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At least 361 records · Page 20Linked to original sources
PubMed2004

Central dexmedetomidine attenuates cardiac dysfunction in a rodent model of intracranial hypertension.

PURPOSE: To determine if central sympathetic blockade by dexmedetomidine, a selective alpha(2) adrenergic receptor agonist, prevents cardiac dysfunction associated with intracranial hypertension (ICH) in a rat model. METHODS: Following intracisternal administration of dexmedetomidine (1 microg.microL(-1), 10 microL volume) or the stereoisomer levomedetomidine (1 microg.microL(-l), 10 microL volume) in halothane-anesthetized rats, a subdural balloon catheter was inflated for 60 sec to produce ICH. Intracranial pressure, hemodynamic, left ventricular (LV) pressures and electrocardiographic (ECG) changes were recorded. Plasma and myocardial catecholamines and malondialdehyde (MDA) levels were measured. RESULTS: After levomedetomidine administration, subdural balloon inflation precipitated an increase in mean arterial pressure (149 +/- 33% of baseline), heart rate (122 +/- 19% of baseline), LV systolic pressure (LVP), LV end-diastolic pressure (LVEDP), LV developed pressure (LVDP), LV dP/dtmax and rate pressure product (RPP) (132 +/- 19%, 260 +/- 142%, 119 +/- 15%, 126 +/- 24% and 146 +/- 33% of baseline value, respectively). ICH decelerated LVP fall (tau), as tau increased from 7.75 +/- 1.1 to 14.37 +/- 4.5 msec. Moreover, plasma norepinephrine levels were elevated (169 +/- 50% of baseline) and there was the appearance of cardiac dysrhythmias and other ECG abnormalities. This response was transient and cardiac function deteriorated in a temporal manner. Intracisternal dexmedetomidine prevented the rise in plasma norepinephrine, blocked the ECG abnormalities, and preserved cardiac function. Moreover, dexmedetomidine attenuated the rise in MDA levels. CONCLUSIONS: The results demonstrate that dexmedetomidine attenuates cardiac dysfunction associated with ICH. Our results provide evidence for the role of central sympathetic hyperactivity in the development of cardiac dysfunction associated with ICH.

Adrenergic alpha-Agonists↗
PubMed2006

Ethanol impairs Rho GTPase signaling and differentiation of cerebellar granule neurons in a rodent model of fetal alcohol syndrome.

Developmental exposure to ethanol impairs fetal brain development and causes fetal alcohol syndrome. Although the cerebellum is one of the most alcohol-sensitive brain areas, signaling mechanisms underlying the deleterious effects of ethanol on developing cerebellar granule neurons (CGNs) are largely unknown. Here we describe the effects of in vivo ethanol exposure on neurite formation in CGNs and on the activation of Rho GTPases (RhoA and Rac1), regulators of neurite formation. Exposure of 7-day-old rat pups to ethanol for 3 h moderately increased blood alcohol concentration (BAC) ( approximately 40 mM) and inhibited neurite formation and Rac1 activation in CGNs. Longer exposure to ethanol for 5 h resulted in higher BAC ( approximately 80 mM), induced apoptosis, inhibited Rac1, and activated RhoA. Studies demonstrated a regulatory role of Rho GTPases in differentiation of cerebellar neurons, and indicated that ethanol-associated impairment of Rho GTPase signaling might contribute to brain defects observed in fetal alcohol syndrome.

Animals↗
PubMed2002

A multi-centre, blinded international trial of the effect of A(1) and A(2) beta-casein variants on diabetes incidence in two rodent models of spontaneous Type I diabetes.

AIMS/HYPOTHESIS: The diabetes-inducing potential of cows' milk is still debated and there is no consensus on the diabetogenicity of individual milk proteins. A(1)-beta-casein has been associated with increased diabetes frequency in ecological studies and in NOD mice. Our aim was to ascertain whether A(1)-beta-casein was more diabetogenic than A(2) and to test the diabetogenicity of a milk-free diet in animals representing different forms of spontaneous Type I (insulin-dependent) diabetes mellitus. METHODS: Defined diets were coded and shipped to laboratories in New Zealand (NOD/NZ), Canada (BB) and the UK (NOD/Ba). Base diets were Pregestimil (PG) and ProSobee (PS). Purified fractions of whole casein (WC), A(1)or A(2)-beta-casein were added at 10%. A milk-free, wheat-predominant, NTP-2000 diet was the control. Animals were fed from weaning up to 150 or 250 days, and insulitis, diabetes frequency and expression of pancreatic cytokines were assessed. RESULTS: Diabetes incidence was highest in three locations in animals fed NTP-2000. PG and PS diets were protective except for NOD/Ba mice fed PG+WC where incidence was similar to NTP-2000. A(1) and A(2) diets were protective in both models, but A(1) beta-casein was slightly more diabetogenic in PS-fed BB rats. The New Zealand study was confounded by an infection. CONCLUSION/INTERPRETATION: A milk-free, wheat-predominant diet was highly diabetogenic in three widely separate locations in both animal models. A previous result that A(1) beta-casein was more diabetogenic than A(2) beta-casein in NOD mice was not confirmed; both beta-casein variants were protective in BB rats and NOD mice. Whole Casein promoted diabetes in NOD/Ba but protected BB showing that unique diabetes haplotypes react differently to dietary proteins. A(1)- was more diabetogenic than A(2)-beta-casein only in PS-fed BB rats. Neither the analysis of insulitis nor of pancreatic cytokine gene expression showed a difference between A(1) or A(2) beta-casein fed animals. Milk caseins are unlikely to be exclusive promoters of Type I diabetes, but could enhance the outcome of diabetes in some cases. Other diet components such as wheat could be more important promoters of Type I diabetes.

Animals↗
PubMed2004

Effects of thoracic epidural anaesthesia on intestinal microvascular perfusion in a rodent model of normotensive endotoxaemia.

OBJECTIVE: To investigate whether sympathetic blockade by means of thoracic epidural anaesthesia (TEA) increases intestinal perfusion during normotensive endotoxaemia. DESIGN: A prospective, randomised and controlled animal study. SETTING: Animal laboratory in a university hospital. SUBJECTS: Sprague-Dawley male rats. INTERVENTIONS: The rats were anaesthetised with urethane and ketamine, mechanically ventilated and haemodynamically monitored. Lidocaine or saline were infused continuously via thoracic epidural catheters followed by a continuous intravenous infusion of Escherichia coli lipopolysaccharide (1.5 mg/kg per h). Densities of perfused and non-perfused capillaries (i.e., with and without erythrocyte perfusion, respectively) as well as erythrocyte velocity in both the mucosa and the muscularis of the terminal ileum were determined using intravital microscopy. MEASUREMENTS AND RESULTS: Measurements were performed at baseline, after 30 min of epidural infusion as well as after 60 and 120 min of lipopolysaccharide infusion. In animals receiving TEA, mean arterial pressure and heart rate were significantly reduced throughout the experiment. In the muscularis the endotoxaemia-induced increase in non-perfused capillaries was absent with epidural lidocaine (0 [0/0] versus 39 [36/137] cm(-1), median [25(th)/75(th) percentile]), whereas in the mucosa perfused capillary density declined to a greater extent than in controls (-47 [-53/-23]%) versus -19 [-34/+10]%, p<0.05). Erythrocyte velocity decreased with endotoxaemia and was not influenced by epidural lidocaine. CONCLUSIONS: Microvascular perfusion data during endotoxaemia show a redistribution of blood flow towards the mucosa. TEA seems to impede this redistribution resulting in improved muscularis and worsened mucosal microvascular perfusion.

Anesthesia, Epidural↗
PubMed1999

Tetramethylpyradizine prevents inducible NO synthase expression and improves survival in rodent models of endotoxic shock.

This study is to investigate the possible mechanism of beneficial effects of tetramethylpyrazine (TMP) on endotoxic shock which we showed in our preliminary study (Liao et al. 1998; Proc Natl Sci Counc Repub China B 22:46-54). Here, we have confirmed the beneficial effects of TMP on the hypotension, vascular hyporeactivity to noradrenaline (NA), release of tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide, LPS). In addition, we further examined the expression of inducible NO synthase in the lung and in the aorta from these rats and evaluated the effect of TMP on the 36-h survival rate in a murine model of endotoxaemia. Male Wistar-Kyoto rats were anaesthetised and instrumented for the measurement of mean arterial pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg(-1), i.v.) resulted in an acute fall followed by a substantial fall in MAP within 4 h and an increase in HR. In contrast, animals pretreated with TMP (10 mg kg(-1), i.p.; at 30 min prior to LPS) maintained a significantly higher MAP but the tachycardia was further enhanced at 1-2 h when compared to rats given only LPS (LPS rats). The pressor effect of NA (1 microg kg(-1), i.v.) was also significantly reduced after the treatment of rats with LPS. Similarly, the thoracic aorta obtained from rats at 4 h after LPS showed a significant reduction in the contractile responses elicited by NA (1 microM). Pretreatment of LPS rats with TMP partially, but significantly, prevented this LPS-induced hyporeactivity to NA in vivo and ex vivo. The injection of LPS resulted in a bell-shaped change in plasma TNF-alpha level which reached a maximum at 1 h, whereas the effect of LPS on the plasma level of nitrate (an indicator of NO formation) was increased in a time-dependent manner. This increment of both TNF-alpha and nitrate levels was significantly reduced in LPS rats pretreated with TMP. Endotoxaemia for 4 h caused a significantly increased protein expression of iNOS in the lung and the aorta. In LPS rats pretreated with TMP, iNOS protein expression in lung and aorta homogenates was attenuated by 75+/-3% and 57+/-6%, respectively. In addition, the lack of evidence of pressor effect of TMP on rats with endotoxaemia for 4 h suggested that TMP inhibits the induction of iNOS rather than directly inhibiting NOS activity. Treatment of conscious ICR mice with a high dose of endotoxin (60 mg kg(-1), i.p.) resulted in a survival rate of only 15% at 36 h (n=20). However, therapeutic application of TMP (10 mg kg(-1), i.p.; at 0, 6, 15 and 24 h after LPS) increased the 36 h survival rate to 55% (n=20). Thus, TMP inhibits the expression of iNOS and mitigates the delayed circulatory failure caused by endotoxic shock in the rat. In addition, TMP also improves survival in a murine model of severe endotoxaemia.

Animals↗
PubMed1998

Chronic haloperidol produces a time- and dose-related slowing of lick rhythm in rats: implications for rodent models of tardive dyskinesia and neuroleptic-induced parkinsonism.

In order to characterize the development of orolingual motor effects of chronic haloperidol treatment in rats, this typical neuroleptic was administered for 102 days while daily measurements of tongue movement dynamics (peak force, lick rhythm, number of licks) during water licking were recorded. After chronic haloperidol dosing (vehicle, 0.06. 0.12, 0.24 mg/kg for four separate groups) for 32 days and continuing every second or third day of the chronic dosing period, the effects of cholinergic (scopolamine: 0.05-0.20 mg/kg; trihexyphenidyl: 0.15-1.0 mg/kg) or serotonergic (ritanserin: 0.5-4.0 mg/kg; quipazine: 0.5-4.0 mg/kg) probe drugs were examined for their capacity to antagonize the alterations in licking behavior induced by haloperidol. Haloperidol dose-dependently reduced peak force and number of licks, effects which were apparent within 2 or 3 days of the start of treatment. Significant effects of haloperidol on lick rhythm first emerged on day 13 and gradually increased in magnitude through the remaining treatment period. Scopolamine, trihexyphenidyl, and quipazine reduced haloperidol's effects on at least one measure of licking behavior. During a 7-day haloperidol withdrawal period, the four dosage groups were similar on all measures of tongue dynamics. Overall, the results exhibited features suggesting the co-occurrence of Parkinson-like and tardive dyskinesia-like effects.

Animals↗
PubMed2002

Rodent model for investigating the effects of estrogen on bone and muscle relationship during growth.

It has been reported that in humans from about 11-12 years of age, bone mass begins to increase faster in girls than in boys with the same muscle mass, and by 14-15 years of age, bone mass per unit mass of muscle was found to be significantly higher in girls than in boys. Because around 15 years is the beginning of reproductive age in women, it was suggested that estrogen was involved in the higher bone mass in women during puberty. The present study was undertaken to determine if bone mass per unit muscle mass is higher in female than in male Sprague Dawley (SD) rats during growth, as has been reported in humans during growth and consequently, whether these SD rats are suitable for studying the musculoskeletal effects of estrogen, as may occur in humans during growth. L-4 vertebra of female and male SD rats aged 1-6 months were studied using peripheral quantitative computed tomography (pQCT). Muscle cross-sectional area was measured as a surrogate for muscle mass and bone mineral content (BMC) was measured as a surrogate for bone mass. From 1 to 6 months of age, total BMC, cortical BMC, and cancellous BMC increased faster in females than in males with similar muscle area, and at 3 and 6 months of age, the above vertebral indices of bone mass were significantly higher in female than in male rats. Since one of the main differences between female and male rats is the level of serum estrogen, the higher bone mass per unit muscle area seen at the L-4 vertebra in these female SD rats is similar to what has been reported in humans during puberty when serum estrogen level is high in females. The findings from this study indicate that female and male SD rats aged 1-6 months can be used as appropriate model for studying the effects of serum estrogen on the skeletal response of voluntary muscle forces, as has been reported in humans during growth.

Animals↗
PubMed2004

Detection of focal hypoxic-ischemic injury and neuronal stress in a rodent model of unilateral MCA occlusion/reperfusion using radiolabeled annexin V.

In this study we wished to determine whether technetium-99m annexin V, an in vivo marker of cellular injury and death, could be used to noninvasively monitor neuronal injury following focal middle cerebral artery (MCA) occlusion/reperfusion injury. Sixteen adult male Sprague-Dawley rats (along with four controls) underwent left (unilateral) MCA intraluminal beaded thread occlusion for 2 h followed by reperfusion. One hour following tail vein injection of 5-10 mCi of (99m)Tc-annexin V, animals underwent either single-photon emission computerized tomography (SPECT) or autoradiography followed by immunohistochemical analyses. There was abnormal, bilateral, multifocal uptake of (99m)Tc-annexin V in each cerebral hemisphere as seen by both SPECT and autoradiography at 4 h and 1, 3, and 7 days after initiation of occlusion. The average maximal annexin V uptake at 4 h was 310%+/-85% and 365%+/-151% above control values (P<0.006) within the right and left hemispheres, respectively, peaking on day 3 with values of 925%+/-734% and 1,194%+/-643% (P<0.03) that decreased by day 7 to 489%+/-233% and 785%+/-225% (P<0.01). Total lesional volume of the left hemisphere was 226%, 261%, and 451% ( P<0.03) larger than the right at 4, 24, and 72 h after injury, respectively. Annexin V localized to the cytoplasm of injured neurons ipsilateral to the site of injury as well as to otherwise normal-appearing neurons of the contralateral hemisphere as confirmed by dual fluorescent microscopy. It is concluded that there is abnormal bilateral, multifocal annexin V uptake, greater on the left than on the right side, within 4 h of unilateral left MCA ischemic injury and that the uptake peaks at 3 days and decreases by 7 days after injury. This pattern suggests that neuronal stress may play a role in the response of the brain to focal injury and be responsible for annexin V uptake outside the region of ischemic insult.

Animals↗
PubMed2001

Imaging macrophages and the apoptosis of granulocytes in a rodent model of subacute and chronic abscesses with radiolabeled monocyte chemotactic peptide-1 and annexin V.

Monocytes/macrophages (Mphis), the predominant cell types in subacute and chronic inflammation, are attracted to and activated by monocyte chemotactic peptide-1 (MCP-1). Mphis promote the resolution of inflammation through the induction of apoptosis and phagocytosis of senescent (spent) and bystander (superfluous) granulocytes. We wished to determine whether MCP-1, which selectively binds to Mphis, could be used to image subacute and chronic inflammation. We also sought to image granulocyte apoptosis within these lesions with technetium-99m labeled annexin V, a marker of apoptotic cells. Sterile inflammation was induced in 45 12-week-old male Sprague-Dawley rats by deep intramuscular injection of turpentine into the right thigh. Groups of four to six animals were then imaged 1 h after tail vein injection of 37-148 MBq (1-4 mCi) of 99mTc-labeled MCP-1 or annexin V 1-14 days after turpentine treatment. Image analysis showed significantly greater activity of both MCP-1 and annexin V in inflamed thighs than in control thighs (165%-290% and 188%-313%, respectively; P<0.01) on days 1-5 after turpentine injection. Dual autoradiography in animals co-injected with iodine-125 labeled bovine serum albumin on days 1 and 4 showed specific location of MCP-1 to infiltrating Mphis while annexin V localized to focal zones of apoptosis within granulocytic infiltrates adjacent to abscess cavities. Scintillation well counting on day 5 demonstrated significantly higher (P<0.005) ratios of abscess to control thigh specific activities for MCP-1 (5.83+/-2.17) and annexin V (9.24 +/- 2.8) as compared to 125I-labeled bovine serum albumin (3.11 +/- 0.65). No significant increases in uptake were noted at imaging or ex vivo analyses on days 13 and 14, when lesions were predominately fibrotic. It is concluded that 99mTc-labeled MCP-1 and 99mTc-labeled annexin V both localize in zones of subacute inflammation, reflecting the density of Mphis and the incidence of apoptotic granulocytes, respectively. These agents may be useful in the characterization of subacute inflammation.

Abscess↗
PubMed2005

Synthetic double-stranded RNA poly(I:C) as a potent peptide vaccine adjuvant: therapeutic activity against human cervical cancer in a rodent model.

Due to the inherent lack of immunogenicity of peptides, it is generally recognized that the strong inflammatory signals that are required to elicit specific responses against peptide-based therapeutic tumor vaccines may not be provided by the standard/conventional vaccine adjuvants. In this study, we have demonstrated dsRNA in the form of synthetic pI:C as a potent adjuvant to enhance the specific anti-tumor immune responses against a peptide-based vaccine. When complexed with an MHC I-restricted minimal peptide epitope derived from the HPV 16 E7 protein, the resulting pI:C/E7(49-57) molecular complex induced strong E7(49-57)-specific CTL responses that caused significant regressions of model human cervical cancer tumors pre-established in mice. In addition, although the proportion of DCs in tumor-bearing mice was significantly decreased when compared to that in naïve mice, immunization with pI:C/E7(49-57 )restored the proportion of DCs in tumor-bearing mice. Double-stranded RNA may hold a great potential as an adjuvant to induce cellular immune responses for tumor immunotherapy.

Adjuvants, Immunologic↗
PubMed2002

Immunological and histopathological studies in a rodent model infected with Leishmania infantum promastigotes or amastigotes.

Infection with Leishmania infantum promastigotes (group I) and amastigotes (group II) was evaluated over 32 weeks, using Syrian golden hamsters as an experimental model. Spleen cells strongly responded to the specific antigen at 12 (group I) and 16 weeks (group II) post-inoculation (p.i.) and lower stimulation index values coincided with the parasite burden peak. Western-blot analysis detected antibodies during the 1st week p.i. and the number of recognized proteins increased with the time of infection, reaching a maximum at the peak parasite burden. Histopathology revealed hypoplasia in spleen white pulp and the liver showed a periportal infiltration of inflammatory cells and small granulomas, becoming increasingly more severe as the infection developed. Both organs exhibited a secondary amyloid deposition at the end of the experiment, especially the spleen. In this study, progressive visceral disease was observed as in natural human and canine infections; however, the incubation period was longer in the promastigote than in the amastigote infection.

Animals↗
PubMed2003

A rodent model for pulmonary paragonimiasis.

This study reports a model of pulmonary paragonimiasis in outbred Wistar rats using the Indian strain of Paragonimus heterotremus isolated from the fresh water crab Barytelphusa lugubris collected from Arunachal Pradesh, India. Feeding metacercariae to the rats led to encapsulated adult worms in the lungs and pleural cavity. Some flukes migrated to the skeletal muscles of the hosts where they remained underdeveloped as immature flukes.

Animals↗
PubMed2006

Antioxidant therapy with N-acetylcysteine plus mesalamine accelerates mucosal healing in a rodent model of colitis.

The aims of this study were to examine the ability of the antioxidant N-acetylcysteine (NAC) and mesalamine (5-ASA) alone and in combination to affect TNBS-induced colitis in rat. Three days following induction of TNBS colitis rats were randomized to receive daily intracolonic treatment with NAC, 5-ASA, and NAC plus 5-ASA for 5 or 8 days. At the end of the treatment period macroscopic and microscopic colonic injuries were scored. Myeloperoxidase (MPO) activity and cytokine gene expression were measured in colonic tissues. Results indicated that treatment with NAC plus 5-ASA caused a significantly greater reduction in colonic injury than either agent alone. Furthermore, combination therapy inhibited significantly MPO activity and inflammatory cytokine gene expression in the distal colon of TNBS-treated animals. The beneficial effects of NAC plus 5-ASA on reduction of colonic injury and promotion of healing were most evident after 8 days of treatment.

Acetylcysteine↗
PubMedDate not supplied

Evaluation of the integrity of the dopamine system in a rodent model of Parkinson's disease: small animal positron emission tomography compared to behavioral assessment and autoradiography.

PURPOSE: In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), it is important to determine lesion severity. This evaluation can be performed in vivo, through evaluation of dopamine (DA)-dependent motor function or with small animal positron emission tomography (microPET), or at postmortem, by examining markers for DA neurons. PROCEDURES: Rats were given mild or severe unilateral 6-OHDA lesions, scanned with the tracer [(11)C](+/-)dihydrotetrabenazine ([(11)C]DTBZ), and tested on a tapered/ledged beam-walking task. At postmortem, autoradiography was performed with [(11)C]DTBZ. RESULTS: Autoradiography was significantly correlated with microPET and behavioral scores, whereas the microPET and behavioral data were not significantly correlated. CONCLUSIONS: This study shows that behavioral analysis, microPET, and autoradiography are all good tools for measuring the integrity of the DA system, and demonstrates the utility of the tapered/ledged beam-walking test to screen for lesion severity, as well as the importance of including postmortem analysis after in vivo imaging studies.

Animals↗
PubMed1991

Reduction of primary posttraumatic adhesion formation with the prostacyclin analog iloprost in a rodent model.

Recent evidence suggests that inhibition of postsurgical adhesion formation may be effected by modulation of the activities of inflammatory cells contributing to mesothelial repair. Iloprost, a stable analog of prostacyclin, has been shown to exert vasodilatory, antiinflammatory, fibrinolytic, and antithrombotic influences. To determine whether these properties of iloprost might protect mesothelial surfaces from perioperative damage and hence prevent adhesion formation, we evaluated the effect of iloprost on peritoneal healing in a hamster model for primary pelvic injury. Perioperative iloprost therapy significantly reduced posttraumatic adhesion formation when compared with that in vehicle-treated controls. Dose-response studies demonstrate adhesion prevention with doses ranging from 0.04 to 4 mg/kg per 8 hours given subcutaneously over the course of 3 days. These data demonstrate that iloprost is a potent positive modulator of peritoneal healing after pelvic trauma. Further studies to characterize the potential application of iloprost as an adjuvant in reproductive surgery are indicated.

Animals↗