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Rat Models (rat + models)
Selected AbstractsThe Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] Inhibition of hepatic stellate cell proliferation and activation by the semisynthetic analogue of fumagillin TNP-470 in ratsHEPATOLOGY, Issue 5 2000Yan Qing Wang Proliferation and activation of hepatic stellate cells (HSCs) are critical steps for the development of postnecrotic fibrosis in the liver. The present study aimed to reveal the inhibitory effect of the semisynthetic analogue of fumagillin TNP-470 on these events for its possible use as an antifibrogenic agent. Rat models of carbon tetrachloride (CCl4)- and dimethylnitrosamine-induced hepatic fibrosis were used for an in vivo study. In both models, the fibrotic area was considerably decreased by concurrent repetitive subcutaneous injections of 30 mg/kg body weight of TNP-470. In CCl4 -induced fibrosis, factor VIII-related antigen-positive blood vessels, desmin-, or ,-smooth muscle actin (,SMA)-positive mesenchymal cells, bromodeoxyuridine (BrdU)-positive mesenchymal cells also decreased in number by treatment with TNP-470. In in vitro experiments, a supplement of 1,000 ng/mL TNP-470 suppressed BrdU incorporation and cyclins D1, D2, and E expression by cultured HSCs in the absence and/or presence of platelet-derived growth factor (PDGF). Expression of HSC activation markers, i.e., ,SMA and PDGF receptor ,, was also suppressed. The present results indicate that TNP-470 inhibits HSC proliferation by blocking the cell-cycle transition from G1 to S and HSC activation, and, as the consequence, prevents the progression of hepatic fibrosis, probably being coupled with its antiangiogenic effect. [source] Arthritis induced in rats with non-immunogenic adjuvants as models for rheumatoid arthritisIMMUNOLOGICAL REVIEWS, Issue 1 2001Rikard Holmdahl Summary: Rat models are useful for studies of the pathogenesis of rheumatoid arthritis (RA) since rats are extraordinarily sensitive to induction of arthritis with adjuvants. Injection of not only the classical complete Freund's adjuvant but also mineral oil without mycobacteria and pure adjuvants such as pristane and squalene, induce severe arthritis in many rat strains. Models like pristane-induced arthritis in rats are optimal models for RA since they fulfill the RA criteria including a chronic relapsing disease course. Arthritogenic adjuvants like pristane, avridine, squalene and mineral oil are not immunogenic since they do not contain major histocompatibility complex (MHC) binding peptides. Nevertheless, the diseases are MHC-associated and dependent on the activation of ,,TCR (T-cell receptor)-expressing T cells. However, it has not been possible to link the immune response to joint antigens or other endogenous components although immunization with various cartilage proteins induce arthritis but with different pathogeneses. To unravel the mechanisms behind adjuvant-induced arthritis, a disease-oriented genetic approach is optimal. Several loci that control onset of arthritis, severity and chronicity of the disease have been identified in genetic crosses and most of these have been confirmed in congenic strains. In addition, many of these loci are found in other autoimmune models in the rat as well as associated with arthritis in mice and humans. [source] Genetic susceptibility to carrageenan-induced innate inflammatory response in inbred strains of ratsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2003B. Joe Summary Rat models are useful for the genetic dissection of the biology of innate immunity. Inbred rat strains were evaluated for carrageenan-induced innate inflammatory responses. Results indicated that the genetic control of innate immune responses is polygenic and influenced by gender, and may not necessarily be consistent with the genetics of experimental arthritis. The newly identified susceptible strains, in order of decreasing susceptibility, include Dahl salt-sensitive (S), Dahl salt-resistant (R), Milan normotensive strain (MNS) and Wistar Kyoto (WKY) rats. Similarly, the newly identified relatively resistant strains, in decreasing order of resistance, include DA rats, spontaneously hypertensive rats (SHRs) and Brown Norway (BN) rats. Linkage analyses using combinations of these susceptible and resistant strains are proposed. [source] Maturation-Dependent Alcohol Resistance in the Developing Mouse: Cerebellar Neuronal Loss and Gene Expression During Alcohol-Vulnerable and -Resistant PeriodsALCOHOLISM, Issue 8 2008Bahri Karaçay Background:, Alcohol abuse during pregnancy injures the fetal brain. One of alcohol's most important neuroteratogenic effects is neuronal loss. Rat models have shown that the cerebellum becomes less vulnerable to alcohol-induced neuronal death as it matures. We determined if maturation-dependent alcohol resistance occurs in mice and compared patterns of gene expression during the alcohol resistant and sensitive periods. Methods:, Neonatal mice received alcohol daily over postnatal day (PD) 2 to 4 or PD8 to 10. Purkinje cells and granule cells were quantified on PD25. The temporal expression patterns of 4 neuro-developmental genes and 3 neuro-protective genes in the cerebellum were determined daily over PD0 to 15 to determine how gene expression changes as the cerebellum transitions from alcohol-vulnerable to alcohol-resistant. The effect of alcohol on expression of these genes was determined when the cerebellum is alcohol sensitive (PD4) and resistant (PD10). Results:, Purkinje and granule cells were vulnerable to alcohol-induced death at PD2 to 4, but not at PD8 to 10. Acquisition of maturation-dependent alcohol resistance coincided with changes in the expression of neurodevelopmental genes. The vulnerability of cerebellar neurons to alcohol toxicity declined in parallel with decreasing levels of Math1 and Cyclin D2, markers of immature granule cells. Likewise, the rising resistance to alcohol toxicity paralleled increasing levels of GABA ,-6 and Wnt-7a, markers of mature granule neurons. Expression of growth factors and genes with survival promoting function (IGF-1, BDNF, and cyclic AMP response element binding protein) did not rise as the cerebellum transitioned from alcohol-vulnerable to alcohol-resistant. All 3 were expressed at substantial levels during the vulnerable period and were not expressed at higher levels later. Acute alcohol exposure altered the expression of neurodevelopmental genes and growth factor genes when administered either during the alcohol vulnerable period or resistant period. However, the patterns in which gene expression changed varied among the genes and depended on timing of alcohol administration. Conclusions:, Mice have a temporal window of vulnerability in the first week of life, during which cerebellar neurons are more sensitive to alcohol toxicity than during the second week. Expression of genes governing neuronal maturation changes in synchrony with the acquisition of alcohol resistance. Growth factors do not rise as the cerebellum transitions from alcohol-vulnerable to alcohol-resistant. Thus, a process intrinsic to neuronal maturation, rather than rising levels of growth factors, likely underlies maturation-dependent alcohol resistance. [source] Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulationDIABETES OBESITY & METABOLISM, Issue 11 2008R. R Ortiz-Andrade Aim:, The present investigation was designed to determine the in vivo antidiabetic effect of naringenin (NG) in normoglycaemic and diabetic rat models through blood glucose (GLU) measurements following acute and subchronic time periods. Possible modes of action of NG were investigated and its acute toxicity determined. Methods:, Normoglycaemic and non-insulin-dependent diabetes mellitus (NIDDM) rat models were treated for acute and subchronic (5 days) time periods with 50 mg/kg/day of NG. Blood biochemical profiles were determined after 5 days of the treatment in normoglycaemic and NIDDM rats using commercial kits for GLU, triglycerides (TG), total cholesterol (CHOL) and high-density lipoprotein (HDL). In order to elucidate its antidiabetic mode of action, NG was administered intragastrically and an oral glucose tolerance test performed using GLU and sucrose (2 g/kg) as substrates. The inhibitory effect of a single concentration of NG (10 ,M) on 11,-hydroxysteroid dehydrogenase type 1 (11,-HSD1) activity in vitro was determined. Finally, the preclinical safety and tolerability of NG was determined by toxicological evaluation in mice and rats using Organization for Economic Cooperation and Development (OECD) protocols. Results:, Intragastrically administered NG (50 mg/kg) induced a significant decrease in plasma GLU in normoglycaemic and NIDDM rat models (p < 0.05) following acute and subchronic time periods. After 5 days of administration, NG produced significant diminished blood GLU and TG levels in streptozotocin,nicotinamide,induced diabetic rats. The administration of NG to normal rats significantly increased the levels of TG, CHOL and HDL (p < 0.05). NG (5 and 50 mg/kg) induced a total suppression in the increase of plasma GLU levels after administration of substrates (p < 0.01), but NG did not produce inhibition of ,-glucosidase activity in vitro. However, NG (10 ,M) was shown to inhibit 11,-HSD1 activity by 39.49% in a cellular enzyme assay. Finally, NG showed a Medium Lethal Dose LD50 > 5000 mg/kg and ranking at level five based on OECD protocols. Conclusion:, Our findings suggest that NG may exert its antidiabetic effect by extra-pancreatic action and by suppressing carbohydrate absorption from intestine, thereby reducing the postprandial increase in blood GLU levels. [source] Effects of dietary fatty acids on insulin sensitivity and secretionDIABETES OBESITY & METABOLISM, Issue 6 2004Melania Manco Globalization and global market have contributed to increased consumption of high-fat, energy-dense diets, particularly rich in saturated fatty acids( SFAs). Polyunsaturated fatty acids (PUFAs) regulate fuel partitioning within the cells by inducing their own oxidation through the reduction of lipogenic gene expression and the enhancement of the expression of those genes controlling lipid oxidation and thermogenesis. Moreover, PUFAs prevent insulin resistance by increasing membrane fluidity and GLUT4 transport. In contrast, SFAs are stored in non-adipocyte cells as triglycerides (TG) leading to cellular damage as a sequence of their lipotoxicity. Triglyceride accumulation in skeletal muscle cells (IMTG) derives from increased FA uptake coupled with deficient FA oxidation. High levels of circulating FAs enhance the expression of FA translocase the FA transport proteins within the myocites. The biochemical mechanisms responsible for lower fatty acid oxidation involve reduced carnitine palmitoyl transferase (CPT) activity, as a likely consequence of increased intracellular concentrations of malonyl-CoA; reduced glycogen synthase activity; and impairment of insulin signalling and glucose transport. The depletion of IMTG depots is strictly associated with an improvement of insulin sensitivity, via a reduced acetyl-CoA carboxylase (ACC) mRNA expression and an increased GLUT4 expression and pyruvate dehydrogenase (PDH) activity. In pancreatic islets, TG accumulation causes impairment of insulin secretion. In rat models, ,-cell dysfunction is related to increased triacylglycerol content in islets, increased production of nitric oxide, ceramide synthesis and ,-cell apoptosis. The decreased insulin gene promoter activity and binding of the pancreas-duodenum homeobox-1 (PDX-1) transcription factor to the insulin gene seem to mediate TG effect in islets. In humans, acute and prolonged effects of FAs on glucose-stimulated insulin secretion have been widely investigated as well as the effect of high-fat diets on insulin sensitivity and secretion and on the development of type 2 diabetes. [source] The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] The Midline Thalamus: Alterations and a Potential Role in Limbic EpilepsyEPILEPSIA, Issue 8 2001Edward H. Bertram Summary: ,Purpose: In limbic or mesial temporal lobe epilepsy, much attention has been given to specific regions or cell populations (e.g., the hippocampus or dentate granule cells). Epileptic seizures may involve broader changes in neural circuits, and evidence suggests that subcortical regions may play a role. In this study we examined the midline thalamic regions for involvement in limbic seizures, changes in anatomy and physiology, and the potential role for this region in limbic seizures and epilepsy Methods: Using two rat models for limbic epilepsy (hippocampal kindled and chronic spontaneous limbic epilepsy) we examined the midline thalamus for evidence of involvement in seizure activity, alterations in structure, changes in the basic in vitro physiology of the thalamic neurons. We also explored how this region may influence limbic seizures. Results: The midline thalamus was consistently involved with seizure activity from the onset, and there was significant neuronal loss in the medial dorsal and reuniens/rhomboid nuclei. In addition, thalamic neurons had changes in synaptically mediated and voltage-gated responses. Infusion of lidocaine into the midline thalamus significantly shortened afterdischarge duration. Conclusions: These observations suggest that this thalamic region is part of the neural circuitry of limbic epilepsy and may play a significant role in seizure modulation. Local neuronal changes can enhance the excitability of the thalamolimbic circuits. [source] The microstructure of ethanol drinking: genetic and behavioral factors in the control of drinking patternsADDICTION, Issue 8s2 2000Herman H. Samson The concept of craving can be examined in many different ways, depending upon the individual definition of the term. Using the concepts and procedures of regulatory behavior analysis, this review explores behavioral studies in rats that have some relationships to some of the possible processes that underlie the concept of craving in humans. Data are reviewed from studies employing both limited and continuous access to ethanol, examining the role of access availability, ethanol initiation, response cost, time since last access, composition of the ethanol containing solution and genetic selection. From this review, it is clear that rat models can implicate important variables involved in the control of human alcohol consumption. [source] 7-Hydroxylated epiandrosterone (7-OH-EPIA) reduces ischaemia-induced neuronal damage both in vivo and in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2003Ashley K. Pringle Abstract Recent evidence suggests that steroids such as oestradiol reduce ischaemia-induced neurodegeneration in both in vitro and in vivo models. A cytochrome P450 enzyme termed cyp7b that 7-hydroxylates many steroids is expressed at high levels in brain, although the role of 7-hydroxylated steroids is unknown. We have tested the hypothesis that the steroid-mediated neuroprotection is dependent on the formation of 7-hydroxy metabolites. Organotypic hippocampal slice cultures were prepared from Wistar rat pups and maintained in vitro for 14 days. Cultures were then exposed to 3 h hypoxia and neuronal damage assessed 24 h later using propidium iodide fluorescence as a marker of cell damage. Neurodegeneration occurred primarily in the CA1 pyramidal cell layer. The steroids oestradiol, dehydroepiandrosterone and epiandrosterone (EPIA) were devoid of neuroprotective efficacy when present at 100 nm pre-, during and post-hypoxia. The 7-hydroxy metabolites of EPIA, 7,-OH-EPIA and 7,-OH-EPIA significantly reduced neurotoxicity at 100 nm and 10 nm. 7,-OH-EPIA was also neuroprotective in two in vivo rat models of cerebral ischaemia: 0.1 mg/kg 7,-OH-EPIA significantly reduced hippocampal cell loss in a model of global forebrain ischaemia, whereas 0.03 mg/kg was neuroprotective in a model of focal ischaemia even when administration was delayed until 6 h after the onset of ischaemia. Taken together, these data demonstrate that 7-hydroxylation of steroids confers neuroprotective efficacy, and that 7,-OH-epiandrosterone represents a novel class of neuroprotective compounds with potential for use in acute neurodegenerative diseases. [source] The prothrombin gene is expressed in the rat kidneyFEBS JOURNAL, Issue 1 2000Implications for urolithiasis research There is considerable interest in determining the role of prothrombin fragments, especially urinary prothrombin fragment 1 (UPTF1), in the pathogenesis of calcium oxalate (CaOx) urinary calculi. This fragment is present in abundance in the matrix of CaOx crystals generated in human urine in vitro and has also been detected in human urinary stones containing calcium. More recently, prothrombin gene expression has been reported in the human kidney. However, studies examining the renal biosynthesis of prothrombin or perhaps only its fragments during experimental lithogenesis, and in consequence, the role of UPTF1 in stone formation, cannot be carried out in humans. The aim of this investigation therefore was to determine whether prothrombin gene expression is present in the rat kidney. Total RNA was isolated from the kidneys and livers of 12 rats. Using reverse transcriptase PCR, mRNAs corresponding to the thrombin and fragment 1 + 2 (F1+2) regions of prothrombin were analysed by agarose gel electrophoresis. The expression of glyceraldehyde 3-phosphate dehydrogenase was also examined to determine whether the quality of the tissue mRNAs was adequate for analyses. The amplified products were identified by sequence analysis. All kidneys displayed evidence of expression of the thrombin and F1+2 domains of the prothrombin gene. Furthermore, the sequences of these PCR-derived products from kidney were identical to those from liver. This suggests that the prothrombins secreted by these two organs are identical. The fact that prothrombin biosynthesis occurs in both the human and rat kidney presents an opportunity for using established rat models of stone disease to evaluate the influence of lithogenic conditions on prothrombin gene expression, and the potential role of UPTF1 in vivo. [source] A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis,,HEPATOLOGY, Issue 6 2005Wim Laleman Reduced intrahepatic endothelial nitric oxide synthase (eNOS) activity contributes to the pathogenesis of portal hypertension (PHT) associated with cirrhosis. We evaluated whether asymmetric dimethylarginine (ADMA), a putative endogenous NOS inhibitor, may be involved in PHT associated with cirrhosis. Two rat models of cirrhosis (thioacetamide [TAA]-induced and bile duct excision [BDE]-induced, n = 10 each), one rat model of PHT without cirrhosis (partial portal vein,ligated [PPVL], n = 10), and sham-operated control rats (n = 10) were studied. We assessed hepatic NOS activity, eNOS protein expression, plasma ADMA levels, and intrahepatic endothelial function. To evaluate intrahepatic endothelial function, concentration,effect curves of acetylcholine were determined in situ in perfused normal rat livers and livers of rats with TAA- or BDE-induced cirrhosis (n = 10) that had been preincubated with either vehicle or ADMA; in addition, measurements of nitrite/nitrate (NOx) and ADMA were made in perfusates. Both models of cirrhosis exhibited decreased hepatic NOS activity. In rats with TAA-induced cirrhosis, this decrease was associated with reduced hepatic eNOS protein levels and immunoreactivity. Rats with BDE-induced cirrhosis had eNOS protein levels comparable to those in control rats but exhibited significantly higher plasma ADMA levels than those in all other groups. In normal perfused liver, ADMA induced impaired endothelium-dependent vasorelaxation and reduced NOx perfusate levels, phenomena that were mimicked by NG -nitro- L -arginine-methyl ester. In contrast to perfused livers with cirrhosis induced by TAA, impaired endothelial cell-mediated relaxation in perfused livers with cirrhosis induced by BDE was exacerbated by ADMA and was associated with a decreased rate of removal of ADMA (34.3% ± 6.0% vs. 70.9% ± 3.2%). In conclusion, in rats with TAA-induced cirrhosis, decreased eNOS enzyme levels seem to be responsible for impaired NOS activity; in rats with biliary cirrhosis, an endogenous NOS inhibitor, ADMA, may mediate decreased NOS activity. (HEPATOLOGY 2005;42:1382,1390.) [source] Biliverdin therapy protects rat livers from ischemia and reperfusion injuryHEPATOLOGY, Issue 6 2004Constantino Fondevila Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1,, tumor necrosis factor ,, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs. (HEPATOLOGY 2004;40:1333,1341.) [source] The nuclear bile acid receptor FXR as a novel therapeutic target in cholestatic liver diseases: Hype or hope?HEPATOLOGY, Issue 1 2004Michael Trauner M.D. Farnesoid X receptor (FXR) is a bile acid,activated transcription factor that is a member of the nuclear hormone receptor superfamily. FXR-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease. [source] The role of radixin in altered localization of canalicular conjugate export pump Mrp2 in cholestatic rat liverHEPATOLOGY RESEARCH, Issue 2 2008Hideyuki Kojima Aim:, Cholestasis has been associated with the endocytic retrieval of multidrug resistance protein 2 (Mrp2), but its mechanism is still unclear. Recent studies have indicated that radixin, a cross-linker between the actin filaments and membrane proteins, may be activated by phosphorylation and may be required for the canalicular localization of Mrp2. Methods:, We investigated the role of radixin in the altered localization of Mrp2 in rat models of intrahepatic (ethinyl estradiol treatment) and extrahepatic (bile duct ligation) cholestasis using immunofluorescence microscopy. The changes in localization and expression were analyzed using Scion Image for Windows. Results:, In both models, Mrp2 was localized outside as well as inside the ZO-1 staining, indicating partial dislocation from the canalicular membrane. In contrast to the steep elevation of the immunostaining intensity curves for Mrp2 in the controls, the corresponding curves in both models were broadened and flattened, confirming endocytic retrieval into the hepatocytes. Mrp2 and radixin were colocalized at the canalicular domain in the controls, whereas in both cholestatic rats they were dissociated at some canaliculi, indicating the disturbed colocalization of Mrp2 and radixin in cholestasis. The fluorescence of phosphorylated radixin, an active form of radixin, markedly decreased in both cholestatic models, which was supported by the reduced peak fluorescence intensities. Conclusion:, The disturbed colocalization of Mrp2 and radixin may contribute to the endocytic retrieval of Mrp2 in cholestasis due to the failure to anchor Mrp2 in the canalicular membrane, in which the phosphorylated radixin may play a major role. [source] Evaluation of analogues of DRDE-07 as prophylactic agents against the lethality and toxicity of sulfur mustard administered through percutaneous routeJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2006A. S. Kulkarni Abstract Sulfur mustard (SM), chemically bis (2-chloroethyl) sulfide is a bifunctional alkylating agent that causes serious blisters on contact with human skin. Although several antidotes have been reported for the systemic toxicity of SM in experimental animals none of them are approved so far and decontamination of SM immediately by physical or chemical means is recommended as the best protection. Two compounds amifostine [S-2(3-aminopropylamino) ethyl phosphorothioate] and DRDE-07 [S-2(2-aminoethylamino) ethyl phenyl sulfide] gave very good protection as an oral prophylactic agent against SM the in mouse model, but in the rat model the protection was only moderate. In the search for more effective and less toxic compounds, a number of analogues of DRDE-07 were synthesised and their protective efficacy was evaluated in mouse and rat models. The LD50 of S-aryl substitution was between 1 and 2 g kg,1 and S-alkyl substitution was more than 2 g kg,1. In the mouse model, DRDE-07, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 gave about 20 fold protection, and DRDE-23 and DRDE-38 gave less protection of 4.8 and 9.0 fold respectively, against percutaneously administered SM. In the rat model, DRDE-07, DRDE-09, DRDE-10 and DRDE-21 gave about two fold protection. Percutaneously administered SM (19.33 mg kg,1) significantly depleted the hepatic GSH content in mice. Pretreatment with DRDE-21 significantly elevated the levels. A 4.4 fold increase in % DNA fragmentation was observed 7 days after SM administration (19.33 mg kg,1) in mice. Pretreatment with DRDE-07, DRDE-09, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 significantly protected the mice from SM induced DNA damage. The histopathological lesions in liver and spleen induced by percutaneously administered SM was reduced by pretreatment with DRDE-07, DRDE-09, DRDE-10 and DRDE-21. These analogues may prove as prototypes for the designing of more effective prophylactic drug for SM. Copyright © 2006 John Wiley & Sons, Ltd. [source] Mechanisms of cardioprotection by lysophospholipidsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2004Joel S. Karliner Abstract The lysophospholipids sphingosine 1-phosphate (S1P) and lysophosphosphatidic acid (LPA) reduce mortality in hypoxic cardiac myocytes. S1P is also cardioprotective in both mouse and rat models of cardiac ischemia/reperfusion (I/R) injury. Although these results are consistent with prior work in other cell types, it is not known what signaling events are critical to cardioprotection, particularly with respect to ceramide and the preservation of mitochondrial function, which is essential for cardiac cell survival. Neither receptor regulation nor signaling has been studied during I/R in the heart with or without the application of S1P or LPA. The role of sphingosine kinase in I/R and in ischemic preconditioning (IPC) has not been defined, nor has the fate or function of S1P generated by this enzyme, particularly during preconditioning or I/R, been elucidated. Whether S1P infused systemically in animal models of myocardial infarction in which survival is an end-point will be hemodynamically tolerated has not been determined. If not, the substitution of agents such as the monosialoganglioside GM-1, which activates sphingosine kinase, or the development of alternative ligands for S1P receptors will be necessary. © 2004 Wiley-Liss, Inc. [source] Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat modelsAGING CELL, Issue 2 2010Li-Fang Hu Summary Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). The present study was designed to examine the therapeutic effect of hydrogen sulfide (H2S, a novel biological gas) on PD. The endogenous H2S level was markedly reduced in the SN in a 6-hydroxydopamine (6-OHDA)-induced PD rat model. Systemic administration of NaHS (an H2S donor) dramatically reversed the progression of movement dysfunction, loss of tyrosine-hydroxylase positive neurons in the SN and the elevated malondialdehyde level in injured striatum in the 6-OHDA-induced PD model. H2S specifically inhibited 6-OHDA evoked NADPH oxidase activation and oxygen consumption. Similarly, administration of NaHS also prevented the development of PD induced by rotenone. NaHS treatment inhibited microglial activation in the SN and accumulation of pro-inflammatory factors (e.g. TNF-, and nitric oxide) in the striatum via NF-,B pathway. Moreover, significantly less neurotoxicity was found in neurons treated with the conditioned medium from microglia incubated with both NaHS and rotenone compared to that with rotenone only, suggesting that the therapeutic effect of NaHS was, at least partially, secondary to its suppression of microglial activation. In summary, we demonstrate for the first time that H2S may serve as a neuroprotectant to treat and prevent neurotoxin-induced neurodegeneration via multiple mechanisms including anti-oxidative stress, anti-inflammation and metabolic inhibition and therefore has potential therapeutic value for treatment of PD. [source] Rapid co-release of interleukin 1, and caspase 1 in spinal cord inflammationJOURNAL OF NEUROCHEMISTRY, Issue 3 2006Anna K. Clark Abstract Mounting evidence supports the hypothesis that pro-inflammatory cytokines secreted by astrocytes and microglia modulate nociceptive function in the injured CNS and following peripheral nerve damage. Here we examine the involvement of interleukin-1, (IL-1,) and microglia activation in nociceptive processing in rat models of spinal cord inflammation. Following application of lipopolysaccharide (LPS) to an ex vivo dorsal horn slice preparation, we observed rapid secretion of IL-1, which was prevented by inhibition of glial cell metabolism and by inhibitors of either p38 mitogen-activated protein kinase (MAPK) or caspase 1. LPS superfusion also induced rapid secretion of active caspase 1 and apoptosis-associated speck-like protein containing a caspase recruitment domain from the isolated dorsal horn. Extensive microglial cell activation in the dorsal horn, as determined by immunoreactivity for phosphorylated p38 MAPK, was found to correlate with the occurrence of IL-1, secretion. In behavioural studies, intrathecal injection of LPS in the lumbar spinal cord produced mechanical hyperalgesia in the rat hind-paws which was attenuated by concomitant injections of a p38 MAPK inhibitor, a caspase 1 inhibitor or the rat recombinant interleukin 1 receptor antagonist. These data suggest a critical role for the cytokine IL-1, and caspase 1 rapidly released by activated microglia in enhancing nociceptive transmission in spinal cord inflammation. [source] Acupuncture in Polycystic Ovary Syndrome: Current Experimental and Clinical EvidenceJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2008E. Stener-Victorin This review describes the aetiology and pathogenesis of polycystic ovary syndrome (PCOS) and evaluates the use of acupuncture to prevent and reduce symptoms related with PCOS. PCOS is the most common female endocrine disorder and it is strongly associated with hyperandrogenism, ovulatory dysfunction and obesity. PCOS increases the risk for metabolic disturbances such as hyperinsulinaemia and insulin resistance, which can lead to type 2 diabetes, hypertension and an increased likelihood of developing cardiovascular risk factors and impaired mental health later in life. Despite extensive research, little is known about the aetiology of PCOS. The syndrome is associated with peripheral and central factors that influence sympathetic nerve activity. Thus, the sympathetic nervous system may be an important factor in the development and maintenance of PCOS. Many women with PCOS require prolonged treatment. Current pharmacological approaches are effective but have adverse effects. Therefore, nonpharmacological treatment strategies need to be evaluated. Clearly, acupuncture can affect PCOS via modulation of endogenous regulatory systems, including the sympathetic nervous system, the endocrine and the neuroendocrine system. Experimental observations in rat models of steroid-induced polycystic ovaries and clinical data from studies in women with PCOS suggest that acupuncture exert long-lasting beneficial effects on metabolic and endocrine systems and ovulation. [source] Aqueous versus non-aqueous salt delivery strategies to enhance oral bioavailability of a mitogen-activated protein kinase-activated protein kinase (MK-2) inhibitor in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2009Po-Chang Chiang Abstract A potent pyridine-containing MK2 inhibitor has recently been internally discovered. In pre-clinical dosing, the low solubility of the neutral form limited oral bioavailability and dose escalation in toxicity studies. A mesylate salt was developed as part of a formulation strategy to enhance both oral bioavailability and dose escalation orally in pre-clinical rat studies. Several non-aqueous systems were used to deliver the mesylate salt, which resulted in varied oral bioavailability. It was found that administration of an aqueous chaser immediately after dosing drastically increased the oral bioavailability of the salt. This finding implies that the quantity of water present in vivo is an important consideration when evaluating salts of free bases with low aqueous solubility in pre-clinical in vivo rat models where limited aqueous vehicle may be presented. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:248,256, 2009 [source] The importance of brain PGE2 inhibition versus paw PGE2 inhibition as a mechanism for the separation of analgesic and antipyretic effects of lornoxicam in rats with paw inflammationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2009Dr Nobuko Futaki Abstract Objectives Lornoxicam is a non-selective cyclooxygenase inhibitor that exhibits strong analgesic and anti-inflammatory effects but a weak antipyretic effect in rat models. Our aim was to investigate the mechanism of separation of potencies or analgesic and antipyretic effecls of lornoxicam in relatioin to its effect on prostaglandin E2 (PGE2) production in the inflammatory paw and the brain. Methods A model of acute or chronic paw inflammation was induced by Freund's complete adjuvant injection into the rat paw. Lornoxicam (0.01,1 mg/kg), celecoxib (0.3,30 mg/kg) or loxoprofen (0.3,30 mg/kg) was administered orally to the rats and the analgesic and antipyretic effects were compared. The paw hyperalgesia was assessed using the Randall,Selitto test or the flexion test. Dorsal subcutaneous body temperature was measured as indicator of pyresis. After the measurement of activities, the rats were sacrificed and the PGE2 content in the paw exudate, cerebrospinal fluid or brain hypothalamus was measured by enzme-immunoassay. Key findings In a chronic model of arthritis, lornoxicam, celecoxib and loxoprofen reduced hyperalgesia with an effective dose that provides 50% inhibition (ED50) of 0.083, 3.9 and 4.3 mg/kg respectively, whereas the effective dose of these drugs in pyresis was 0.58, 0.31 and 0.71 mg/kg respectively. These drugs significantly reduced the PGE2 level in paw exudate and the cerebrospinal fluid. In acute oedematous rats, lornoxicam 0.16 mg/kg, celecoxib 4 mg/kg and loxoprofen 2.4 mg/kg significantly reduced hyperalgesia to a similar extent. On the other hand, lornnoxicam did not affect the elevated body temperature, whereas celecoxib and loxoprofen siginificantly reduced the pyrexia to almost the normal level. These drugs significantly reduced the PGE2 level in inflamed paw exudate lo almost the normal level. On the other hand, lornoxicam did not change PGE2 level in the brain hypothalamus, whereas celecoxib and loxoprofen strongly decreased it. Conclusions Lornoxicam exhibits strong analgesic but weak antipyretic effects in rats with paw inflammation. Such a separation of effects is related to its efficacy in the reduction of PGE2 levels in the paw and brain hypothalamus. [source] Effect of sodium houttuyfonate on myocardial hypertrophy in mice and ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2009Jian Ping Gao Abstract Objectives The aim of the study was to determine the effect of sodium houttuyfonate on myocardial hypertrophy and its mechanism of action in mice and rats. Methods A mouse model of myocardial hypertrophy was established by subcutaneous injection with isoproterenol. Mice were randomly divided into five groups: normal control; isoproterenol control; isoproterenol plus metoprolol; isoproterenol plus low- and high-dose sodium houttuyfonate. A rat model of myocardial hypertrophy was established by intraperitoneal injection with l -thyroxine. Rats were randomly divided into five groups: normal control; l -thyroxine control; l -thyroxine plus captopril; l -thyroxine plus low- and high-dose sodium houttuyfonate. At the end of the experiments, the left ventricular weight index and heart weight index were determined in mice and rats, the size of cardiomyocytes was measured in rats and the concentrations of cAMP in plasma and angiotensin II in ventricular tissue of mice were detected by radioimmunoassay. The endothelin-1 concentration was measured by radioimmunoassay and the hydroxyproline content was measured by a digestive method in ventricular tissue of rats. Key findings After 7,9 days of treatment, sodium houttuyfonate significantly reduced the left ventricular weight index and heart weight index in mice and rats with myocardial hypertrophy, decreased the size of cardiomyocytes in rats, and reduced the content of cAMP and angiotensin II in mice with myocardial hypertrophy. It also decreased the endothelin-1 concentration and the hydroxyproline content in ventricular tissue in rats. Conclusions Sodium houttuyfonate can inhibit myocardial hypertrophy in mouse and rat models by restricting the activity of the sympathetic nervous system and decreasing the levels of angiotensin II and endothelin-1 in ventricular tissue. [source] In-vitro and in-vivo antioxidant activity of different extracts of the leaves of Clerodendron colebrookianum Walp in the ratJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2003D. Rajlakshmi ABSTRACT The in-vitro antioxidant activities of different concentrations of the water, alcoholic, petroleum ether and ethyl acetate extracts of the dried leaves of Clerodendron colebrookianum Walp, and in-vivo antioxidant activity of the water extract was studied in experimental rat models. The results obtained from in-vitro lipid peroxidation induced by FeSO4 -ascorbate in rat liver homogenate showed a significant inhibition of lipid peroxidation by different extracts of C. colebrookianum leaf. Water extracts at concentrations (w/v) of 1:30, 1:50, 1:200 and 1:1000 showed the strongest inhibitory activity over the other organic extracts, suggesting maximum antioxidant effect. Chronic feeding of the water extract to Wistar albino rats (both sexes, 150,200g) in 1 or 2g kg,1/day doses for 14 days significantly increased the ferric reducing ability of plasma by 19% and 40% on the seventh day, and by 45% and 57% on the fourteenth day of treatment, respectively. Thiobarbituric acid reactive substances (TBARS), as a marker of lipid peroxidation, and some cellular antioxidants (superoxide dismutase, catalase and reduced glutathione) were estimated in heart, liver and kidney. There was a significant reduction in hepatic and renal TBARS with both the doses, without any change in myocardial TBARS. There was no change in the level of antioxidants in heart, liver and kidney, except for the hepatic superoxide dismutase. The findings of this study showed that the leaf extract of C. colebrookianum increased the antioxidant capacity of blood and had an inhibitory effect on the basal level of lipid peroxidation of liver and kidney. This lends scientific support to the therapeutic use of the plant leaves, as claimed by the tribal medicine of North-East India. [source] Adolescent C57BL/6J (but not DBA/2J) Mice Consume Greater Amounts of Limited-Access Ethanol Compared to Adults and Display Continued Elevated Ethanol Intake into AdulthoodALCOHOLISM, Issue 4 2010Eileen M. Moore Background:, Alcohol use is common during the adolescent period, a time at which a number of crucial neurobiological, hormonal, and behavioral changes occur (Spear, 2000). In order to more fully understand the complex interaction between alcohol use and these age-typical neurobiological changes, animal models must be utilized. Rodents experience a developmental period similar to that of adolescence. Although rat models have shown striking adolescent-specific differences in sensitivity to ethanol, little work has been done in mice despite the fact that the C57BL/6J (B6) and DBA2/J (D2) mice have been shown to markedly differ in ethanol preference drinking and exhibit widely different sensitivities to ethanol. Methods:, The current study examined ethanol intake in adolescent and adult B6 and D2 mice using a limited access alcohol exposure paradigm called Drinking in the Dark (DID). Additionally, the effect of adolescent (or adult) ethanol exposure on subsequent adult ethanol intake was examined by re-exposing the mice to the same paradigm once the adolescents reached adulthood. We hypothesized that adolescent (P25,45) mice would exhibit greater binge-like alcohol intake compared to adults (P60,80), and that B6 mice would exhibit greater binge-like alcohol intake compared to D2 mice. Moreover, we predicted that relative difference in binge-like alcohol intake between adolescents and adults would be greater in D2 mice. Results:, Adolescent B6 mice consumed more ethanol than adults in the DID model. There was no difference between adolescent and adult D2 mice. Conclusions:, This work adds to the literature suggesting that adolescents will consume more ethanol than adults and that this exposure can result in altered adult intake. However, this effect seems largely dependent upon genotype. Future work will continue to examine age-related differences in ethanol intake, preference, and sensitivity in inbred mouse strains. [source] Linaclotide , a secretagogue and antihyperalgesic agent , what next?NEUROGASTROENTEROLOGY & MOTILITY, Issue 3 2010A. E. Bharucha Abstract Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase-C (GC-C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation- and stress-induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint-induced stress) but not in naďve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC-C receptors. Dose,effect relationships of linaclotide were complicated and non-linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC-C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress-induced increased intestinal permeability. However, the data need to be confirmed in humans and in long-term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide's known effects on epithelial GC-C receptors. [source] ,3 -Adrenoceptors in urinary bladder,,NEUROUROLOGY AND URODYNAMICS, Issue 6 2007Osamu Yamaguchi Abstract The ,-adrenoceptor (AR) is currently classified into ,1, ,2, and ,3 subtypes. A third subtype, ,3 -AR, was first identified in adipose tissue, but has also been identified in smooth muscle tissue, particularly in the gastrointestinal tract and urinary bladder smooth muscle. There is a predominant expression of ,3 -AR messenger RNA (mRNA) in human bladder, with 97% of total ,-AR mRNA being represented by the ,3 -AR subtype and only 1.5 and 1.4% by the ,1 -AR and , 2 -AR subtypes, respectively. Moreover, the presence of ,1 -, ,2 -, and ,3 -AR mRNAs in the urothelium of human bladder has been identified. The distribution of ,-AR subtypes mediating detrusor muscle relaxation is species dependent, the predominant subtype being the ,3 -AR in humans. Recent studies have suggested that cAMP-dependent routes are not exclusive mechanisms triggering the ,-AR-mediated relaxation of smooth muscle. It has been demonstrated in rats detrusor muscle that cAMP plays a greater role in ,-adrenergic relaxation against basal tone than against KCl-induced tone and that conversely calcium-activated K+ channels (BKca channels) play a greater role under the latter circumstances. In rat models, ,3 -AR agonists increase bladder capacity without influencing bladder contraction and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of ,3 -AR agonists as therapy for overactive bladder (OAB), pharmacological differences exist between rat and human ,3 -ARs. Development of compounds with high selectivity for the human ,3 -AR, identified by screening techniques using cell lines transfected with the human ,1 -, ,2 -, and ,3 -AR genes, may mitigate against such problems. The association between the tryptophan 64 arginine polymorphism in the ,3 -AR gene and idiopathic OAB is discussed. Neurourol. Urodynam. 26:752,756, 2007. © 2007 Wiley-Liss, Inc. [source] Assessment of blood volume, vessel size, and the expression of angiogenic factors in two rat glioma models: a longitudinal in vivo and ex vivo studyNMR IN BIOMEDICINE, Issue 10 2008Samuel Valable Abstract Assessment of angiogenesis may help to determine tumor grade and therapy follow-up. In vivo imaging methods for non-invasively monitoring microvasculature evolution are therefore of major interest for tumor management. MRI evaluation of blood volume fraction (BVf) and vessel size index (VSI) was applied to assess the evolution of tumor microvasculature in two rat models of glioma (C6 and RG2). The results show that repeated MRI of BVf and VSI , which involves repeated injection of an iron-based MR contrast agent , does not affect either the physiological status of the animals or the accuracy of the MR estimates of the microvascular parameters. The MR measurements were found to correlate well with those obtained from histology. They indicate that microvascular evolution differs significantly between the two glioma models, in good agreement with expression of angiogenic factors (vascular endothelial growth factor, angiopoietin-2) and with activities of matrix metalloproteinases, also assessed in this study. These MRI methods thus provide considerable potential for assessing the response of gliomas to anti-angiogenic and anti-vascular agents, in preclinical studies as well as in the clinic. Furthermore, as differences between the fate of tumor microvasculature may underlie differences in therapeutic response, there is a need for preclinical study of several tumor models. Copyright © 2008 John Wiley & Sons, Ltd. [source] Diffusion tensor MRI in rat models of invasive and well-demarcated brain tumorsNMR IN BIOMEDICINE, Issue 3 2008Sungheon Kim Abstract Diffusion tensor imaging (DTI) and its metrics, such as mean diffusivity (MD) and fractional anisotropy (FA), have been used to detect the extent of brain tumors and understand tumor growth and its influence on the surrounding tissue. However, there are conflicting reports on how DTI metrics can be used for tumor diagnosis. The physiological interpretation of these metrics in terms of tumor growth is also not clear. The objective of this study was to investigate the DTI parameters in two rat brain tumor models (9L and F98) with different patterns of aggressiveness by longitudinal monitoring of tumor growth and comparing the DTI parameters of these two tumor models. In addition to the standard DTI metrics, MD and FA, we measured other metrics representing diffusion tensor shape, such as linear and planar anisotropy coefficients (CL and CP), and orientational coherence measured by lattice index (LI), to characterize the two tumor models. The 9L tumor had higher FA, CL, and LI than the F98 tumor. F98 had a larger difference in anisotropies between tumor and peritumor regions than 9L. From the eigenvalues, it was found that the increase in CL and trace of the 9L tumor was due to an increase in the primary eigenvalue, whereas the increase in CP in the peritumor region was due to an increase in both primary and secondary eigenvalues and a decrease in tertiary eigenvalue. Our results indicate that shape-oriented anisotropy measures, such as CL and CP, and orientational coherence measures, such as LI, can provide useful information in differentiating these two tumor models and also differentiating tumor from peritumoral regions. 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