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PubMed2006

Current scenario of drug development for leishmaniasis.

Although three new drugs or drug formulations, liposomal amphotericin B (AmBisome), miltefosine and paromomycin should be available for the treatment of visceral leishmaniasis (VL) within the next year, they all suffer from limitations of either cost, specific toxicities or parenteral administration. As part of research to identify better treatments for VL and cutaneous leishmaniasis (CL), alternative and potentially cheaper formulations of amphotericin B, alklyphosphocholines other than miltefosine and improved formulations of paromomycin for CL have been identified. Other drugs or compounds that have demonstrated activity in experimental rodent models of infection include licochalcone derivatives, quinoline derivatives, bisphosphonates and a maesabalide; further chemistry based upon these leads is warranted. The process for discovery and development of new antileishmanials would also benefit from improved models, for example, transfected parasites, and non invasive methods of measuring parasite load in rodent models of infection.

Amphotericin B↗
PubMed2003

Rodent nutritional model of non-alcoholic steatohepatitis: species, strain and sex difference studies.

BACKGROUND AND AIM: The methionine choline-deficient (MCD) diet leads to steatohepatitis in rodents. The aim of the present study was to investigate species, strain and sex differences in this nutritional model of non-alcoholic steatohepatitis (NASH). METHODS: Male and female Wistar, Long-Evans and Sprague-Dawley rats, and C57/BL6 mice (n = 6 per group) were fed a MCD diet for 4 weeks. Control groups received an identical diet supplemented with choline bitartrate (0.2% w/w) and methionine (0.3% w/w). Liver pathology (steatosis and inflammation) and ultrastructure, liver lipid profile (total lipids, triglycerides, lipid peroxidation products), liver : body mass ratios and serum alanine aminotransferase (ALT) levels were compared between these groups. RESULTS: The MCD diet-fed male rats developed greater steatosis (P < 0.001), had higher liver lipid content (P < 0.05) and had higher serum ALT levels (P < 0.005) than did female rats. Wistar rats (both sexes) had higher liver lipid levels (P < 0.05), serum ALT levels (P < 0.05), and liver mass : body mass ratios (P < 0.025) than did Long-Evans and Sprague-Dawley rats. In female groups, Wistar rats showed greater fatty change than did the other two strains (P < 0.05). All rats fed the MCD diet developed hepatic steatosis, but necrosis and inflammation were minor features and fibrosis was absent. Compared with Wistar rats, male C57/BL6 mice showed a marked increase in inflammatory foci (P < 0.001), end products of lipid peroxidation (free thiobarbituric acid reactive substances) (P < 0.005), and mitochondrial injury, while showing less steatosis (P < 0.005), lower hepatic triglyceride levels, (P < 0.005) and lower early lipid peroxidation products (conjugated dienes and lipid hydroperoxides; P < 0.005 and P < 0.01, respectively). CONCLUSIONS: The Wistar strain and the male sex are associated with the greatest degree of steatosis in rats subjected to the MCD diet. Of the groups studied, male C57/BL6 mice develop the most inflammation and necrosis, lipid peroxidation, and ultrastructural injury, and best approximate the histological features of NASH.

Alanine Transaminase↗
PubMed1991

Suitability of rodent tumor models for experimental PET with L-[1-11C]tyrosine and 2-[18F]fluoro-2-deoxy-D-glucose.

The applicability of five different rodent tumors for experimental PET has been investigated. L-[1-11C]Tyrosine was a better indicator for the growth activity of the tumors than [18F]FDG. For experimental PET, the three mice models studied appeared inappropriate; the Lewis lung tumor and the fibrosarcomateous FIO 26 had too low a tyrosine utilization, while the lymphosarcomateous LY showed insufficient tumor-to-background ratios. Of the two rat models, the necrotic Walker 256 carcinosarcoma was less suitable. By using L-[1-11C]tyrosine, the solid, rhabdomyosarcoma tumor offers good possibilities of monitoring therapeutic interventions with PET.

Animals↗
PubMed2003

Expression of hepatoma-derived growth factor in hepatocarcinogenesis.

BACKGROUND AND AIM: The present study investigated the expression of hepatoma-derived growth factor (HDGF) in human hepatocellular carcinoma (HCC) and in the liver during hepatocarcinogenesis in two rodent models. METHODS: Expression of HDGF was analyzed using northern blotting and immunohistochemistry in the human and rodent models. RESULTS: Hepatoma-derived growth factor was more highly expressed in HCC than in the adjacent liver in humans with hepatitis, as shown by northern blotting. Using immunohistochemistry with the specific anti-HDGF antibody, HDGF was more strongly and frequently expressed in the nucleus and cytoplasm of HCC cells than in the adjacent normal hepatocytes. Hepatoma-derived growth factor was also more strongly expressed in the tumors than in the adjacent fatty liver of fatty liver Shionogi (FLS) mice, than in the cirrhotic liver of choline-deficient amino acid feeding rats, as shown by northern blotting and immunohistochemistry. In the liver of FLS mice, HDGF expression increased gradually from the age of 24 weeks through to 52 weeks after birth, showing that HDGF expression was already increased at an early stage before tumor development. In the non-tumorous liver with fatty change, the foci expressing HDGF appeared at 24 weeks of age, which were the activated macrophage clusters with enhanced DNA synthesis and fat droplets. It is suggested that HDGF was secreted or released from these foci and stimulated hepatocyte proliferation in a paracrine manner in FLS mice, and stimulated the proliferation of hepatic tumor cells in an autocrine manner. CONCLUSIONS: The present findings suggest that HDGF plays an important role in the development or progression of HCC in humans and rodents.

Animals↗
PubMed1993

Metabolic basis of the synergistic antitumor activities of 5-fluorouracil and cisplatin in rodent tumor models in vivo.

The biochemical mechanism of the synergy of 5-fluorouracil (FUra) and cisplatin (CDDP) was studied using transplantable tumors in rodents in vivo. The reduced folate 5,10-methylenetetrahydrofolate (CH2FH4) and its precursor tetrahydrofolate (FH4) are essential cofactors for the formation of a tight ternary complex of thymidylate synthase (TS) and 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) derived from FUra. Intraperitoneal administration of CDDP (5 mg/kg) inhibited the incorporation of exogenous L-methionine into ascitic tumor cells and increased the levels of CH2FH4 and FH4 in ascitic Yoshida sarcoma and P-388 cells transplanted into rats and mice to levels about 2-3 times those measured in cells from animals that were not treated with CDDP. Preincubation with 10(-6) M FUra in Hanks' medium inhibited [6-3H]-2'-deoxyuridine incorporation into DNA of tumor cells from CDDP-treated rats 3 times more than that into cells from untreated rats, indicating that the inhibition of TS by FdUMP derived from FUra was enhanced in the presence of CH2FH4. Intraperitoneal administration of CDDP on day 1 and continuous infusion of FUra from day 1 to day 6 had synergistic effects in inhibiting tumor growth in Yoshida sarcoma-bearing rats. Oral administration of UFT, a combined form of 1 M tegafur and 4 M uracil, for 7 consecutive days beginning at 24 h after tumor implantation and a single i.p. injection of CDDP on day 1 had a significantly greater effect than did either agent alone. These results suggest that CDDP significantly enhances FUra cytotoxicity by inhibiting intracellular L-methionine metabolism and consequently increasing the reduced folate pool in mammalian tumor models in vivo.

Animals↗
PubMed1995

Augmented expression of the obese gene in the adipose tissue from rats fed high-fat diet.

Expression of the obese (ob) gene is augmented in the adipose tissue in several rodent models of genetic obesity. In the present study, we examined the ob gene expression in a rodent model of acquired obesity obtained by pure overfeeding of normal rats. Male Sprague-Dawley rats at 8 weeks of age were fed standard diet or high-fat diet. Rats fed high-fat diet developed moderate degree of obesity, hyperglycemia, and hyperlipidemia as compared with rats fed standard diet. Northern blot analysis revealed that the ob gene is expressed abundantly in the adipose tissue obtained from the epididymal, mesenteric, subcutaneous, retroperitoneal, and interscapular fat pads in rats fed standard diet. Expression of the ob gene was augmented in all the adipose tissue examined in rats fed high-fat diet. The present study demonstrates that the ob gene expression is augmented in the adipose tissue in diet-induced obesity, thereby suggesting the pathophysiologic roles of the ob gene in acquired obesity.

Adipose Tissue↗
PubMed1999

Experimental cardiac tachyarrhythmias in guinea pigs.

Despite years of intense research into the mechanisms of defibrillation, there remain many unanswered questions. In many fields, hypotheses are first tested in rodent models before confirming the results in larger animals. This work suggests the guinea pig as a rodent model for defibrillation. Twenty-eight guinea pigs were studied, all male retired breeders weighing over 900 g. T-wave stimuli (upper limit of vulnerability [ULV]) were given after 15 rapid pacing beats, since the rapid pacing has been suggested to extend the tachyarrhythmia. Defibrillation (DF) was attempted after 5 seconds. The correlation between the ULV50 and DF50 in guinea pigs (0.82, n = 8) is very close to that seen in dogs (0.85). Also, the sensitivity of the DF50 to waveform is similar (476 +/- 176 for monophasic vs 364 +/- 94 V for biphasic P < 0.005, n = 10). The dose-response curve widths (2.3 +/- 1.7 for ULV vs 1.9 +/- 1.8 for defibrillation, n = 10) show the same trend of increasing curve widths for ULV, and similar magnitude to dogs (mean 1.8). We rarely (<1.5%) observed spontaneous conversion in less than 10 seconds. The guinea pig can be used as a model for defibrillation as it shows many of the same characteristics as dogs.

Animals↗
PubMed2005

Genetic variations of tubular sodium reabsorption leading to "primary" hypertension: from gene polymorphism to clinical symptoms.

The definition of the most appropriate strategy to demonstrate causation of a given genetic-molecular mechanism in a complex multifactorial polygenic disease like hypertension is hampered by the underestimation of the complexity arising from the genetic and environmental interactions. To disentangle this complexity, we developed a strategy based on six steps: 1) isolation of a rodent model of hypertension (Milan hypertensive strain and Milan normotensive strain) that shares some pathophysiological abnormalities with human primary hypertension; 2) definition in the model of the sequence of events linking these abnormalities to a genetic molecular mechanism; 3) determination of the polymorphism of the three adducin genes discovered in the model both in rats and in humans; 4) comparison at biochemical and physiological levels between the rodent models and the hypertensive carriers of the "mutated" gene variants; 5) evaluation of the impact of the adducin genes in hypertension and its organ complications with association and linkage studies in humans, also considering the genetic and environmental interactions; and 6) development of a pharmacogenomic approach aimed at establishing the therapeutic benefit of a drug interfering with the sequence of events triggered by adducin and their effect's size. The bulk of data obtained demonstrates the importance of a multidisciplinary approach considering a variety of genetic and environmental interactions. Adducin functions within the cells as a heterodimer composed of a combination of three subunits. Each of these subunits is coded by genes mapping to different chromosomes. Therefore, the interaction among these genes, taken together with the interactions with other modulatory genes or with the environment, is indispensable to establish the adducin clinical impact. The hypothesis that adducin polymorphism favors the development of hypertension via an increased tubular sodium reabsorption is well supported by a series of consistent experimental and clinical data. Many mechanistic aspects, underlying the link between these genes and clinical symptoms, need to be clarified. The clinical effect size of adducin must be established also with the contribution of pharmacogenomics with a drug that selectively interferes with the sequence of events triggered by the mutated adducin.

Animals↗
PubMed2005

Cytokines as potential biomarkers of liver toxicity.

Several important drug classes show pre-clinical hepatotoxicity or, in some cases hepatotoxicity in man in Phase III/IV not predicted by pre-clinical studies. This hepatotoxicity is associated with death of the parenchyma by both necrosis and apoptosis. Recent data have implicated molecular mediators of the immune response such as tumor necrosis factor alpha (TNFalpha), interleukin 1beta(1L-1beta) and interleukin 6 (IL6) in acute and chronic liver damage. These cytokines networks have been implicated in mediating the hepatic response to xenobiotics as diverse as PPAR ligands, acetaminophen and phenobarbitone. Thus, pro-inflammatory cytokines such as TNFalpha, IL1 beta and IL6 are released into the bloodstream both from the liver and from distal sites during hepatic toxic injury. Probably due to differences in the responses of rodent and human hepatocytes to cytokines, some clinical hepatotoxicities are not predicted by rodent models. However, the cytokine changes implicated in this human hepatic cell death could be manifest in rodent models and thus could be detected at the molecular level. Here we review the role of cytokines in different types of drug-induced liver injury and discuss whether these cytokine fingerprints are potential biomarkers of so-called idiosyncratic human liver toxicity.

Animals↗
PubMed1991

Animal test systems to study behavioral dysfunctions of neurodegenerative disorders.

The Eighth International Neurotoxicology Conference, Role of Toxicants in Neurological Disorders (1990), evaluated the evidence that chemical exposures may play a role in the development of neurodegenerative disorders. This article describes the major neurodegenerative disorders (Amyotrophic Lateral Sclerosis, Huntington disease, Parkinson disease, and Alzheimer disease) addressed at the conference, followed by a description of test systems or models developed to study behavioral aspects of these disorders in animals. However, due to the complexity of the disorders and the species in which they are found, fully-developed models in animals of neurodegenerative disorders are lacking. This suggests the need for a clear strategy for selecting behavioral tests in animals to study aspects of any neurodegenerative disorders. Such a strategy is here exemplified for Alzheimer disease (AD) as a prototypical neurodegenerative disorder. Since an animal model cannot provide the full range of effects of human neurodegenerative diseases, particularly AD which produces incompletely characterized cognitive deficits, a rodent model must at this time be drawn from multiple sources, including: (1) Tests currently used to identify in rodents deficits associated with AD; (2) tests to identify Alzheimer-related signs in patients; and, (3) tests that relate to theoretical constructs of human and animal cognition. A battery that draws from those sources could include tests of: (a) Spatial learning and memory (Morris Water Maze and Radial Arm Maze), (b) delayed recall match-to-sample; (c) serial response learning; and, (d) visual discrimination (e.g., vertical vs. horizontal stimuli). This battery will identify behavioral changes characteristic of early-, middle- and late-stage AD, afford the potential to relate the findings to theoretical constructs of cognition, and evaluate learning capabilities not previously studied in rodent models of neurodegenerative disorders.

Alzheimer Disease↗
PubMed2000

Characterization of the inflammatory response to biomaterials using a rodent air pouch model.

Using a rodent air pouch, the inflammatory responses to biomaterials with distinct physical properties and chemical compositions were compared. The polymers examined were expanded poly(tetrafluoroethylene) (ePTFE), silicone, low-density polyethylene (LDPE), poly(L-lactic acid) (PLLA), poly(desaminotyrosyl-tyrosine ethyl carbonate) [poly(DTE carbonate)], and poly(desaminotyrosyl-tyrosine benzyl carbonate) [poly(DTBzl carbonate)]. We found that implantation of disks (4.5-4.8 mm) of these materials into rodent air pouches for 2 days had no effect on the number or type of cells recovered relative to sham controls. With each of the materials, macrophages were the predominant cell type identified (60-75%), followed by granulocytes (20-25%) and lymphocytes (10%). Implantation of poly(DTE carbonate), ePTFE, LDPE, or poly(DTBzl carbonate) into the pouches for 2 days caused an increase in release of superoxide anion by the pouch cells. Cells from pouches containing poly(DTE carbonate) also released more hydrogen peroxide and were more phagocytic. In contrast, PLLA and silicone had no effect on the functional activity of cells recovered from the pouches. Prolonging the implantation time of poly(DTE carbonate) or PLLA to 7 days did not alter the number or type of cells isolated from the pouches. However, cells from pouches containing poly(DTE carbonate) for 7 days continued to produce increased quantities of superoxide anion relative to sham control pouch cells. These results suggest that the air pouch model is a highly sensitive method and therefore useful for evaluating the functional responses of inflammatory cells to biomaterials.

Animals↗
PubMed2004

The role of lymph factors in lung injury, bone marrow suppression, and endothelial cell dysfunction in a primate model of trauma-hemorrhagic shock.

Studies in rodent models of trauma-hemorrhagic shock (T/HS) have shown that factors contained in the intestinal lymph are responsible for acute lung injury and bone marrow suppression, and that they contribute to a systemic inflammatory state. Because results observed in rodent T/HS models may not fully reflect the response of injured patients, it is necessary to determine if these results can be replicated in primates before the institution of invasive studies in humans. Thus, the three goals of this study were to determine if diversion of thoracic duct lymph reduced T/HS-induced lung injury; to compare the biologic activity of thoracic duct lymph from baboons subjected to T/HS or trauma sham-shock (T/SS); and to compare the biologic activity and composition of plasma from baboons subjected to T/SS, T/HS, and T/HS with thoracic duct lymph drainage. Three groups of baboons were studied: T/SS plus lymph diversion via a thoracic duct catheter, T/HS, and T/HS plus lymph diversion (T/HS-LD). The trauma component consisted of a neck dissection with resection of the proximal clavicle plus a laparotomy. HS was to a mean arterial pressure of 40 mmHg and was maintained at 40 mmHg until the base excess reached -5 mEq or the total shock period reached 3 h. Volume resuscitation was carried out by reinfusing the shed blood plus crystalloids. Before, during, and after the T/HS or T/SS period, blood and lymph samples were obtained for analysis, and lung samples were harvested for measurement of lung wet-to-dry ratio at 5 h after the end of the shock period. Diversion of thoracic duct lymph prevented T/HS-induced lung injury as reflected in lung wet-to-dry weight ratios (T/SS = 4.6 +/- 0.5; T/HS+LD = 4.8 +/- 0.7; T/HS = 5.4 +/- 0.6; P < 0.05). Lymph from the T/HS group collected during the early postshock period was cytotoxic for human endothelial cells (HUVECs; 16% vs. 100% survival in T/SS lymph) and increased HUVEC monolayer permeability almost 2-fold (P < 0.01). T/HS lymph and plasma also suppressed red blood cell (erythroid burst-forming unit) and white blood cell (granulocyte-monocyte colony-forming unit) progenitor cell growth of human bone marrow to approximately 50% of control, whereas T/SS lymph and plasma were not suppressive (P < 0.05). Plasma cytokine levels were increased to a similar degree in the two T/HS groups. Thus, in a primate model of T/HS, gut-derived factors carried in the lymph potentiates lung injury and endothelial dysfunction, and suppresses bone marrow progenitor cell growth.

Animals↗
PubMed2002

Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy.

PURPOSE: Animal models in which seizures are elicited by chemical or electrical means are commonly used for identification and preclinical testing of novel antiepileptic drugs (AEDs). Such models have been successful in discovering all the new AEDs. However, despite the high efficacy of AEDs against elicited seizures in rodent models, a significant proportion of epilepsy patients with spontaneous recurrent seizures is resistant to these drugs. It is not known whether drug testing in rodent models with spontaneous recurrent seizures would yield a more predictive result with respect to AED efficacy in the clinic. This led us to test one of the novel AEDs, levetiracetam (LEV), in a rat model of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures. METHODS: Wistar rats were subjected to pilocarpine-induced status epilepticus and recorded for spontaneous recurrent seizures in the months after pilocarpine treatment. A group of rats with frequent spontaneous seizures was used for the drug trial with LEV. The experimental protocol for drug testing in these rats was as follows. For 2 weeks, rats received subcutaneous implantation of osmotic minipumps filled with saline (predrug control period), followed by a 2-week period with implantation of LEV-filled minipumps (drug period), after which pumps were replaced by drug-free pumps for 2 weeks (postdrug control period). The LEV concentration in the pumps during the drug period was adjusted to give daily doses resulting in the maximal plasma concentration range determined previously in patients with TLE during prolonged treatment with LEV. During the 6 weeks of the experiment in epileptic rats, seizures were recorded by video monitoring. RESULTS: Average seizure frequency during the pre- and postdrug control period in a group of eight epileptic rats was 21 and 25 seizures. This was reduced to an average seizure frequency of 8 seizures during the 2 weeks of treatment with LEV. However, the individual response of rats to LEV varied markedly from complete seizure control to no effect at all, although plasma drug levels were within the therapeutic range in all rats. When seizure frequency was separately calculated for the first and second week of treatment, the significant anticonvulsant effect determined in the first week was partially diminished in the second week, suggesting that tolerance may have developed in some of the rats. CONCLUSIONS: The data demonstrate that interesting results can be obtained by drug testing in epileptic rats, giving a more realistic prediction of clinical efficacy than results from drug testing in animal models with elicited seizures. Thus, although drug trials in rats with spontaneous recurrent seizures are laborious and time-consuming, such trials should be added to the preclinical characterization of novel AEDs.

Animals↗
PubMed2004

Joint cytokine quantification in two rodent arthritis models: kinetics of expression, correlation of mRNA and protein levels and response to prednisolone treatment.

Biomarker quantification in disease tissues from animal models of rheumatoid arthritis (RA) can help to provide insights into the mechanisms of action of novel therapeutic agents. In this study we validated the kinetics of IL-1beta, TNF-alpha and IL-6 mRNA and protein expression levels in joints from DBA/1OlaHsd murine collagen-induced arthritis (CIA) and Lewis rat Streptococcal cell wall (SCW)-induced arthritis by real-time polymerase chain reaction (PCR) TaqMan and Enzyme-linked immunosorbent assay (ELISA). Prednisolone was used as a reference to investigate any correlation between clinical response and cytokine levels at selected time-points. To our knowledge this is the first report showing a close pattern of expression between mRNA and protein for IL-1beta and IL-6, but not for TNF-alpha, in these two models of RA. The kinetics of expression for these biomarkers suggested that the optimal sampling time-points to study the effect of compounds on both inflammation and cytokine levels were day 4 postonset in CIA and day 3 after i.v challenge in SCW-induced arthritis. Prednisolone reduced joint swelling through a mechanism associated with a reduction in IL-1beta and IL-6 protein and mRNA expression levels. At the investigated time points, protein levels for TNF-alpha in arthritic joints were lower than the lower limit of detection of the ELISA, whereas mRNA levels for this cytokine were reliably detected. These observations suggest that RT-PCR TaqMan is a sensitive technique that can be successfully applied to the quantification of mRNA levels in rodent joints from experimental arthritis models providing insights into mechanisms of action of novel anti-inflammatory drugs.

Animals↗
PubMed2002

A review of studies on the effects of ultraviolet irradiation on the resistance to infections: evidence from rodent infection models and verification by experimental and observational human studies.

Recent studies on the immunosuppressive effects of ultraviolet radiation (UVR) and the related resistance to infections in rodents and humans are presented. The waveband dependency of trans-to-cis isomerisation of urocanic acid in the stratum corneum and the role of DNA damage in UVR-induced erythema and immunosuppression were investigated to further elucidate the underlying mechanisms. Furthermore, human experimental studies on UVR-induced immunomodulation were performed. It appeared that the doses needed to suppress various immune parameters in humans (e.g. NK activity, contact hypersensitivity) were higher than those needed in experiments in rodents. Still, extrapolation of experimental animal data to the human situation showed that UVR may impair the resistance to different systemic infections at relevant outdoor doses. In observational human studies we aimed to substantiate the relevance of UVR for infections in humans. It was shown that sunny season was associated with a slightly retarded but clinically non-relevant antibody response to hepatitis B vaccination. Furthermore, sunny season appeared to be associated with a small decline in the number of CD4+ T-helper cells in a cohort of HIV-infected persons and a higher recurrence of herpes simplex and herpes zoster in a cohort of renal transplant recipients. However, in a study among young children a higher exposure to solar UVR was associated with a lower occurrence of upper respiratory tract symptoms. As disentangling the effects of UVR from other relevant factors is often impossible in observational studies, concise quantitative risk estimations for the human situation cannot be given at present.

Animals↗
PubMed2006

Mechanical unloading of the heart activates the calpain system.

The mechanism for the decrease in cardiomyocyte size with mechanical unloading is unknown. The calpain system regulates cardiomyocyte atrophy. We obtained samples from failing human hearts at the time of implantation and explantation of a left ventricular assist device. For mechanical unloading, we also heterotopically transplanted rat or mouse hearts for 1 week. The effect of calpain inhibition on cardiac atrophy was assessed in transplanted hearts overexpressing calpastatin. We measured transcript levels of calpain 1 and 2 in the human and the rodent model, as well as calpain activity, a calpain-specific degradation product and cardiomyocyte size in the two rodent models. Mechanical unloading of the failing human heart significantly increased calpain 2 gene expression. Transcript levels of calpain 1 and 2, calpain activity and a calpain-specific degradation product all significantly increased in the unloaded rat heart. Unexpectedly, in hearts of animals overexpressing calpastatin, cardiomyocyte size also decreased. Mechanical unloading of the mammalian heart activates the calpain system, although other proteolytic systems may compensate for decreased calpain activity when calpastatin is overexpressed.

Animals↗
PubMed2005

Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease.

The development of dyskinesias and other motor complications greatly limits the use of levodopa therapy in Parkinson's disease (PD). Studies in rodent models of PD suggest that an important mechanism underlying the development of levodopa-related motor complications is alterations in striatal NMDA receptor function. We examined striatal NMDA receptors in the MPTP-lesioned primate model of PD. Quantitative immunoblotting was used to determine the subcellular abundance of NR1, NR2A and NR2B subunits in striata from unlesioned, MPTP-lesioned (parkinsonian) and MPTP-lesioned, levodopa-treated (dyskinetic) macaques. In parkinsonian macaques, NR1 and NR2B subunits in synaptosomal membranes were decreased to 66 +/- 11% and 51.2 +/- 5% of unlesioned levels respectively, while the abundance of NR2A was unaltered. Levodopa treatment eliciting dyskinesia normalized NR1 and NR2B and increased NR2A subunits to 150 +/- 12% of unlesioned levels. No alterations in receptor subunit tyrosine phosphorylation were detected. These results demonstrate that altered synaptic abundance of NMDA receptors with relative enhancement in the abundance of NR2A occurs in primate as well as rodent models of parkinsonism, and that in the macaque model, NR2A subunit abundance is further increased in dyskinesia. These data support the view that alterations in striatal NMDA receptor systems are responsible for adaptive and maladaptive responses to dopamine depletion and replacement in parkinsonism, and highlight the value of subtype selective NMDA antagonists as novel therapeutic approaches for PD.

Animals↗
PubMed2006

Evaluation of the antinociceptive effect of Rosmarinus officinalis L. using three different experimental models in rodents.

The rationale of this investigation was to examine the antinociceptive effect of an ethanol extract of Rosmarinus officinalis (RO) aerial parts, using three different experimental models: acetic acid-induced writhing test and formalin test in mice; and a model of arthritic pain: "pain-induced functional impairment model in the rat (PIFIR model)". The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from RO extract were compared with the antinociceptive effect of either tramadol (TR: 3.16-50 mg/kg, i.p. in mice, and 1.0-31.62 mg/kg, i.p. in rats) or acetylsalicylic acid (AA: 31.62-562.32 mg/kg, p.o.). RO extract (10-300 mg/kg, p.o.) significantly (P < 0.001) reduced the number of writhing movement induced by the i.p. administration of acetic acid solution in a dose-dependent way (ED50 = 108.84 mg/kg, whereas, TR showed an ED50 = 12.38 mg/kg). In addition, RO extract (30-300 mg/kg) significantly (P < 0.001) inhibited licking and shaking behaviours in both early (neurogenic pain) and in the late (inflammatory pain) phases of the formalin test. These effects were like those produced by TR. Concerning the results using the PIFIR model, RO extract (30-3000 mg/kg, p.o.) like either TR or AA, produced a significant (P < 0.001) and dose-dependent antinociceptive response in rats (RO: ED50 = 222.78 mg/kg versus TR: ED50 = 11.06 mg/kg and AA: ED50 = 206.13 mg/kg). These results strongly suggest that aerial parts of RO possess antinociceptive and anti-inflammatory activity, and reinforce the use of this plant in folk medicine.

Analgesics↗