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At least 487 records · Page 27Linked to original sources
PubMed2000

Structure of the intestinal flora responsible for development of the gut immune system in a rodent model.

The intestinal flora comprising indigenous, autochthonous bacteria is constantly present in the alimentary tract of host animals, including humans. The indigenous bacteria greatly affect the structure and functions of the intestinal mucosa. Studies involving gnotobiotic mice or rats have shown that the presence of limited kinds of intestinal bacteria is responsible for the development of the gut immune system, such as secretory IgA, major histocompatibility complex molecules and intraepithelial lymphocytes. Understanding of the structure of the intestinal flora or the organization of the microbial population in the intestine, based on evaluation of the immunological responses, may clarify its functions in the host animal.

Animals↗
PubMed1999

A novel inhibitor of the tyrosine kinase Src suppresses phosphorylation of its major cellular substrates and reduces bone resorption in vitro and in rodent models in vivo.

The tyrosine kinase Src has been implicated in the process of osteoclast-mediated bone resorption. Here, we describe a novel class of Src inhibitors, substituted 5,7-diphenyl-pyrrolo[2,3-d]pyrimidines, and characterize one of them, CGP77675, in vitro and in models of bone resorption in vivo. In vitro, CGP77675 inhibited phosphorylation of peptide substrates and autophosphorylation of purified Src (concentration producing half-maximal inhibition [IC50] values 5-20 and 40 nmol/L, respectively). The compound was selective toward other protein kinases: the Src IC50 value was lower than those for Cdc2 (>500-fold), epidermal growth factor (EGF) receptor (7.5-fold), and vascular endothelial growth factor receptor (>50-fold), and for v-Abl (15-fold) and focal adhesion kinase (Fak) (>25-fold). The Src kinase family members Lck and Yes were inhibited with IC50 values 20-fold higher than or equal to Src. To measure the inhibition of cellular Src activity, we identified the major tyrosine-phosphorylated proteins in an Src-overexpressing cell line IC8.1 as Src, Fak, and paxillin. CGP77675 potently inhibited tyrosine phosphorylation of the Src substrates Fak and paxillin, but had much less effect on Src (IC50 values 0.3, 0.5, and 5.7 micromol/L). The phosphorylation of Src in IC8.1 cells reflected phosphorylation of the negative regulatory tyrosine 527 (Y527); thus, the inhibitor was selective against the Y527 C-terminal Src kinase Csk. In osteoblastic MC3T3-E1 cells, CGP77675 inhibited signaling induced by PDGF at the receptor level, but not signaling by EGF, basic fibroblast growth factor, insulin-like growth factor-1, and phorbol 12-myristate 13-acetate. The effect of CGP77675 on bone resorption was evaluated in vitro and in vivo. The parathyroid hormone-induced bone resorption in rat fetal long bone cultures was inhibited with an IC50 of 0.8 micromol/L. CGP77675 dose-dependently reduced the hypercalcemia induced in mice by interleukin-1beta and partly prevented bone loss and microarchitectural changes in young ovariectomized rats, showing that the protective effect on bone was exerted via the inhibition of bone resorption. Thus, specific Src family kinase inhibitors may be useful for the treatment of diseases associated with elevated bone loss.

3T3 Cells↗
PubMed2003

Plasma homocysteine and glycine are sensitive indices of folate status in a rodent model of folate depletion and repletion.

The objectives of the current studies included the characterization of the temporal changes in indices of folate status and amino acid concentrations during both folate depletion and repletion phases. In trial 1, a 6 week folate depletion protocol was employed, using 60 weanling rats assigned to receive an amino acid-defined diet with or without 1 mg/kg folic acid. A 4 week folate depletion period was judged to be optimal on the basis of the development of nadirs in both plasma and hepatic folate stores and elevated (>6-fold relative to folate-adequate controls) concentrations of plasma homocysteine and glycine. In trial 2, 54 weanling rats, previously maintained on a folate-devoid diet for 4 weeks, were assigned to receive 0.25 mg/kg folate as either crystalline folic acid or folate from a folate-enriched egg yolk powder. Both forms of folate supported similar rates of gain, increases in plasma and hepatic folate stores, and reductions in plasma glycine concentrations, whereas the folate in egg yolk powder lowered plasma homocysteine concentrations further than the crystalline folic acid (P < 0.05). These data support the use of both plasma glycine and homocysteine as sensitive response criteria for folate status in a rat bioassay of folate depletion and repletion and establish appropriate temporal end-points for such studies.

Animals↗
PubMed2000

5-aminosalicyclic acid and olsalazine inhibit tumor growth in a rodent model of colorectal cancer.

The ability of 5-aminosalicylic acid and olsalazine to inhibit colonic aberrant crypts and tumors was investigated in 1,2-dimethylhydrazine-treated rats. The effect of these drugs on the rates of tumor apoptosis and proliferation was studied as potential mechanisms for their action. 5-Aminosalicylic acid reduced the number of aberrant crypt foci by over one third, while olsalazine had no effect on this parameter. However, both agents effectively reduced tumor number and load, increased the rate of tumor apoptosis, and reduced the rate of tumor cell proliferation. In conclusion, 5-aminosalicylic acid and olsalazine are both ultimately effective chemopreventive agents in this model; however, only 5-aminosalicylic acid inhibited the formation of aberrant crypt foci. The inhibitory effect of these agents in tumors is related to the inhibition of proliferation and the induction of apoptosis.

Aminosalicylic Acids↗
PubMedDate not supplied

Omega-3 polyunsaturated fatty acids in rodent models of breast cancer.

Quantitative increases in certain dietary fats promote mammary tumor growth, but the experimental data indicate that this tumor promoting capability is not equally expressed by all fatty acid families. There is a large body of evidence from experiments using either carcinogen-induced or transplanted animal mammary tumor models, as well as in vitro studies, which demonstrates that the omega-6 polyunsaturated fatty acids (PUFA) promote mammary tumor development more effectively than omega-3 PUFA. These data indicate that increases in the dietary levels of omega-6 PUFA enhance tumor development, while equivalent increases in dietary levels of omega-3 PUFA often delay or reduce tumor development. Several theoretical mechanisms have been proposed for these contrasting results, but as yet, no definitive explanation has been universally accepted.

Animals↗
PubMed2003

In vivo NMR studies of neurodegenerative diseases in transgenic and rodent models.

In vivo magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) provide unique quality to attain neurochemical, physiological, anatomical, and functional information non-invasively. These techniques have been increasingly applied to biomedical research and clinical usage in diagnosis and prognosis of diseases. The ability of MRS to detect early yet subtle changes of neurochemicals in vivo permits the use of this technology for the study of cerebral metabolism in physiological and pathological conditions. Recent advances in MR technology have further extended its use to assess the etiology and progression of neurodegeneration. This review focuses on the current technical advances and the applications of MRS and MRI in the study of neurodegenerative disease animal models including amyotrophic lateral sclerosis, Alzheimer's, Huntington's, and Parkinson's diseases. Enhanced MR measurable neurochemical parameters in vivo are described in regard to their importance in neurodegenerative disorders and their investigation into the metabolic alterations accompanying the pathogenesis of neurodegeneration.

Animals↗
PubMed2003

Pharmacokinetic-pharmacodynamic relationships of (2S,3S)-valnoctamide and its stereoisomer (2R,3S)-valnoctamide in rodent models of epilepsy.

PURPOSE: Racemic valnoctamide (VCD) is a central nervous system-active drug commercially available in Europe. VCD possesses two chiral centers and, therefore, it exists as a mixture of four stereoisomers. The purpose of this study was to evaluate the anticonvulsant activity of two VCD stereoisomers in comparison with VCD (racemate), valpromide (VPD), and valproic acid (VPA) and to study their pharmacokinetic-pharmacodynamic relationships. METHODS: The ability of racemic VCD, (2S,3S)-VCD, (2R,3S)-VCD and VPD to block partial seizures was studied in the 6Hz psychomotor seizure model in mice and in the hippocampal kindled rat. The ability of (2S,3S)-VCD and (2R,3S)-VCD to prevent generalized seizures was evaluated in the maximum electroshock (MES) and subcutaneous metrazole (sc Met) seizure tests. The PK of (2S,3S)-VCD, (2R,3S)-VCD, and VPD was studied in the mice utilized in the 6Hz model. RESULTS: All of the tested compounds were effective in the models tested. No significant difference in ED50 values was observed but the plasma and brain EC50 values of (2R,3S)-VCD in the 6Hz model at 32 mA stimulation were 2-fold higher than the EC50 values of (2S,3S)-VCD. An excellent pharmacokinetic-pharmacodynamic correlation was found between the plasma and brain concentrations of the VCD stereoisomers and their anticonvulsant effect in mice. Stereoselectivity was observed in clearance, volume of distribution, and in brain-to-plasma AUC ratio at a dose of 25 mg/kg, but the difference disappeared at higher doses as the clearance of the stereoisomers decreased and their half-life increased. For (2R,3S)-VCD the brain-to-plasma AUC ratio doubled at the tested dose range, while it remained constant for (2S,3S)-VCD. CONCLUSIONS: Racemic VCD, VPD, (2R,3S)-VCD, and (2S,3S)-VCD are effective anticonvulsants in animal models of partial seizures and are more potent than VPA. The more favorable brain penetration of (2S,3S)-VCD and its lower EC50 value in the 6Hz test provides one advantage over (2R,3S)-VCD as a new antiepileptic drug.

Amides↗
PubMed1990

A new rodent model for neuroleptic-induced pseudo-parkinsonism: low doses of haloperidol increase forelimb tremor in the rat.

Rats were trained to use the right forelimb to exert continuous downward pressure on a force transducer and simultaneously to drink sweetened milk from a dipper controlled by the emitted force. Oscillations in forelimb force during this performance were spectrally analyzed to describe the tremorogenic effects of haloperidol (0.04, 0.08, or 0.16 mg/kg). Haloperidol reduced time-on-task and increased the variance of force oscillations in the 10.0-25.0-Hz frequency band. When atropine sulfate (5 mg/kg) was given along with haloperidol, time-on-task was partially restored, and the effects of haloperidol on the 10.0-25.0-Hz band were diminished. These data suggest that the behavioral deficits produced by relatively low doses of haloperidol in rats are analogous (and possibly homologous) to neuroleptic-induced Parkinsonian symptoms in humans.

Animals↗
PubMed1999

Chronic morphine reduces pain-related disability in a rodent model of chronic, inflammatory pain.

Chronic pain is disabling, and the adverse effects of morphine are also disabling. The best way to assess the beneficial effects relative to the potential adverse effects of chronic morphine may be through the use of quantitative measures of functional disability in people and animals experiencing pain. If chronic morphine alleviates chronic pain and its beneficial analgesic effects outweigh whatever adverse effects it may produce, then it should reduce pain-related disability. Rats with adjuvant-induced arthritis were implanted with subcutaneous morphine pellets. Continuous morphine reduced pain-related disability in tasks motivated by food reward or shock avoidance throughout the 35 days of continuous administration--first, in tests that primarily assessed the function of the less severely affected forelimbs, and later, as the inflammation subsided, in tests more dependent on the function of the more severely affected hind limbs.

Analgesics, Opioid↗
PubMed2000

The analgesic potential of intraventricular polymer-encapsulated adrenal chromaffin cells in a rodent model of chronic neuropathic pain.

Adrenal chromaffin cells reportedly produce analgesic effects when implanted in the periaqueductal gray and the intrathecal space near the spinal cord. Chromaffin cells implanted in the cerebral ventricles may also produce analgesic effects, and the availability of the cerebral ventricles as a potential implant site could be advantageous for some patients. In fact, some of the first patients were implanted in the intraventricular site, even though the analgesic potential of that site had never been demonstrated. The present study was conducted to assess the analgesic potential of intraventricular, polymer-encapsulated calf adrenal chromaffin cells in the Bennett model. Sciatic nerve ligations produced substantial, long-lasting pain-related behaviors. However, there was no evidence that polymer-encapsulated adrenal chromaffin cells implanted in the cerebral ventricles produce analgesic effects in this model of chronic neuropathic pain.

Adrenal Glands↗
PubMed2001

Drug-induced reinstatement to heroin and cocaine seeking: a rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 microg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine- associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug. These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration.

Animals↗
PubMed1993

A rodent model for testicular involvement in acute lymphoblastic leukaemia.

The testis is the third common site of relapse after primary treatment of childhood acute lymphoblastic leukaemia, but in adults relatively few testicular relapses of acute lymphoblastic leukaemia have been reported. In the present investigation the differences in the behaviour of leukaemia in immature and mature rat testis and the interactions of testicular and leukaemic cells were studied. Intraperitoneal injection of rat T-leukaemic cells to sexually immature animals induced testicular infiltrations in 100% of animals in 17 days. The infiltrations were small and located perivascularly in the interstitial tissue. Intraperitoneal injection of T-leukaemic cells to sexually mature animals induced testicular infiltrates in 42% of the animals. Leukaemic cells injected directly to the lymph sinusoids of sexually immature and mature testis proliferated rapidly causing testicular enlargement. The M(r) > 5 K fraction of extracts of 50 days old normal rat testes inhibited 3H-TdR incorporation of both normal and leukaemic ConA-stimulated rat lymphoblasts significantly. The same fraction of extracts of testes of 25 days old rats did not have any effect on 3H-TdR incorporation. The normally occurring pubertal increase in the lymphocyte inhibitory effect of the M(r) > 5 K fraction of testis extracts on 3H-TdR incorporation of PBL was prevented following either intraperitoneal or intratesticular injection of rat leukaemic lymphoblasts administered at the age of 25 days. The present observations suggest that physiological pubertal changes in the permeability of vascular endothelium and immunosuppressive effect of the testis may be important explanatory factors for the smaller number of testicular relapses in men compared to boys seen after treatment of ALL.

Age Factors↗
PubMed1996

Efficacy of a therapeutic cocaine vaccine in rodent models.

Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.

Animals↗
PubMed2000

Antidystonic efficacy of nitric oxide synthase inhibitors in a rodent model of primary paroxysmal dystonia.

In a hamster model (genetic symbol dt(sz)) of primary paroxysmal non-kinesiogenic dystonic choreoathetosis, recent studies have shown beneficial effects of glutamate and dopamine receptor antagonists. Nitric oxide (NO), synthesized from L-arginine by NO synthase in response to glutamate receptor activation, elicits cyclic GMP and modulates glutamate-mediated processes and striatal dopamine release. Therefore, the effects of NO synthase inhibitors and of L-arginine on severity of dystonia were investigated in dt(sz) hamsters in which dystonic attacks, characterized by twisting movements and postures, can be induced by stress. The NO synthase inhibitors N(G)-nitro-L-arginine (L-NNA), N(G)-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole significantly reduced the severity of dystonia. At antidystonic effective doses neither L-NNA nor L-NAME caused observable side effects, whereas 7-nitroindazole exerted moderate reduction of locomotor activity. The antidystonic effect of L-NAME was reversed by co-administration of the NO precursor L-arginine. However, L-arginine administered alone did not exert any effect on severity of dystonia. Cerebellar cyclic GMP levels in brains of mutant hamsters in comparison to non-dystonic control hamsters did not significantly differ, but the cerebellar cyclic GMP levels tended to be increased in dt(sz) hamsters during a dystonic attack. L-NAME significantly decreased the cerebellar cyclic GMP levels in both dt(sz) and control hamsters. Although an overproduction of NO is probably not critically involved in the pathogenesis of paroxysmal dystonia, it may contribute to the manifestation of dystonic attacks, as indicated by the antidystonic effects of NO synthase inhibitors. Peripheral side effects may limit the clinical use of NO synthase inhibitors, but more selective inhibitors of the neuronal NO synthase should be considered as interesting candidates for the treatment of paroxysmal dystonia.

Animals↗
PubMed2006

Lysophosphatidylcholine reduces the organ injury and dysfunction in rodent models of gram-negative and gram-positive shock.

1. Lysophosphatidylcholine (LPC) modulates the inflammatory response and reduces mortality in animal models of sepsis. Here, we investigate the effects of LPC from synthetic (sLPC) and natural, soy bean derived LPC, (nLPC) sources on the organ injury/dysfunction caused by systemic administration of lipopolysaccharide (LPS) or peptidoglycan (PepG) and lipoteichoic acid (LTA). 2. Rats were subjected to (i) endotoxaemia (LPS 6 mg kg(-1) i.v.) and treated with sLPC (1-100 mg kg(-1)), (ii) endotoxaemia and treated with nLPC (10 mg kg(-1)) or (iii) gram-positive shock (PepG 10 mg kg(-1) and LTA 3 mg kg(-1) i.v.) and treated with sLPC (10 mg kg(-1)). 3. Endotoxaemia or gram-positive shock for 6 h resulted in increases in serum makers of renal dysfunction and liver, pancreatic and neuromuscular injury. 4. Administration of sLPC, at 1 or 2 h after LPS, dose dependently (1-10 mg kg(-1)) reduced the organ injury/dysfunction. High doses of sLPC (30 and 100 mg kg(-1)) were shown to be detrimental in endotoxaemia. sLPC also afforded protection against the organ injury/dysfunction caused by gram-positive shock. nLPC was found to be protective in endotoxaemic animals. 5. The beneficial effects of sLPC were associated with an attenuation in circulating levels of interleukin-1beta (IL-1beta). 6. In conclusion, LPC dose and time dependently reduces the organ injury and circulating IL-1beta levels caused by gram-negative or gram-positive shock in the rat. Thus, we speculate that appropriate doses of LPC may be useful in reducing the degree of organ injury and dysfunction associated with shock of various aetiologies.

Animals↗