). This markedly reduced the proliferation of SMCs and significantly decreased the neointimal area (IA/IELA = 31.2 +/- 4.6%) measured 2 weeks following the catheterization. 6. According to the results of a time-dependent study in which GR144053 was given in combination with post injury treatment with losartan for 1, 3, 7 or 14 days, neointima formation could be reduced by treatment with GR144053 for just 7 days. 7. In conclusion, GR144053, a fibrinogen receptor antagonist, enhanced the inhibitory effect of losartan, an AT1 receptor antagonist, on neointima formation in the damaged carotid artery of hamsters.

Prolongation of the Life Span of Cardiomyopath : Hamster by the Adrenergic β1-Selective Partial Agonist Denopamine

Influence of cardiotonic agents on the prognosis of heart failure depends on the individual therapeutic agents, and favorable and unfavorable effects of these agents have been reported in clinical trials. We studied the effect of the cardiotonic agent denopamine on the life span of cardiomyopathic hamsters (BIO 14.6 strain) in the heart failure period. Non-treated hamsters started to die at 40 weeks of age, and their survival rate decreased to 23.8% at the age of 65 weeks. Hamsters treated with denopamine (400 ppm in diet) from 36 weeks of age did not die until the age of 52 weeks, except in cases of accidental death. The survival rate of this group at 65 weeks of age was about 40%. Survival rates of these 2 groups were significantly different (P<0.05) when animals with accidental death were excluded. To elucidate the mechanism of the effect of dt.iopamine, we performed several experiments after dietary treatment with denopamine for 4 to 6 weeks from 37 weeks of age. Denopamine treatment lowered plasma levels of noradrenaline and dopamine (P<0.05), but affected neither the cardiac contractility nor the β-adrenoceptor density. In summary, denopamine significantly decreases the mortality of cardiomyopathic hamsters. Its effect to lower the plasma catecholamine levels may be responsible for the beneficial effect of denopamine.

Experimental lethal infection of Leptospira interrogans in mice treated with cyclophosphamide

After preadministration of cyclophosphamide (300 mg/kg), BALB/c mice were lethally infected with Leptospira interrogans serovar lai and a virulent strain of Leptospira interrogans serovar copenhageni, and leptospiral cells were detected in both kidneys of infected mice by indirect immunofluorescent assay. Nonpathogenic leptospirae, Leptospira biflexa serovar patoc, Leptonema illini, and an avirulent strain of L. interrogans serovar copenhageni, were not parasitic to the mice treated with cyclophosphamide. The cyclophosphamide-treated mice were protected from the homologous leptospiral infection by passive immunization with anti-leptospiral monoclonal antibody or with rabbit antiserum and by active immunization with lyophilized organisms or with protective antigen. The results of active immunization in mice treated with cyclophosphamide agreed well with those in nontreated hamsters, which were sensitive to the organisms. Furthermore, these experiments were reproducible with any lot of cyclophosphamide used. These results indicated that cyclophosphamide-treated mice can be used in the experimental infection of Leptospira in place of hamsters or guinea pigs.

Survival, strobilation and sexual maturation of Echinococcus multilocularis in the small intestine of golden hamsters

Echinococcus multilocularis survived, strobilated and matured sexually in the small intestine of 6-week-old male golden hamsters that were either non-treated or treated with prednisolone tertiary-butylacetate (PTBA), following oral administration of 20 000 protoscoleces. Non-treated hamsters harboured the adult worms for up to 25 days post-infection (p.i.). Hamsters treated with PTBA from the day of infection (day 0 p.i.) harboured more adults than the non-treated, and their survival periods were extended. Moreover, a remarkable improvement in worm recovery, development and survival periods was observed in hamsters additionally treated with PTBA on days -- 14 and -- 12 p.i., and the worm development including proglottisation, sexual maturation and egg formation was comparable with that in dogs. With the present results it is suggested that Echinococcus/rodent systems represented by the E. multilocularis/golden hamsters may rejuvenate the current stagnant research on host-parasite interactions of the definitive host-stage and egg-stage of Echinococcus.

Behavior of Leishmania braziliensis s.l. in Golden Hamsters: Evolution of the Infection under Different Experimental Conditions

Reproducibility of Leishmania braziliensis s.l. metastatic behavior in hamsters was studied for 9 isolates of L.b. panamensis and 2 of L.b. guyanensis with a previous record of metastasis. Also, the influence of corticosteroids and trauma was evaluated. In the corticosteroid-treated group, metastases appeared earlier than in the nontreated group, and localization at the site of trauma was more frequent (4/9) than in the nontreated hamsters (1/5). Nine of the 11 strains (82%) were capable of reproducing metastatic behavior. Studies on dissemination of L. b. panamensis showed that the regional lymph node is invaded as soon as 5 days postinfection, with further nonhematic dissemination to other tissues and organs in less than 4 wk.

2,2,2-Trifluoroethanol toxicity in hamsters (Mesocricetus auratus).

As part of an effort to further elucidate the mechanism whereby fluorinated ether anesthetics express their various toxic effects, Golden Syrian hamsters were utilized to determine acute and subchronic toxicities of the anesthetic metabolite 2,2,2-trifluoroethanol (TFE). The major lesion observed with the TFE (0.25 g/kg ip) was coagulation necrosis characterized by nuclear pyknosis in epithelial cells of intestinal villi, the deeper portion of gastric mucosae, lymphoid organs such as thymus, spleen and mesenteric lymph nodules and brain. Hepatocyte hypertrophy with diffuse vacuolar degeneration was also found. Lungs had a characteristic focal terminal bronchiolar epithelial hyperplasia with discrete mucous metaplasia in the terminal bronchioles. In subchronic studies, hamsters were injected with sublethal doses of TFE (0.20 g/kg once per week for 5 weeks). The major lesions observed were severe hepatocyte hyperplasia and hypertrophy with fatty degeneration, necrosis of hair germinal matrix, urinary bladder transitional epithelial cellular hypertrophy, and hyperplasia with vacuolar degeneration and submucosal edema. Ultrastructural studies of acutely treated animals indicate that fat vacuoles formed within the hepatic endoplasmic reticulum characterized by lamellar bodies forming multiple myelin figures within the fat vacuoles. Hepatic cytochrome P-450 concentrations measured as a possible index of endoplasmic reticulum damage, failed to reveal any significant differences between the treated and non-treated hamsters.

Enhancement of amyloidosis by chenodeoxycholic acid ingestion in the hamster.

A long-term experiment was performed to test the ability of chenodeoxycholic acid (CDCA) to induce intestinal tumors in the Syrian golden hamster. Animals were fed a CDCA-enriched diet up to 12 months, and 4 of them were sacrificed every 2 months. CDCA exhibited no carcinogenic activity. However, unexpected amyloid deposits were discovered in both treated and nontreated animals. Their incidence was significantly higher in treated (71%) than in nontreated (27%) hamsters. During CDCA administration, amyloidosis appeared as early as the second month of treatment. It involved the liver, spleen and kidneys in more than half of the animals. On the contrary, in control animals, amyloid deposits appeared later and were most frequently restricted to one organ. The intensity of the lesions also appeared to be greater in the treated group. No monoclonal components were found in either serum or urine of the amyloidotic hamsters. Such an amyloidosis-promoting effect of CDCA has never been reported.

Effect of pre-pubertal gonadectomy and treatment with sex hormones on body growth, weight of organs and skin collagen of hamsters.

ABSTRACT Gonadectomy was performed in young hamsters of both sexes at the age of 21 days, immediately after weaning. Animals were then treated for 14 weeks with testosterone propionate or oestrone. Intact controls and gonadectomized non-treated hamsters were also studied. Ponderal and linear growth was determined by weekly measurements. At the end of the experiment the weight of some organs was determined. Skin was studied for collagen content by the determination of total and saline-soluble hydroxyproline. Previously reported effects of sex hormones and gonadectomy on the growth of hamsters and on adrenals were confirmed. Females grew larger than males of the same age and after gonadectomy the growth of males of the same age was accelerated. Another sexual dimorphism reversed in hamsters in comparison with other rodents was adrenal weight: males had heavier adrenals than females. These differences were considered to be due to the action of androgens. Skin hydroxyproline was significantly higher in hamsters of both sexes treated with testosterone propionate than in intact, castrated and/or in oestrone-treated animals. The stimulatory action of male hormone on both total and soluble hydroxyproline was considered due to the anabolic effect of testosterone propionate on both synthesis and metabolism of skin collagen in hamsters.

Poliomyelitis infection in cortisone-treated hamsters induced by the intraperitoneal route.

SummaryIt was possible to produce a violent and uniformly fatal poliomyelitis infection in the hamster by the intraperitoneal route following treatment with cortisone. The disease was accompanied by a pronounced viremia apparently due to the multiplication of the virus outside of the central nervous system under these conditions. No clinical infection was observed in non-treated hamsters thus inoculated. No disease was produced following the intraperitoneal inoculation of the virus in the hamsters receiving ACTH.