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PubMed2006

Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study.

Cannabinoid receptor (CBR) stimulation inhibits motility and increases food intake in rodents. Effects of CBR stimulation in human gastrointestinal (GI) tract are unclear. We compared effects of dronabinol (DRO) and placebo (PLA) on GI transit, gastric volume and satiation in humans. In a double-blind, randomized study, 30 healthy volunteers were randomly assigned to DRO 5 mg b.i.d. or PLA for three doses. We measured GI functions noninvasively: day 0, Ensure satiation test to measure maximum tolerated volume (MTV) and 30-min post-Ensure symptoms; day 1, scintigraphic transit ((111)In-egg meal) and fasting and postprandial gastric volume ((99Tcm)-SPECT); day 2, 24-h colonic transit and repeat satiation test. ancova was used to compare treatment groups with gender, age, and, for the satiation test, the baseline MTV, as covariates. A log-rank test was used to assess treatment effects on gastric emptying. Planned sample size had 80% power to detect 25-30% differences in primary end points. There was an overall retardation of gastric emptying with DRO (P = 0.018); this was more pronounced in females (P = 0.011), than in males (P = 0.184). No significant treatment differences were detected for gastric volumes, MTV, post-Ensure(R) symptoms, small bowel and colonic transit. Fasting gastric volume was greater in males receiving DRO compared with PLA (238 +/- 17 vs 185 +/- 16, P = 0.04). DRO retards gastric emptying in humans; effects are gender-related. Dronabinol also increases fasting gastric volumes in males.

Age Factors↗

PubMed1987

Energy and water requirements of lactation in the North American porcupine, Erethizon dorsatum.

1. Energy and water requirements of lactating porcupines were compared with results of previous studies on energetics of reproduction in small-bodied rodents. 2. Mass-specific food and water intake of control and lactating porcupines was examined throughout the 68-78 days of lactation. Water intake of lactating females was 16% higher than that of non-lactating animals. 3. Digestive efficiency of porcupines fed commercial rabbit chow was 54-60%; there was no significant difference in efficiency between lactating and non-lactating animals. 4. Total mean energetic intake throughout lactation was only 17% greater than that of non-lactating animals. 5. Reproductive rate and costs of lactation in porcupines are considerably less than in other rodents and other comparably-sized mammals, but the amount of energy allocated to each offspring is quite high. 6. The reproductive pattern of porcupines is associated with low juvenile mortality and long adult lifespan (both of which reflect the porcupine's protective morphology), and may be related to the quality of winter diets.

Animals↗

PubMed2004

Cell cycle arrest and modulation of HO-1 expression induced by acetyl salicylic acid in hepatocarcinogenesis.

BACKGROUND AND AIMS: Control of cell proliferation is important for cancer prevention since cell proliferation has an essential role in carcinogenesis. In rodent carcinogenesis models, antioxidant agents suppress carcinogen-induced cellular hyper proliferation in the target organs. Strict control of cell division is an essential process to ensure that DNA synthesis and mitotic division are accurately and coordinately executed. We studied the interplay between cell cycle and heme oxygenase-1 (HO-1) and the effect of the acetylsalicylic acid (ASA) in hepatic carcinogenesis. METHODS: Male CF1 mice pre-treated with dietary p-dimethylaminoazobenzene (DAB; 0.5%, w/w) were fed with ASA (0.16%, w/w). We investigated the hepatic expression of cyclin D1, cyclin E, Cdk2, Cdk4, p21, p27, p53; the level of bcl-2, an antiapoptotic protein and of heme oxygenase-1 (HO-1), a marker of oxidative stress, by Western blot analysis. RESULTS: The treatment with ASA produced an important attenuation in the induction of cyclin E and cyclin D1 provoked by DAB. p21 and p27 levels were increased when animals received both drugs. The administration of ASA to DAB treated animals induced Cdk2 (29%). HO-1 induction (65%) provoked by DAB was diminished by ASA administration reaching lower induction levels (23%). CONCLUSION: The deregulation of cyclin/CDK expression and the up-regulation of p21 and p27 with the administration of ASA, post-treatment of the carcinogen administration, would block the pass through out to the G0/G1 check point to permit the cells to repair their DNA and HO-1 protected the liver from reactive oxygen species produced from DAB.

Animals↗

PubMed1991

Neuronal-epithelial interactions in mammalian gustatory epithelium.

There are two neurally controlled morphogenetic programmes in the fungiform papillae of the rodent tongue. When gustatory axons are present they not only promote the expression of taste receptor cells but also simultaneously suppress the outgrowth of an ectopic filiform spine. Innervation during development is essential for the initial formation of taste buds. Consequently, denervation during development irreversibly prevents the establishment of a permanent line of stem cells for taste buds, in contrast to the reliable re-emergence of taste buds after the reinnervation of denervated adult gustatory epithelium. Monoclonal antibodies to keratins selectively recognize cells in particular differentiated states and may contribute to an understanding of the cell lineages and cell-cell interactions that lead to taste buds and filiform spines. Regeneration may recapitulate the late steps in taste development but not the early steps, which are slower and subject to irreversible alteration with denervation. Arguments are set forth that the nerve dependence of taste buds and some other cutaneous receptor cells provides an important selective advantage. Nerve dependence ensures that a more protective integumental covering will replace any superficial, secondary sensory cells rendered useless by denervation.

Adaptation, Physiological↗

PubMed1987

Effects of orthodontic forces on the morphology and diameter of Sharpey fibers of the alveolar bone of the rat.

There is little information available concerning the effects of functional and therapeutic forces on Sharpey fibers and adjacent bone matrix. In the present study, springs were placed between the left first and second maxillary molar teeth of rats and retained for 1, 2, 3, 4, or 5 days. The right side served as a control. Tissues from sham-operated, untreated animals were also studied. Maxillae were removed, fractured, rendered anorganic with sodium hypochlorite, and then examined by scanning electron microscopy (SEM). Some tissues were demineralized and examined by high-voltage electron microscopy (HVEM). Sharpey fibers were studied at the alveolar wall and at the midline of the interdental septum (intra-septal Sharpey fibers). In 5-day experimental tissues, SEM showed intra-septal Sharpey fibers had either a reduced number of, or lacked, unmineralized cores. Unit collagen fibrils in 5-day tissues viewed by HVEM were densely packed into Sharpey fibers which had no afibrillar areas. Sharpey fibers at the alveolar wall demonstrated no observable changes in morphology or in pattern of mineralization. After 5 days of spring placement, the mean diameters of intra-septal fibers were significantly less than those at the alveolar wall (p less than 0.001). The disparity in Sharpey fiber diameters of treated and untreated control animals suggests that untreated controls are essential to the design of studies of rodent tooth movement. This study suggests that orthodontic tooth movement produces changes in the morphology and mineralization patterns of Sharpey fibers which might affect the mechanical strength of the periodontium.

Alveolar Process↗

PubMed1995

Factors influencing mossy fiber collateral sprouting in organotypic slice cultures of neonatal mouse hippocampus.

Collateral sprouting of dentate granule cell axons, the mossy fibers, occurs in response to denervation, kindling, or excitotoxic damage to the hippocampus. Organotypic slice culture of rodent hippocampal tissue is a model system for the controlled study of collateral sprouting in vitro. Organotypic roller-tube cultures were prepared from hippocampal slices derived from postnatal day 7 mice. The Timm heavy metal stain and densitometry were used to assay the degree of mossy fiber collateral sprouting in the molecular layer of the hippocampal dentate gyrus. Factors influencing mossy fiber collateral sprouting were time in culture, positional origin of the slice culture along the septotemporal axis of the hippocampus, and presence of attached subicular-entorhinal cortical tissues. Collateral sprouting in the molecular layer was first detected after 6 days in culture and increased steadily thereafter. By 2 weeks considerable sprouting was apparent, and at 3 weeks intense sprouting was observed within the molecular layer. An intrinsic septal-to-temporal gradient of collateral sprouting was apparent at 14 days in culture. To determine whether differential damage to the mossy fibers was the basis for the differences in collateral sprouting along the septotemporal axis, we made complete transections of the mossy fiber projection as it exited the dentate hilus at various levels along the septotemporal axis; no differences were found on subsequent collateral sprouting in the dentate molecular layer. Timm-stained hippocampal cultures with an attached entorhinal cortex, a major source of afferent innervation to the dentate granule cells, displayed significantly less collateral sprouting at 10 days in culture compared to that in cultures from adjacent sections without attached subicular-entorhinal tissues present. Thus, time in culture, position along the septotemporal axis, and presence of afferent cortical tissues influence aberrant neurite collateral sprouting in organotypic slice cultures of neonatal mouse hippocampus.

Animals↗

PubMed2002

Genotoxicity biomonitoring in regions exposed to vehicle emissions using the comet assay and the micronucleus test in native rodent Ctenomys minutus.

Exposure to motor vehicle emissions represents an important concern for possible long-term health effects. The present report describes: 1) the application and verification of the alkaline comet assay in Ctenomys minutus to detect the possible genotoxicity of automobile emissions; 2) a comparison of the comet assay results with peripheral blood micronucleus (MN) assay results performed in the same animals; and 3) the identification of agents involved in the responses and in the seasonal variation of the effects. Ctenomys minutus (Octodontidae-Rodentia) were captured in two different fields from both sides of RS/030, a highway on the coastal plain of the Brazilian state of Rio Grande do Sul. Reference animals were obtained from a nearby field that was about 3 km distant from any road. By the end of this study, 123 rodents (73 females and 50 males) were live-trapped. Our results indicate that there was an increase in cells with DNA damage for C. minutus environmentally exposed to automobile emissions, as demonstrated by the alkaline comet assay, but there was no increase in micronucleated cells. The alkaline comet assay showed age and gender differences in the response. The comet assay results suggest that adult females are the principal population affected by air pollutants from vehicle emissions. Chemical data were also collected from areas exposed to automobile exhaust and these indicated that elevated levels of hydrocarbons, metals, and NO(2) were associated with the elevated levels of damaged cells observed in the wild rodent C. minutus. Our results agree with previous data on engine and fuel components, where weak increases in damage for native rodents exposed to emissions have been observed. Other larger, controlled studies are needed to better understand how the metabolism of C. minutus affects its response to emission exposure.

Animals↗

PubMed1995

Glucose-responsive neurons in the brainstem.

AREA POSTREMA: The influence on feeding behavior caused by ablation of the area postrema (AP) in rodents indicates the participation of this structure in the control of ingestion. Two types of glucose responsive neurons were identified in the AP: one is characterized by increasing the discharge rate in response to glucose (glucoreceptor type) and the other by decreasing the discharge rates in response to glucose (glucose sensitive type). These glucose responsive neurons may participate in glycemic homeostasis. NUCLEUS OF SOLITARY TRACT: The glucose responsive neurons exist within the caudal portion of nucleus of the solitary tract (NTS), a relay station in visceral afferents. Two types similar to the AP were also recognized. It is confirmed that hepatic glucose sensitive afferents terminate on some of the glucose sensitive neurons. This convergence may serve as a fail-safe mechanism. In addition, the NTS involving complex neural networks of excitatory and inhibitory interneurons may be concerned with integration of glycemic information. DORSAL MOTOR NUCLEUS OF VAGUS: Some neurons within the dorsal motor nucleus of the vagus (DMV) were identified as the glucose responsive ones. Both types were also recognized. It is confirmed by antidromic activation that these glucose responsive DMV neurons send their axons toward the gastric or coeliac branch that innervates either the stomach, intestine or pancreas. Some of the DMV neurons may subserve an enteroceptor function by themselves. They may also play a role in the brainstem neural control of glycemic homeostasis as the fail-safe mechanism.

Animals↗

PubMed2006

Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels.

We investigated the involvement of endocannabinoids in the control of neuronal damage and memory retention loss in rodents treated with the beta-amyloid peptide (1-42) (BAP). Twelve days after stereotaxic injection of BAP into the rat cortex, and concomitant with the appearance in the hippocampus of markers of neuronal damage, 2-arachidonoyl glycerol, but not anandamide, levels were enhanced in the hippocampus. VDM-11 (5 mg/kg, i.p.), an inhibitor of endocannabinoid cellular reuptake, significantly enhanced rat hippocampal and mouse brain endocannabinoid levels when administered sub-chronically starting either 3 or 7 days after BAP injection and until the 12-14th day. VDM-11 concomitantly reversed hippocampal damage in rats, and loss of memory retention in the passive avoidance test in mice, but only when administered from the 3rd day after BAP injection. We suggest that early, as opposed to late, pharmacological enhancement of brain endocannabinoid levels might protect against beta-amyloid neurotoxicity and its consequences.

Amyloid beta-Peptides↗

PubMed1991

Hormonal control of precopulatory sebaceous scent marking and ultrasonic mating vocalizations in male rats.

The effects of testosterone (T) and its major metabolites, estradiol (E2) and dihydrotestosterone (DHT), on the restoration of sebaceous scent marking and 50-kHz ultrasonic vocalizations in male rats were measured in two studies (Experiments 1 and 2) employing different hormone levels. Silastic capsule administration of high and low doses of T (10 and 20 mm) or E2 (5%; 5 and 10 mm) completely restored marking to precastration levels. Both doses of DHT (30 and 40 mm) or no hormone replacement were without effect when tested in presence of estrous odor cues. In our testing paradigm, males appeared to mark glass objects with a sebaceous secretion rather than urine. Only the high dose of T (20 mm) restored vocalizations to intact levels, while animals receiving the high or low dose of E2 or DHT showed no restoration of behavior. In Experiment 3, habituation to estrous odor cues over weekly tests was not observed for marking or vocalizations. These results are discussed with respect to similarities and differences in the hormonal control of signaling behaviors by androgen metabolites in male rodents.

Animals↗

PubMed1991

Hamsters versus rats: ventilatory responses in adults and newborns.

Burrowing mammals often demonstrate structural and functional characteristics which could be interpreted as aspects of adaptation to the low PO2 and high PCO2 of their environment. Whether these characteristics are acquired by each individual as the result of life in the burrow or are genetic traits established through evolution is not clear. To examine the latter possibility aspects of ventilatory control were studied in newborns and adults of two rodents, the surface dwelling white rat (Rattus norvegicus, R) and the semifossorial syrian hamster (Mesocricetus auratus, H), both born and raised in normoxia. Adult H, but not R, manifested the burrowing preference whenever offered the opportunity. Adult H presented numerous differences from the adult R, including a higher normoxic oxygen consumption (VO2, +44%), higher hematocrit and heavier right heart. Ventilation (VE) was similar between the two species both in air and hyperoxia, although H had a deeper and slower pattern. Hence, resting VE/VO2 in H was low, probably contributing to the hypoxemia reported in this species. The acute ventilatory response to hypoxia (10 min 10% FIO2), was less in H, because of no increase in tidal volume. Most of the morphological and functional differences between adult hamsters and rats were not apparent between the newborns of the corresponding species. It is concluded that some of the physiological characteristics reported in burrowing species are also observed in adult hamsters which never lived in burrows, but not in the newborns; hence, they could represent genetic traits which are expressed postnatally with no needs of the special environmental conditions of the burrow.

Adaptation, Physiological↗

PubMed1988

Effect of chronic undernutrition on susceptibility to cold stress in young adult and aged rats.

Chronically undernourished laboratory rodents live as much as 50% longer than matched control animals fed ad libitum. In their natural habitats, however, most mammals, including humans, appear to have shorter life expectancies when chronically undernourished. The present research demonstrated that both brief and chronic undernutrition speeds rate of body temperature drop in rats exposed to cold air. Furthermore, chronic undernutrition also decreased the rate at which body temperature returned to normal after animals had been removed from the cold environment. These results suggest that while chronic undernutrition may slow the rate of physiological aging it also increases the organism's susceptibility to stressor stimuli.

Aging↗

PubMed1990

Host-parasite interactions and immunity to irradiated sporozoites.

We compare and contrast the results of immunizing mice with irradiated sporozoites of Plasmodium berghei and Plasmodium yoelii. Host genetic control of protective immunity is different in the two rodent malarias. Few mouse strains are strongly protected by P. yoelii sporozoites, while all are protected by P. berghei sporozoite immunization. The role of CD8+ T cells in the protective immune response to each of these malarias varies with the strain of mouse. Moreover, a single strain will use a CD8+ T cell-dependent mechanism against one malaria, and a CD8+ independent mechanism against the other. Thus, each host-parasite pairing in these rodent malarias engenders a unique set of immune responses. Such variety should be expected in the immune response to the human malarias, and may complicate the development of universally applicable vaccines.

Animals↗

PubMedDate not supplied

Relationship of hematological variables to learning performance in aged Fischer-344 rats.

The relationship between hematological variables and the ability to perform behaviorally in two learning tests was evaluated in male F344 rats aged 22-24 months. Rats were screened for ability to meet criterion for learning one-way active avoidance in a straight runway task. Rats failing to meet criterion were given no further testing and were assigned to Group 1 (G1). Rats meeting criterion were tested in a 14-unit T-maze (2 days, 10 trials/day). Failure to negotiate the T-maze within 600 s on any three trials resulted in assignment to Group 2 (G2) with no further testing. Rats successfully completing both tasks constituted Group 3 (G3). Trunk blood was collected following behavioral testing and was assayed to determine red blood cell count (RBC), hematocrit (HCT), hemoglobin (HGB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell count (WBC), bands (BND), polymorphs (POLY), lymphocytes (LYM), monocytes (MON), and eosinophils (EOS). The combined G1/G2 group had significantly lower RBC, HCT, HGB, and EOS but significantly higher MCV and MCH than G3 rats. Correlation analysis revealed a positive relationship of group membership (i.e., learning test completion) to RBC, HCT, HGB, and EOS, but a negative correlation of group membership to MCH. No significant correlation emerged between any hematological characteristic and performance in either behavioral task. These results suggest that a simple blood test to determine HCT may be a useful screen for removal of moribund rats from aging studies attempting to control for effects of health on behavioral performance in rodent models.

Aging↗

PubMed2006

An assessment of structure and toxicity correlation in organochlorine pesticides.

Organochlorines are the most successful, profitably utilized and commercialized group of pesticides. They have gained huge popularity and prominence in a short span of time by virtue of their ability to control almost all kinds of pests including insect, fungi, rodent, etc. The toxicity of an individual pesticide to the pests is predominantly determined by its structure, the different moieties attached to parent compound, their spatial arrangements within molecule, nature of substituents, polarity, symmetry and asymmetry of molecules, the solubility and sorption values. The present paper discusses the toxicity in terms of LD(50) of organochlorine pesticides on the basis of their structures. Further, the mode of action of these pesticides has been discussed for a better understanding of toxicity. Finally an attempt has been made to understand the structure toxicity relationship in organochlorine pesticides.

Hydrocarbons, Chlorinated↗

PubMed1999

Complete locomotor recovery following corticospinal tract lesions: measurement of ground reaction forces during overground locomotion in rats.

The corticospinal tract is a prominent descending pathway in rodents which is thought to be involved in motor control. The purpose of this study was to investigate whether the lesions of the corticospinal tract affected overground locomotion in rats using a method of assessment which is relatively novel in this field, the evaluation of ground reaction forces. Ground reaction forces, i.e. the forces acting through the limbs on the ground, are a non-invasive, sensitive and quantitative method with which to assess gait compensation and the function of individual limbs during locomotion. We compared the three-dimensional ground reaction forces produced by locomoting rats with a unilateral corticospinal tract transection to those of control rats. Corticospinal-lesioned animals showed transient locomotor deficits 24-48 h after the lesion which quickly recovered to normal symmetrical locomotion. The initial locomotor deficits consisted of an asymmetric gait during which abnormal braking forces were produced during the dual contact time of the forelimb contralateral to the lesion (the impaired forelimb) and the ipsilateral (unimpaired) hindlimb. Normal forces were produced during the dual contact time of the ipsilateral (unimpaired) forelimb and the contralateral (impaired) hindlimb. The presence of the initial deficits may be a result of inflammation in the area of the lesion or may reflect a loss of normal locomotor contribution of the corticospinal tract. If the latter, the nature of the locomotor deficit suggests that (a) the forelimb may be more influenced by corticospinal lesions than is the hindlimb and/or (b) that the asymmetric gait produced is a general compensatory response to unilateral CNS injury in a quadruped. Complete recovery from corticospinal tract transection provides unequivocal evidence that input from the corticospinal tract is not essential for normal overground locomotion in the rat.

Animals↗

PubMed1999

Effects of hyperthermia and continuous hippocampal stimulation on the immature and adult brain.

Whether febrile seizures lead to hippocampal necrosis is a question of paramount clinical importance. This study attempted to simulate a complex febrile seizure, compared with hyperthermia (HYP) alone and prolonged seizure alone (produced by continuous hippocampal stimulation (CHS)). Four groups of rats were studied at each of two ages, immature (postnatal day, P20) and adult (P60). Group 1 was subjected to 45 min of HYP (body temperature 40 degrees C) plus CHS, Group 2 received 45 min of HYP alone, Group 3 got 45 min of CHS alone, and Group 4 was sham-handled control rats. Baseline and post-session EEGs were recorded in all groups. Subsequently, brains were examined histologically for evidence of hippocampal damage. Both CHS-treated groups (with and without HYP) exhibited behavioral and EEG seizures while the group undergoing HYP alone did not have seizures. There were no gross histological lesions in any group. Cell counts in regions CA1, CA3, dentate gyrus and dentate hilus did not differ in rats under any condition of hyperthermia and CHS, in either P20 or P60 rats compared to age-matched controls. These results indicate that both immature and mature rodents are resistant to hyperthermic brain damage and raises the question of whether febrile seizures play a role in the genesis of mesial temporal sclerosis.

Aging↗

PubMed2000

Chemoprevention: general perspective.

Chemoprevention is the use of natural or synthetic compounds to block, reverse, or prevent the development of invasive cancers. Cellular carcinogenesis forms the biologic basis for the identification of chemopreventives, assessment of their activity, and ultimately the success or failure of a chemopreventive. Chemopreventive agents undergo multistep evaluations to assess efficacy that are similar in concept but vastly different in practice to standard ablative oncologic therapeutics. In vitro assessments of potential anticarcinogenesis efficacy include measurements of an agent's antioxidant activity, induction of phase II metabolizing enzymes and effects upon cellular proliferation and apoptotic control pathways. In vivo efficacy is assessed primarily in rodent models of carcinogenesis that are specific for a given organ target. The role of genetically modified animal models in the in vivo assessment of chemoprevention agents remains unclear. Clinical assessment of chemopreventive agent efficacy consists of a multistep process of identification of an optimal chemopreventive agent (phase 1), demonstration of efficacy in humans through the modulation of reversal of a tissue, biochemical, and molecular surrogates for neoplastic transformation and invasion (phase 2) and cancer risk reduction in large cohort trials (phase 3). Opportunities and future needs include the development of reliable, predictive in vivo models of carcinogenesis, careful exploration of the preventive pharmacology of therapeutic agents being used for non-cancer prevention indications, and the incorporation of genetic risk cohorts to define cancer chemopreventive efficacy.

Animals↗