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Rapid and persistent impairments of the forelimb motor representations following cervical deafferentation in rats.  


Skilled motor control is regulated by the convergence of somatic sensory and motor signals in brain and spinal motor circuits. Cervical deafferentation is known to diminish forelimb somatic sensory representations rapidly and to impair forelimb movements. Our focus was to determine what effect deafferentation has on the motor representations in motor cortex, knowledge of which could provide new insights into the locus of impairment following somatic sensory loss, such as after spinal cord injury or stroke. We hypothesized that somatic sensory information is important for cortical motor map topography. To investigate this we unilaterally transected the dorsal rootlets in adult rats from C4 to C8 and mapped the forelimb motor representations using intracortical microstimulation, immediately after rhizotomy and following a 2-week recovery period. Immediately after deafferentation we found that the size of the distal representation was reduced. However, despite this loss of input there were no changes in motor threshold. Two weeks after deafferentation, animals showed a further distal representation reduction, an expansion of the elbow representation, and a small elevation in distal movement threshold. These changes were specific to the forelimb map in the hemisphere contralateral to deafferentation; there were no changes in the hindlimb or intact-side forelimb representations. Degradation of the contralateral distal forelimb representation probably contributes to the motor control deficits after deafferentation. We propose that somatic sensory inputs are essential for the maintenance of the forelimb motor map in motor cortex and should be considered when rehabilitating patients with peripheral or spinal cord injuries or after stroke. PMID:24329730

Jiang, Yu-Qiu; Williams, Preston T J A; Martin, John H



Characteristics of leading forelimb movements for obstacle avoidance during locomotion in rats.  


Walking smoothly and safely often involves stepping over an obstacle. The purpose of this study was to examine forelimb movements and toe trajectories in stepping over an obstacle during overground locomotion in rats. We performed a kinematic analysis of forelimb movements and measured electromyographic (EMG) activities in the biceps and triceps brachii of the forelimbs. We found that mean toe height just above the obstacle was lower in the leading forelimb than in the trailing forelimb. The toe positions of the leading forelimb at maximal elevation over the obstacle (peak toe position) were closer to the upper edge of the obstacle than those of the trailing forelimb. The linear distance between peak toe position and the upper edge of the obstacle was significantly less in the leading forelimb compared to the trailing forelimb. The peak toe position of the leading forelimb spatially corresponds to the transition point from flexion to extension of the elbow joint. This transition appeared to be controlled mainly by an offset of EMG activity of the elbow flexor, the biceps brachii muscle. In contrast, the trailing forelimb appeared to be controlled by the shoulder and wrist joints. These results suggest that the toe trajectory of the leading forelimb is more accurately regulated than that of the trailing forelimb. In addition, the activities of the elbow flexor may in part contribute to the toe trajectory of the leading forelimb. PMID:22902354

Aoki, Sho; Sato, Yamato; Yanagihara, Dai



Body-weight distribution on forelimbs in rat tail-suspension model.  


To understand the tail-suspension model to simulate weightlessness better, this study was to investigate the relationship of the amount of body weight supported by forelimbs between the tilt angles of rat in the model. Normal rat had at least two basic postures. One was standing or walking, in which the forelimbs bear 44.6% of the body weight; the other one was resting, in which 23.9% of body weight was placed on the forelimbs. As for tail-suspended rat, body-weight distribution on forelimbs was linearly related to tilt angle. The linear relationship was y = -0.7423x + 70.849, R2 = 0.9269. The tilt angle should be approximately 35 degrees if normal standing load of 44.6% body weight was placed on the forelimbs. On the other hand, it should be approximately 63 degrees if normal resting load of 23.9% of body weight was placed on forelimbs. Furthermore, the body load on forelimbs in tail-suspension model became much larger if the period of different postures was considered. Therefore, it should be careful if forelimbs are used to be as convenient internal control in tail-suspended rats. PMID:20803996

Sun, Lian-Wen; Wang, Chao; Xie, Tian; Pu, Fang; Sun, Yao; Fan, Yu-Bo



Spinocerebellar Purkinje cells and rat forelimb postures: a direction-dependent activity.  


On anesthetized adult rats, we examined the possibility that the discharges of spinocerebellar Purkinje cells (PCs) are modulated by passive limb positioning. The rat forelimb was passively placed in four different sagittal positions while the simple spike spontaneous activity of single PCs was recorded; recordings started 5 s after the reaching of the posture and the forelimb remained at each position for at least 30 s. Although the activity of the PCs did not reflect the forelimb position, it showed hysteresis that depended in a cosine fashion on the direction of the preceding movement. This implies that the directional sensitivity of spinocerebellar PCs is persistent, since the activity levels were almost constant throughout the recording time. PMID:9605490

Giaquinta, G; Casabona, A; Valle, M S; Bosco, G; Perciavalle, V



Changes in forelimb-hindlimb coordination after partial spinal lesions of different extent in the rat.  


Forelimb-hindlimb coordination in adult rats moving freely along 2m long runway was investigated using the method of footprint recording. Rats were divided into 3 groups with different extent of spinal lesions (T(9)). Before surgery rats moved with a mean locomotor speed of 73±20 to 96±18cms(-1), stride lengths of 17.5±2.0 to 21.2±2.0cm, and trot like coordination. Early after surgery the locomotor speed and the stride lengths were decreased. The forelimb steps were shorter than hindlimb steps, which led to the occurrence of unpaired forelimb steps. Unpaired steps occurred when the hind paw print lay more than half the hindlimb stride length in front of the ipsilateral paw. The number of unpaired steps was negatively correlated with the difference between the fore- and hindlimb step lengths. The recovery of locomotor speed, stride length, and step sequence patterns took up to 3.5 months depending on the extent of lesion. In the last testings the coordination was characterized by increased distances between ipsilateral footprints leading to a change from an almost synchronized trot to a lesion-dependent walk. This change was accompanied by a switch from the use of both patterns A and C to the most frequent use of the Aa pattern that is better adapted to maintain the body balance. All locomotor changes depended on the extent of the injury of lateral and ventral funiculi. These results demonstrate that footprint analysis can be used for the evaluation of forelimb-hindlimb coordination after spinal lesion in rats. PMID:23142611

Górska, Teresa; Chojnicka-Gittins, Barbara; Majczy?ski, Henryk; Zmys?owski, Wojciech



Cortical PKC Inhibition Promotes Axonal Regeneration of the Corticospinal Tract and Forelimb Functional Recovery After Cervical Dorsal Spinal Hemisection in Adult Rats.  


Our previous study shows that conventional protein kinases C (cPKCs) are key signaling mediators that are activated by extracellular inhibitory molecules. Inhibition of cPKC by intrathecal infusion of a cPKC inhibitor, GÖ6976, into the site of dorsal hemisection (DH) induces regeneration of lesioned dorsal column sensory, but not corticospinal tract (CST), axons. Here, we investigated whether a direct cortical delivery of GÖ6976 into the soma of corticospinal neurons promotes regeneration of CST and the recovery of forelimb function in rats with cervical spinal cord injuries. We report that cortical delivery of GÖ6976 reduced injury-induced activation of conventional PKC? and PKC?1 in CST neurons, promoted regeneration of CST axons through and beyond a cervical DH at C4, formed new synapses on target neurons caudal to the injury, and enhanced forelimb functional recovery in adult rats. When combined with lenti-Chondroitinase ABC treatment, cortical administration of GÖ6976 promoted even greater CST axonal regeneration and recovery of forelimb function. Thus, this study has demonstrated a novel strategy that can promote anatomical regeneration of damaged CST axons and partial recovery of forelimb function. Importantly, such an effect is critically dependent on the efficient blockage of injury-induced PKC activation in the soma of layer V CST neurons. PMID:23810979

Wang, Xiaofei; Hu, Jianguo; She, Yun; Smith, George M; Xu, Xiao-Ming



CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury  

Microsoft Academic Search

We have reviewed a battery of useful tests for evaluating sensorimotor function and plasticity acutely and chronically in unilateral rat models of central nervous system injury. These tests include forelimb use for weight shifting during vertical exploration in a cylindrical enclosure, an adhesive removal test of sensory function, and forelimb placing. These tests monitor recovery of sensorimotor function independent of

Timothy Schallert; Sheila M Fleming; J. Leigh Leasure; Jennifer L Tillerson; Sondra T Bland



Forelimb muscle activity following nerve graft repair of ventral roots in the rat cervical spinal cord.  


Current research on the cellular mechanisms of nerve regeneration suggests the application of nerve growth factors at the repair sites to be beneficial. To test the effectiveness of this approach, we performed transections of the C6 and C7 ventral rootlets from their original sites in the spinal cord of 18 rats. We investigated the electrophysiological changes in three groups of rats operated on by different repair strategies. Six rats comprised the control group (G1). In the other 12 rats, 24 rootlets were implanted into the spinal cord by means of an intercostal nerve graft through the pia mater immediately after transection. Six rats (G2) had fibrin glue applied at the incision. The last 6 rats (G3) had grafts with acidic fibroblast growth factor (aFGF) added to the fibrin glue. The rats' functional recovery was evaluated electrophysiologically at 6 weeks and 6 months after the operation. Needle electromyography showed profound fibrillation potentials (Daube's scoring system) in the deltoid, biceps, and triceps of the operated forelimbs in all groups 6 weeks after the operation. After 6 months, there was a significant decrease in the amount of fibrillation potentials in all groups (G1, G2 and G3, p < 0.0001, 0.0001, 0.0009, respectively, generalized estimating equation, repeated measures) and a significantly high probability for motor units present in sampled muscles of G2 and G3 as compared to G1 (log odds ratio in G2 = 51.8316, G3 = 57.4262, generalized estimating equation). We conclude that several cervical roots can regenerate through intercostal nerve grafts applied using fibrin glue. Adding aFGF may increase the efficacy of sprouting. PMID:12052433

Chuang, Tien-Yow; Huang, Ming-Chao; Chen, Kuo-Chih; Chang, Yue-Cune; Yen, Yu-Shu; Lee, Liang-Shong; Cheng, Henrich



Abnormalities in skilled reaching movements are improved by peripheral anesthetization of the less-affected forelimb after sensorimotor cortical infarcts in rats  

PubMed Central

Unilateral damage to sensorimotor cortical (SMC) regions can profoundly impair skilled reaching function in the contralesional forelimb. Such damage also results in impairments and compensatory changes in the less-affected/ipsilesional forelimb, but these effects remain poorly understood. Furthermore, anesthetization of the ipsilesional hand in humans with cerebral infarcts has been reported to produce transient functional improvements in the paretic hand [14,48]. One aim of this study was to sensitively assay the bilateral effects of unilateral ischemic SMC damage on performance of a unimanual skilled reaching task (the single pellet retrieval task) that rats had acquired pre-operatively with each forelimb. The second aim was to determine whether partially recovered contralesional reaching function is influenced by anesthetization of the ipsilesional forelimb. Unilateral SMC lesions were found to result in transient ipsilesional impairments in reaching success and significant ipsilesional abnormalities in reaching movements compared with sham-operates. There were major contralesional reaching impairments which improved during a 4 week training period, but movements remained significantly abnormal. Anesthetization of the ipsilesional forelimb with lidocaine at this time attenuated the contralesional movement abnormalities. These findings indicate that unilateral ischemic SMC lesions impair skilled reaching behavior in both forelimbs. Furthermore, after partial recovery in the contralesional forelimb, additional improvements can be induced by transient anesthetization of the ipsilesional forelimb. This is consistent with the effects of unilateral anesthetization in humans which have been attributed to the modulation of competitive interhemispheric interactions. The present findings suggest that such interactions are also likely to influence skilled reaching function in rats. PMID:17173985

O’Bryant, A.; Bernier, B.; Jones, T.A.



Early life versus lifelong oral manganese exposure differently impairs skilled forelimb performance in adult rats  

PubMed Central

Recent studies of children suggest that exposure to elevated manganese (Mn) levels disrupt aspects of motor, cognitive and behavioral functions that are dependent on dopamine brain systems. Although basal ganglia motor functions are well-known targets of adult occupational Mn exposure, the extent of motor function deficits in adults as a result of early life Mn exposure is unknown. Here we used a rodent model early life versus lifelong oral Mn exposure and the Montoya staircase test to determine whether developmental Mn exposure produces long-lasting deficits in sensorimotor performance in adulthood. Long-Evans male neonate rats (n=11/treatment) were exposed daily to oral Mn at levels of 0, 25, or 50 mg Mn/kg/d from postnatal day (PND) 1-21 (early life only), or from PND 1 - throughout life. Staircase testing began at age PND 120 and lasted 1 month to objectively quantify measures of skilled forelimb use in reaching and pellet grasping/retrieval performance. Behavioral reactivity also was rated on each trial. Results revealed that (1) behavioral reactivity scores were significantly greater in the Mn-exposed groups, compared to controls, during the staircase acclimation/training stage, but not the latter testing stages, (2) early life Mn exposure alone caused long-lasting impairments in fine motor control of reaching skills at the higher, but not lower Mn dose, (3) lifelong Mn exposure from drinking water led to widespread impairment in reaching and grasping/retrieval performance in adult rats, with the lower Mn dose group showing the greatest impairment, and (4) lifelong Mn exposure produced similar (higher Mn group) or more severe (lower Mn group) impairments compared to their early life-only Mn exposed counterparts. Collectively, these results substantiate the emerging clinical evidence in children showing associations between environmental Mn exposure and deficits in fine sensorimotor function. They also show that the objective quantification of skilled motor performance using the staircase test can serve as a sensitive measure of early life insults from environmental agents. Supported by NIEHS R01ES018990. PMID:23623961

Beaudin, Stephane A.; Nisam, Sean; Smith, Donald R.



Early onset of forced impaired forelimb use causes recovery of forelimb skilled motor function but no effect on gross sensory-motor function after capsular hemorrhage in rats  

Microsoft Academic Search

Intensive use of the impaired forelimb promotes behavioral recovery and induces plastic changes of the central nervous system after stroke. However, the optimal onset of intensive use treatment after stroke is controversial. In this study, we investigated whether early forced impaired limb use (FLU) initiated 24h after intracerebral hemorrhage (ICH) of the internal capsule affected behavioral recovery and histological damage.

Akimasa Ishida; Keigo Tamakoshi; Michiru Hamakawa; Haruka Shimada; Hiroki Nakashima; Tadashi Masuda; Hideki Hida; Kazuto Ishida



Young and middle-aged rats exhibit isometric forelimb force control deficits in a model of early-stage Parkinson's disease.  


Deficits in manual motor control often accompany the early stages of Parkinson's disease (PD), and are often revealed through isometric force tasks. In order to determine whether similar deficits occur in a rat model of early-stage PD, young (8 months) and middle-aged (18 months) rats were trained to produce sustained press-hold-release isometric forelimb responses that allowed for analyses of force output and spectral analysis of forelimb stability and tremor. Rats then received a 6-hydroxydopamine (6-OHDA) infusion into the striatum contralateral to the trained forelimb and were tested for 4 weeks post-lesion. The resulting partial striatal dopamine depletions (which at 41±12% and 43±6% in young and middle-aged rats, respectively, did not differ between the two groups) resulted in isometric forelimb deficits. Specifically, rats exhibited significantly diminished force stability and increased high frequency (10-25Hz) tremor, indicating potential postural disturbances and increased postural tremor, respectively. Durations of press-hold-release bouts were also increased post-lesion, suggesting difficulty in task disengagement. Despite pre-lesion differences in some of the force measures, the effects of partial nigrostriatal DA depletion did not differ between the two age groups. These results support the use of the press-while-licking task in preclinical studies modeling isometric force control deficits in PD. PMID:21767573

Bethel-Brown, Crystal S; Morris, Jill K; Stanford, John A



Forelimb amputation-induced reorganization in the ventral posterior lateral nucleus (VPL) provides a substrate for large-scale cortical reorganization in rat forepaw barrel subfield (FBS).  


In this study, we examined the role of the ventral posterior lateral nucleus (VPL) as a possible substrate for large-scale cortical reorganization in the forepaw barrel subfield (FBS) of primary somatosensory cortex (SI) that follows forelimb amputation. Previously, we reported that, 6 weeks after forelimb amputation in young adult rats, new input from the shoulder becomes expressed throughout the FBS that quite likely has a subcortical origin. Subsequent examination of the cuneate nucleus (CN) 1 to 30 weeks following forelimb amputation showed that CN played an insignificant role in cortical reorganization and led to the present investigation of VPL. As a first step, we used electrophysiological recordings in forelimb intact adult rats (n=8) to map the body representation in VPL with particular emphasis on the forepaw and shoulder representations and showed that VPL was somatotopically organized. We next used stimulation and recording techniques in forelimb intact rats (n=5) and examined the pattern of projection (a) from the forelimb and shoulder to SI, (b) from the forepaw and shoulder to VPL, and (c) from sites in the forepaw and shoulder representation in VPL to forelimb and shoulder sites in SI. The results showed that the projections were narrowly focused and homotopic. Electrophysiological recordings were then used to map the former forepaw representation in forelimb amputated young adult rats (n=5) at 7 to 24 weeks after amputation. At each time period, new input from the shoulder was observed in the deafferented forepaw region in VPL. To determine whether the new shoulder input in the deafferented forepaw VPL projected to a new shoulder site in the deafferented FBS, we examined the thalamocortical pathway in 2 forelimb-amputated rats. Stimulation of a new shoulder site in deafferented FBS antidromically-activated a cell in the former forepaw territory in VPL; however, similar stimulation from a site in the original shoulder representation, outside the deafferented region, in SI did not activate cells in the former forepaw VPL. These results suggest that the new shoulder input in deafferented FBS is relayed from cells in the former forepaw region in VPL. In the last step, we used anatomical tracing and stimulation and recording techniques in forelimb intact rats (n=9) to examine the cuneothalamic pathway from shoulder and forepaw receptive field zones in CN to determine whether projections from the shoulder zone might provide a possible source of shoulder input to forepaw VPL. Injection of biotinylated dextran amine (BDA) into physiologically identified shoulder responsive sites in CN densely labeled axon terminals in the shoulder representation in VPL, but also gave off small collateral branches into forepaw VPL. In addition, microstimulation delivered to forepaw VPL antidromically-activated cells in shoulder receptive field sites in CN. These results suggest that forepaw VPL also receives input from shoulder receptive sites in CN that are latent or subthreshold in forelimb intact rats. However, we speculate that following amputation these latent shoulder inputs become expressed, possibly as a down-regulation of GABA inhibition from the reticular nucleus (RTN). These results, taken together, suggest that VPL provides a substrate for large-scale cortical reorganization that follows forelimb amputation. PMID:25058605

Li, Cheng X; Chappell, Tyson D; Ramshur, John T; Waters, Robert S



Lesion in the lateral cerebellum specifically produces overshooting of the toe trajectory in leading forelimb during obstacle avoidance in the rat.  


During locomotion, stepping over an obstacle under visual guidance is crucial to continuous safe walking. Studies of the role of the central nervous system in stepping movements have focused on cerebral cortical areas such as the primary motor cortex and posterior parietal cortex. There is speculation that the lateral cerebellum, which has strong anatomical connections with the cerebral cortex, also plays a key role in stepping movements over an obstacle, although this function of the lateral cerebellum has not yet been elucidated. Here we investigated the role of the lateral cerebellum during obstacle avoidance locomotion in rats with a lateral cerebellar lesion. A unilateral lesion in the lateral cerebellum did not affect limb movements during overground locomotion. Importantly, however, the lesioned animals showed overshooting of the toe trajectory specific to the leading forelimb ipsilateral to the lesion when stepping over an obstacle, and the peak toe position, in which the toe is maximally raised during stepping, shifted away from the upper edge of the obstacle. Recordings of EMG activity from elbow flexor and extensor muscles suggested that the overshooting toe trajectory in the ipsilateral leading forelimb possibly resulted from sustained elbow flexion and delayed elbow extension following prolonged activity of the biceps brachii. These results suggest that the lateral cerebellum specifically contributes to generating appropriate toe trajectories in the ipsilateral leading forelimb and to controlling related muscle activities in stepping over an obstacle, especially when accurate control of the distal extremity is achieved under visual guidance. PMID:23615542

Aoki, Sho; Sato, Yamato; Yanagihara, Dai



Selective Forelimb Impairment in Rats Expressing a Pathological TDP-43 25 kDa C-terminal Fragment to Mimic Amyotrophic Lateral Sclerosis  

PubMed Central

Pathological inclusions containing transactive response DNA-binding protein 43?kDa (TDP-43) are common in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 normally localizes predominantly to the nucleus, but during disease progression, it mislocalizes to the cytoplasm. We expressed TDP-43 in rats by an adeno-associated virus (AAV9) gene transfer method that transduces neurons throughout the central nervous system (CNS). To mimic the aberrant cytoplasmic TDP-43 found in disease, we expressed a form of TDP-43 with mutations in the nuclear localization signal sequence (TDP-NLS). The TDP-NLS was detected in both the cytoplasm and the nucleus of transduced neurons. Unlike wild-type TDP-43, expression of TDP-NLS did not induce mortality. However, the TDP-NLS induced disease-relevant motor impairments over 24 weeks. We compared the TDP-NLS to a 25?kDa C-terminal proaggregatory fragment of TDP-43 (TDP-25). The clinical phenotype of forelimb impairment was pronounced with the TDP-25 form, supporting a role of this C-terminal fragment in pathogenesis. The results advance previous rodent models by inducing cytoplasmic expression of TDP-43 in the spinal cord, and the non-lethal phenotype enabled long-term study. Approaching a more relevant disease state in an animal model that more closely mimics underlying mechanisms in human disease could unlock our ability to develop therapeutics. PMID:23689600

Dayton, Robert D; Gitcho, Michael A; Orchard, Elysse A; Wilson, Jon D; Wang, David B; Cain, Cooper D; Johnson, Jeffrey A; Zhang, Yong-Jie; Petrucelli, Leonard; Mathis, J Michael; Klein, Ronald L



Characterization of tests of functional recovery after median and ulnar nerve injury and repair in the rat forelimb.  


The majority of human peripheral nerve injuries occur in the upper limb but the majority of studies in the rat are performed in the hindlimb. The upper and lower limbs differ in dexterity and control by supraspinal systems, so an upper limb model is a better representation of the common form of human injury. The purpose of this study was to further develop a rat model involving lesions of the median and ulnar nerves. To produce different degrees of misdirection of axons following nerve repair, we studied nerve crush, cut and repair of the two nerves, and cut and repair with crossover. Assessment of functional recovery was performed using a battery of motor and sensory tests: the staircase test, which assesses skilled forepaw reaching; grip strength meter, which assesses grip strength; pawprint analysis, which assesses toe spread and print length; horizontal ladder, which assesses forepaw placement during skilled locomotion; modified Randall-Selitto device and electronic von Frey probes, which assess fine touch; and cold probes, which assess temperature sensation. All tests revealed deficits in forepaw function after nerve injury except the print length and modified Randall-Selitto device. The time course of functional recovery was observed over 15 weeks. The final degree of functional recovery achieved was related to the misdirection of axon regeneration. The tests that most clearly revealed the effects of axon misdirection on function were the skilled paw reaching and grip strength tests. The lesion model and functional tests that we have developed will be useful in testing therapeutic strategies for treating the consequences of inaccurate axon regeneration following peripheral nerve injury in humans. PMID:17374098

Galtrey, Clare M; Fawcett, James W



Unilateral lesions of the forelimb area of rat motor cortex: lack of evidence for use-dependent neural growth in the undamaged hemisphere  

Microsoft Academic Search

Unilateral lesions of the forelimb area of the motor cortex have been reported to produce enhanced dendritic outgrowth in the undamaged hemisphere in response to the behavioral asymmetry produced by the lesions (e.g. Jones, T.A. and Schallert, T., Use-dependent growth of pyramidal neurons after neocortical damage,J. Neurosci., 14 (1994) 2140–2152). We attempted to replicate this result and to determine if

Margaret L. Forgie; Robbin Gibb; Bryan Kolb



Cineradiographic (video X-ray) analysis of skilled reaching in a single pellet reaching task provides insight into relative contribution of body, head, oral, and forelimb movement in rats.  


The forelimb movements (skilled reaching) used by rats to reach for a single food pellet to place into the mouth have been used to model many neurological conditions. They have been described as a sequence of oppositions of head-pellet, paw-pellet and pellet-mouth that can be described as movements of the distal portion of body segments in relation to their fixed proximal joints. Movement scoring is difficult, however, because the location and movement of body segments is estimated through the overlying fur and skin, which is pliable and partially obscures movement. Using moderately high-speed cineradiographic filming from lateral, dorsal, and frontal perspectives, the present study describes how forelimb and skeletal bones move during the skilled reaching act. The analysis indicates that: (i) head movements for orienting to food, enabled by the vertical orientation of the rostral spinal cord, are mainly independent of trunk movement, (ii) skilled reaching consists of a sequence of upper arm and extremity movements each involving a number of concurrent limb segment and joint movements and (iii) food pellets are retrieved from the paw using either the incisors and/or tongue. The findings are discussed in relation to the idea that X-ray cinematography is valuable tool for assisting descriptive analysis and can contribute to understanding general principles of the relations between whole body, head, oral, and upper extremity movement. PMID:18514337

Alaverdashvili, Mariam; Leblond, Hugues; Rossignol, Serge; Whishaw, Ian Q



Reduced myelinogenesis and recovery in hyperphenylalaninemic rats  

Microsoft Academic Search

In a previous paper (Burri et al., 1990), we have shown that experimental hyperphenylalaninemia (hyper-Phe) in 3–17 d-old\\u000a rats leads to reduced myelinogenesis. Such treated rats recover during a 6 w low phenylalanine (Phe) period between days 17\\u000a and 59. In order to get more detailed information about the disturbed myelinogenesis and recovery, we measured in hyper-Phe\\u000a rats the developmental

R. Burri; Ch. Steffen; S. Stieger; U. Brodbeck; J. P. Colombo; N. Herschkowitz



Therapeutic intraspinal microstimulation improves forelimb function after cervical contusion injury  

NASA Astrophysics Data System (ADS)

Objective. Intraspinal microstimulation (ISMS) is a promising method for activating the spinal cord distal to an injury. The objectives of this study were to examine the ability of chronically implanted stimulating wires within the cervical spinal cord to (1) directly produce forelimb movements, and (2) assess whether ISMS stimulation could improve subsequent volitional control of paretic extremities following injury. Approach. We developed a technique for implanting intraspinal stimulating electrodes within the cervical spinal cord segments C6-T1 of Long-Evans rats. Beginning 4 weeks after a severe cervical contusion injury at C4-C5, animals in the treatment condition received therapeutic ISMS 7 hours/day, 5 days/week for the following 12 weeks. Main results. Over 12 weeks of therapeutic ISMS, stimulus-evoked forelimb movements were relatively stable. We also explored whether therapeutic ISMS promoted recovery of forelimb reaching movements. Animals receiving daily therapeutic ISMS performed significantly better than unstimulated animals during behavioural tests conducted without stimulation. Quantitative video analysis of forelimb movements showed that stimulated animals performed better in the movements reinforced by stimulation, including extending the elbow to advance the forelimb and opening the digits. While threshold current to elicit forelimb movement gradually increased over time, no differences were observed between chronically stimulated and unstimulated electrodes suggesting that no additional tissue damage was produced by the electrical stimulation. Significance. The results indicate that therapeutic intraspinal stimulation delivered via chronic microwire implants within the cervical spinal cord confers benefits extending beyond the period of stimulation, suggesting future strategies for neural devices to promote sustained recovery after injury.

Kasten, M. R.; Sunshine, M. D.; Secrist, E. S.; Horner, P. J.; Moritz, C. T.



Transplants of Adrenal Medullary Chromaffin Cells Reduce Forelimb and Hindlimb Allodynia in a Rodent Model of Chronic Central Pain after Spinal Cord Hemisection Injury  

Microsoft Academic Search

In the majority of patients, spinal cord injury (SCI) results in abnormal pain syndromes in which nonnoxious stimuli become noxious (allodynia). To reduce allodynia, it would be desirable to implant a permanent biological pump such as adrenal medullary chromaffin cells (AM), which secrete catecholamines and opioid peptides, both antinociceptive substances, near the spinal cord. We tested this approach using a

Bryan C. Hains; Kathy M. Chastain; Alex W. Everhart; David J. McAdoo; Claire E. Hulsebosch



Activity-Based Therapies To Promote Forelimb Use after a Cervical Spinal Cord Injury  

PubMed Central

Abstract Significant interest exists in strategies for improving forelimb function following spinal cord injury. We investigated the effect of enriched housing combined with skilled training on the recovery of skilled and automatic forelimb function after a cervical spinal cord injury in adult rats. All animals were pretrained in skilled reaching, gridwalk crossing, and overground locomotion. Some received a cervical over-hemisection lesion at C4-5, interrupting the right side of the spinal cord and dorsal columns bilaterally, and were housed in standard housing alone or enriched environments with daily training. A subset of animals received rolipram to promote neuronal plasticity. Animals were tested weekly for 4 weeks to measure reaching, errors on the gridwalk, locomotion, and vertical exploration. Biotinylated dextran amine was injected into the cortex to label the corticospinal tract. Enriched environments/daily training significantly increased the number and success of left reaches compared to standard housing. Animals also made fewer errors on the gridwalk, a measure of coordinated forelimb function. However, there were no significant improvements in forelimb use during vertical exploration or locomotion. Likewise, rolipram did not improve any of the behaviors tested. Both enriched housing and rolipram increased plasticity of the corticospinal tract rostral to the lesion. These studies indicate that skilled training after a cervical spinal cord injury improves recovery of skilled forelimb use (reaching) and coordinated limb function (gridwalk) but does not improve automatic forelimb function (locomotion and vertical exploration). These studies suggest that rehabilitating forelimb function after spinal cord injury will require separate strategies for descending and segmental pathways. PMID:19317604

Dai, Haining; MacArthur, Linda; McAtee, Marietta; Hockenbury, Nicole; Tidwell, J. Lille; McHugh, Brian; Mansfield, Kevin; Finn, Tom; Hamers, Frank P.T.



Large-scale reorganization of corticofugal fibers after neonatal hemidecortication for functional restoration of forelimb movements.  


As an experimental model to study the mechanism of large-scale network plasticity of the juvenile brain, functional compensation after neonatal brain damage was studied in rats that received unilateral decortication at postnatal day 5. These animals exhibited a marked ability in reaching and grasping movements in the contralesional side of the forelimb when tested at 10-14 weeks of age. Additional lesion of the sensorimotor cortex in the remaining contralesional hemisphere at this stage resulted in severe impairment of both forelimbs. It was suggested that the sensorimotor cortex on the contralesional side was controlling the movements of both forelimbs. Following the injection of an anterograde tracer into the remaining sensorimotor cortex, the corticofugal axons from the remaining sensorimotor cortex were found to issue aberrant projections to the contralateral red nucleus, contralateral superior colliculus, contralateral pontine nuclei, ipsilateral dorsal column nucleus and ipsilateral gray matter of the cervical spinal cord, all of which appeared to be necessary for the control of contralesional forelimb movements. These results suggest that the forelimb movements on the contralesional side were compensated by large-scale reorganization of the corticofugal axons from the remaining sensorimotor cortex. PMID:19895560

Takahashi, Masahito; Vattanajun, Anusara; Umeda, Tatsuya; Isa, Kaoru; Isa, Tadashi



Ketogenic Diet Improves Forelimb Motor Function after Spinal Cord Injury in Rodents  

PubMed Central

High fat, low carbohydrate ketogenic diets (KD) are validated non-pharmacological treatments for some forms of drug-resistant epilepsy. Ketones reduce neuronal excitation and promote neuroprotection. Here, we investigated the efficacy of KD as a treatment for acute cervical spinal cord injury (SCI) in rats. Starting 4 hours following C5 hemi-contusion injury animals were fed either a standard carbohydrate based diet or a KD formulation with lipid to carbohydrate plus protein ratio of 3:1. The forelimb functional recovery was evaluated for 14 weeks, followed by quantitative histopathology. Post-injury 3:1 KD treatment resulted in increased usage and range of motion of the affected forepaw. Furthermore, KD improved pellet retrieval with recovery of wrist and digit movements. Importantly, after returning to a standard diet after 12 weeks of KD treatment, the improved forelimb function remained stable. Histologically, the spinal cords of KD treated animals displayed smaller lesion areas and more grey matter sparing. In addition, KD treatment increased the number of glucose transporter-1 positive blood vessels in the lesion penumbra and monocarboxylate transporter-1 (MCT1) expression. Pharmacological inhibition of MCTs with 4-CIN (?-cyano-4-hydroxycinnamate) prevented the KD-induced neuroprotection after SCI, In conclusion, post-injury KD effectively promotes functional recovery and is neuroprotective after cervical SCI. These beneficial effects require the function of monocarboxylate transporters responsible for ketone uptake and link the observed neuroprotection directly to the function of ketones, which are known to exert neuroprotection by multiple mechanisms. Our data suggest that current clinical nutritional guidelines, which include relatively high carbohydrate contents, should be revisited. PMID:24223849

Streijger, Femke; Plunet, Ward T.; Lee, Jae H. T.; Liu, Jie; Lam, Clarrie K.; Park, Soeyun; Hilton, Brett J.; Fransen, Bas L.; Matheson, Keely A. J.; Assinck, Peggy; Kwon, Brian K.; Tetzlaff, Wolfram



Essential oil compounds as stress reducing agents in rats.  


Essential oil compounds were studied to demonstrate their potential as stress reducing agents against rats. Rats were intraperitoneal administered with Linalool, Cineole and Thymol, respectively. Anxiety-related behaviors were determined by open field test and elevated plus maze test. Thymol reduced anxiety-related behavior of the animals. Linalool had no effect in both sexes of rats in the open field test. Thus, the results suggested that Thymol and Linalool are safe to control pets without harming non-target mammals PMID:25145237

Kaewwongse, M; Sanesuwan, K; Pupa, P; Bullangpoti, V



Arginine and Conjugated Linoleic Acid Reduce Fat Mass in Rats  

E-print Network

to produce livestock efficiently and to produce a high-quality product. For humans, this information will help us begin to treat obesity and associated diseases such as type-II diabetes and cardiovascular disease. The objectives for this study were: 1..., it was demonstrated that dietary arginine reduced adiposity in Zucker diabetic fat (ZDF) rats (16). These rats genetically resemble human Type II diabetics. After a 10-wk treatment period, the rats fed 1.25% arginine in drinking water had 25% less epididymal fat...

Nall, Jennifer L.



Interlimb coordination in 20-day-old rat fetuses.  


Evidence for short sequences of interlimb coordination was found in 20-day-old rat fetuses. Frame-by-frame analysis of videotape records showed phase relationships indicating a pattern of alternation in sequences involving forelimb-forelimb and hindlimb-hindlimb coordination. Forelimb-hindlimb coordination was not observed. PMID:7462983

Bekoff, A; Lau, B



Precocial hindlimbs and altricial forelimbs: partitioning ontogenetic strategies in mallards (Anas platyrhynchos).  


Precocial development, in which juveniles are relatively mature at hatching or birth, is more common among vertebrates than altricial development, and is likely to be the basal condition. Altricial development characterizes many birds and mammals and is generally viewed as an alternate strategy, promoting fast growth rates, short developmental periods and relatively poor locomotor performance prior to attaining adult size. Many aquatic birds such as Anseriformes (ducks, geese and swans), Charadriformes (gulls and terns) and Gruiformes (rails) undergo distinctive developmental trajectories, in that hatchlings are able to run and swim the day they hatch, yet they do not begin to fly until fully grown. We hypothesized that there should be tradeoffs in apportioning bone and muscle mass to the hindlimb and forelimb that could account for these patterns in locomotor behavior within the mallard (Anas platyrhynchos). Growth of the musculoskeletal system in the forelimbs and hindlimbs was measured and compared with maximal aquatic and terrestrial sprint speeds and aerial descent rates throughout the 2-month-long mallard ontogenetic period. At 30 days post hatching, when body mass is 50% of adult values, hindlimb muscle mass averages 90% and forelimb muscle mass averages 10% of adult values; similarly, bone growth (length and width) in the hindlimbs and forelimbs averages 90 and 60% of adult values, respectively. The attainment of mallard locomotor performance parallels the morphological maturation of forelimb and hindlimb morphometrics - hindlimb performance initiates just after hatching at a relatively high level (~50% adult values) and gradually improves throughout the first month of development, while forelimb performance is relatively non-existent at hatching (~10% adult values), experiencing delayed and dramatic improvement in function, and maturing at the time of fledging. This divergence in ontogenetic strategy between locomotor modules could allow developing Anseriformes to inhabit aquatic, predator-reduced refuges without relying on flight for juvenile escape. Furthermore, by freeing the forelimbs from locomotor demand early in ontogeny, Anseriformes may bypass the potential canalization (i.e. retention) of juvenile form present within their precocial hindlimbs, to dramatically depart in forelimb form and function in the adult. PMID:22855613

Dial, Terry R; Carrier, David R



Prenatal alcohol exposure reduces the size of the forelimb representation in motor cortex in rat: an intracortical microstimulation (ICMS) mapping study  

Microsoft Academic Search

Children with fetal alcohol spectrum disorder (FASD) often exhibit sensorimotor dysfunctions that include deficits in motor coordination and fine motor control. Although the underlying causes for these motor abnormalities are unknown, they likely involve interactions between sensory and motor systems. Rodent animal models have been used to study the effects of prenatal alcohol exposure (PAE) on skilled reaching and on

Ni Xie; Qiuhong Yang; Tyson D. Chappell; Cheng-Xiang Li; Robert S. Waters



Red maca (Lepidium meyenii) reduced prostate size in rats  

PubMed Central

Background Epidemiological studies have found that consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer. This effect seems to be due to aromatic glucosinolate content. Glucosinolates are known for have both antiproliferative and proapoptotic actions. Maca is a cruciferous cultivated in the highlands of Peru. The absolute content of glucosinolates in Maca hypocotyls is relatively higher than that reported in other cruciferous crops. Therefore, Maca may have proapoptotic and anti-proliferative effects in the prostate. Methods Male rats treated with or without aqueous extracts of three ecotypes of Maca (Yellow, Black and Red) were analyzed to determine the effect on ventral prostate weight, epithelial height and duct luminal area. Effects on serum testosterone (T) and estradiol (E2) levels were also assessed. Besides, the effect of Red Maca on prostate was analyzed in rats treated with testosterone enanthate (TE). Results Red Maca but neither Yellow nor Black Maca reduced significantly ventral prostate size in rats. Serum T or E2 levels were not affected by any of the ecotypes of Maca assessed. Red Maca also prevented the prostate weight increase induced by TE treatment. Red Maca administered for 42 days reduced ventral prostatic epithelial height. TE increased ventral prostatic epithelial height and duct luminal area. These increases by TE were reduced after treatment with Red Maca for 42 days. Histology pictures in rats treated with Red Maca plus TE were similar to controls. Phytochemical screening showed that aqueous extract of Red Maca has alkaloids, steroids, tannins, saponins, and cardiotonic glycosides. The IR spectra of the three ecotypes of Maca in 3800-650 cm (-1) region had 7 peaks representing 7 functional chemical groups. Highest peak values were observed for Red Maca, intermediate values for Yellow Maca and low values for Black Maca. These functional groups correspond among others to benzyl glucosinolate. Conclusions Red Maca, a cruciferous plant from the highland of Peru, reduced ventral prostate size in normal and TE treated rats. PMID:15661081

Gonzales, Gustavo F; Miranda, Sara; Nieto, Jessica; Fernandez, Gilma; Yucra, Sandra; Rubio, Julio; Yi, Pedro; Gasco, Manuel



Character Phylogeny of the Primate Forelimb Superficial Venous System  

Microsoft Academic Search

The ontogeny and comparative anatomy of the forelimb superficial veins were investigated in humans, non-human primates and other mammals. Adult humans and the orangutan (Pongo) possess two autonomous forelimb veins, one on the lateral (preaxial) margin of the limb, the other on the medial (postaxial) margin. All other adult primates and mammals examined possess a lateral vein alone. In African

A. T. Chamberlain; B. A. Wood



Power flow in the equine forelimb.  


A method is described for the estimation of segmental powers and power flow during the stance phase in the equine forelimb, to demonstrate the sources and paths of energy flow through the limb segments. S-VHS video and force platform data were collected for 5 walking trials in a sound Dutch Warmblood horse. Two camera views were combined using direct linear transformation and the resultant sagittal plane positional and angular data used together with the vertical and cranio-caudal ground reaction forces to calculate moments about the ends of the 4 lowermost segments of the forelimb, and the reaction forces at the segment ends. Power flows were calculated across the proximal and distal ends of each segment and total segmental power computed. During initial and terminal stance, power flowed into the cannon segment proximally, and out distally. For the rest of stance, the flow in the cannon was distal to proximal. At the pastern, power flowed in proximally during initial loading, and out distally. For most of the rest of stance, the pattern of flow was distal to proximal, except for terminal stance, when power flowed in through both ends. The largest effect at the hoof is a loss of energy in terminal stance as power flowed out proximally and into the pastern. The pastern appears to receive most of the energy during loading and pushoff and transfers this energy up the limb during midstance. PMID:9354286

Colborne, G R; Lanovaz, J L; Sprigings, E J; Schamhardt, H C; Clayton, H M



Reduced motoneuron excitability in a rat model of sepsis  

PubMed Central

Many critically ill patients in intensive care units suffer from an infection-induced whole body inflammatory state known as sepsis, which causes severe weakness in patients who survive. The mechanisms by which sepsis triggers intensive care unit-acquired weakness (ICUAW) remain unclear. Currently, research into ICUAW is focused on dysfunction of the peripheral nervous system. During electromyographic studies of patients with ICUAW, we noticed that recruitment was limited to few motor units, which fired at low rates. The reduction in motor unit rate modulation suggested that functional impairment within the central nervous system contributes to ICUAW. To understand better the mechanism underlying reduced firing motor unit firing rates, we moved to the rat cecal ligation and puncture model of sepsis. In isoflurane-anesthetized rats, we studied the response of spinal motoneurons to injected current to determine their capacity for initiating and firing action potentials repetitively. Properties of single action potentials and passive membrane properties of motoneurons from septic rats were normal, suggesting excitability was normal. However, motoneurons exhibited striking dysfunction during repetitive firing. The sustained firing that underlies normal motor unit activity and smooth force generation was slower, more erratic, and often intermittent in septic rats. Our data are the first to suggest that reduced excitability of neurons within the central nervous system may contribute to ICUAW. PMID:23303860

Nardelli, Paul; Khan, Jaffar; Powers, Randall; Cope, Tim C.



A silver-reducing component in rat striated muscle  

Microsoft Academic Search

This study reports the presence of a silver-reducing constituent in rat striated muscle fiber located selectively at the level of the terminal cistern\\/transverse tubulc system. It is related to the T tubule network at or near sites that participate in junctions with terminal cisternae, i.e., at both sides of the T tubule in skeletal muscle (triad) and, predominantly, at one

C. J. Tandler; A. Pellegrino de Iraldi



Chronic clozapine reduces rat brain arachidonic acid metabolism by reducing plasma arachidonic acid availability  

PubMed Central

Chronic administration of mood stabilizers to rats downregulates the brain arachidonic acid (AA) cascade. This downregulation may explain their efficacy against bipolar disorder (BD), in which brain AA cascade markers are elevated. The atypical antipsychotics, olanzapine (OLZ) and clozapine (CLZ), also act against BD. When given to rats, both reduce brain cyclooxygenase activity and prostaglandin E2 concentration; OLZ also reduces rat plasma unesterified and esterified AA concentrations, and AA incorporation and turnover in brain phospholipid. To test whether CLZ produces similar changes, we used our in vivo fatty acid method in rats given 10 mg/kg/day i.p. CLZ, or vehicle, for 30 days; or 1 day after CLZ washout. [1-14C]AA was infused intravenously for 5 min, arterial plasma was collected and microwaved brain was analyzed. CLZ increased incorporation coefficients ki? and rates Jin,i of plasma unesterified AA into brain phospholipids i, while decreasing plasma unesterified but not esterified AA. These effects disappeared after washout. Thus, CLZ and OLZ similarly downregulated kinetics and cyclooxygenase expression of the brain AA cascade, likely by reducing plasma unesterified AA availability. Atypical antipsychotics and mood stabilizers may be therapeutic in BD by downregulating, indirectly or directly respectively, the elevated brain AA cascade of that disease. PMID:23121637

Modi, Hiren R.; Taha, Ameer Y.; Kim, Hyung-Wook; Chang, Lisa; Rapoport, Stanley I.; Cheon, Yewon



The transformation suppressor gene Reck is required for postaxial patterning in mouse forelimbs  

PubMed Central

Summary The membrane-anchored metalloproteinase-regulator RECK has been characterized as a tumor suppressor. Here we report that mice with reduced Reck-expression show limb abnormalities including right-dominant, forelimb-specific defects in postaxial skeletal elements. The forelimb buds of low-Reck mutants have an altered dorsal ectoderm with reduced Wnt7a and Igf2 expression, and hypotrophy in two signaling centers (i.e., ZPA and AER) that are essential for limb outgrowth and patterning. Reck is abundantly expressed in the anterior mesenchyme in normal limb buds; mesenchyme-specific Reck inactivation recapitulates the low-Reck phenotype; and some teratogens downregulate Reck in mesenchymal cells. Our findings illustrate a role for Reck in the mesenchymal-epithelial interactions essential for mammalian development. PMID:23213437

Yamamoto, Mako; Matsuzaki, Tomoko; Takahashi, Rei; Adachi, Eijiro; Maeda, Yasuhiro; Yamaguchi, Sachiyo; Kitayama, Hitoshi; Echizenya, Michiko; Morioka, Yoko; Alexander, David B.; Yagi, Takeshi; Itohara, Shigeyoshi; Nakamura, Takashi; Akiyama, Haruhiko; Noda, Makoto



Astaxanthin reduces ischemic brain injury in adult rats.  


Astaxanthin (ATX) is a dietary carotenoid of crustaceans and fish that contributes to their coloration. Dietary ATX is important for development and survival of salmonids and crustaceans and has been shown to reduce cardiac ischemic injury in rodents. The purpose of this study was to examine whether ATX can protect against ischemic injury in the mammalian brain. Adult rats were injected intracerebroventricularly with ATX or vehicle prior to a 60-min middle cerebral artery occlusion (MCAo). ATX was present in the infarction area at 70-75 min after onset of MCAo. Treatment with ATX, compared to vehicle, increased locomotor activity in stroke rats and reduced cerebral infarction at 2 d after MCAo. To evaluate the protective mechanisms of ATX against stroke, brain tissues were assayed for free radical damage, apoptosis, and excitoxicity. ATX antagonized ischemia-mediated loss of aconitase activity and reduced glutamate release, lipid peroxidation, translocation of cytochrome c, and TUNEL labeling in the ischemic cortex. ATX did not alter physiological parameters, such as body temperature, brain temperature, cerebral blood flow, blood gases, blood pressure, and pH. Collectively, our data suggest that ATX can reduce ischemia-related injury in brain tissue through the inhibition of oxidative stress, reduction of glutamate release, and antiapoptosis. ATX may be clinically useful for patients vulnerable or prone to ischemic events. PMID:19218497

Shen, Hui; Kuo, Chi-Chung; Chou, Jenny; Delvolve, Alice; Jackson, Shelley N; Post, Jeremy; Woods, Amina S; Hoffer, Barry J; Wang, Yun; Harvey, Brandon K



New, puzzling insights from comparative myological studies on the old and unsolved forelimb/hindlimb enigma.  


Most textbooks and research reports state that the structures of the tetrapod forelimbs and hindlimbs are serial homologues. From this view, the main challenge of evolutionary biologists is not to explain the similarity between tetrapod limbs, but instead to explain why and how they have diverged. However, these statements seem to be related to a confusion between the serial homology of the vertebrate pelvic and pectoral appendages as a whole, and the serial homology of the specific soft- and hard-tissue structures of the tetrapod forelimbs and hindlimbs, leading to an even more crucial and puzzling question being overlooked: why are the skeletal and particularly the muscle structures of the forelimb and hindlimb actually so strikingly similar to each other? Herein we provide an updated discussion of these questions and test two main hypotheses: (i) that the similarity of the limb muscles is due to serial homology; and (ii) that tetrapods that use hindlimbs for a largely exclusive function (e.g. bipedalism in humans) exhibit fewer cases of similarity between forelimbs and hindlimbs than do quadrupedal species. Our review shows that of the 23 arm, forearm and hand muscles/muscle groups of salamanders, 18 (78%) have clear 'topological equivalents' in the hindlimb; in lizards, 14/24 (58%); in rats, 14/35 (40%); and in modern humans, 19/37 (51%). These numbers seem to support the idea that there is a plesiomorphic similarity and subsequent evolutionary divergence, but this tendency actually only applies to the three former quadrupedal taxa. Moreover, if one takes into account the total number of 'correspondences', one comes to a surprising and puzzling conclusion: in modern humans the number of forelimb muscles/muscle groups with clear 'equivalents' in the hindlimb (19) is substantially higher than in quadrupedal mammals such as rats (14), lizards (14) and even salamanders (18). These data contradict the hypothesis that divergent functions lead to divergent morphological structures. Furthermore, as we show that at least five of the 19 modern human adult forelimb elements that have a clear hindlimb 'equivalent' derive from embryonic anlages that are very different from the ones giving rise to their adult hindlimb 'equivalents', they also contradict the hypothesis that the similarity in muscle structures between the forelimb and hindlimb of tetrapods such as modern humans are due to their origin as serial homologues. This similarity is instead the result of phylogenetically independent evolutionary changes leading to a parallelism/convergence due to: (i) developmental constraints, i.e. similar molecular mechanisms are involved (particularly in the formation of the neomorphic hand), but this does not necessarily mean that similar anlages are used to form the similar adult structures; (ii) functional constraints, related to similar adaptations; (iii) topological constraints, i.e. limited physical possibilities; and even (iv) phylogenetic constraints, which tend to prevent/decrease the occurrence of new homoplasic similarities, but also help to keep older, ancestral homoplasic resemblances. PMID:22958734

Diogo, Rui; Linde-Medina, Marta; Abdala, Virginia; Ashley-Ross, Miriam A



Ibandronate affects bone growth and mineralization in rats with normal and reduced renal function.  


Bisphosphonates have been shown to attenuate ectopic calcification in experimental uremia. While they are known to reduce bone turnover, the effects on endochondral bone formation have not yet been addressed. To address this issue, we administered male Sprague-Dawley rats weekly subcutaneous injections of either vehicle or ibandronate (1.25 ?g/kg body weight) for a total of 10 weeks. The rats were randomly allocated into one of four groups: (1) vehicle-treated, sham-operated rats; (2) ibandronate-treated, sham-operated rats; (3) vehicle-treated, 5/6 nephrectomized rats; (4) ibandronate-treated, 5/6 nephrectomized rats. Bones were double labeled with tetracycline and demeclocycline in vivo, and tibiae were removed for analysis. Weight gain was similar in all groups. Ibandronate reduced body length gain and tibial growth rate in the sham-operated animals but not in the rats showing chronic renal failure (CRF). The height of the proliferative zone of the epiphyseal growth plate was reduced in the ibandronate-treated controls and tended to be reduced in CRF rats. A significant correlation between tibial growth rate and height of the proliferative zone was observed. Mineral apposition rates were significantly reduced in ibandronate-treated, sham-operated rats and tended to be reduced in CRF rats. In conclusion, ibandronate interferes with tibial growth and bone mineralization in young rats with normal and reduced renal function. PMID:20953634

Fischer, Dagmar-Christiane; Jensen, Claudia; Rahn, Anja; Salewski, Birgit; Kundt, Günther; Behets, Geert J; D'Haese, Patrick; Haffner, Dieter



Anatomical, architectural, and biochemical diversity of the murine forelimb muscles  

PubMed Central

We characterized the architecture, fiber type, titin isoform distribution, and collagen content of 27 portions of 22 muscles in the murine forelimb. The mouse forelimb was different from the human arm in that it had the extensor digitorum lateralis muscle and no brachioradialis muscle. Architecturally, the mouse forelimb differed from humans with regard to load bearing, having a much larger contribution from extensors than flexors. In mice, the extensor : flexor PCSA ratio is 2.7, whereas in humans it is only 1.4. When the architectural difference index was calculated, similarities became especially apparent between flexors and extensors of the distal forelimb, as well as pronators. Discriminant analysis revealed that biochemical measures of collagen, titin, and myosin heavy chain were all strong between-species discriminators. In terms of composition, when compared with similar muscles in humans, mice had, on average, faster muscles with higher collagen content and larger titin isoforms. This report establishes the anatomical and biochemical properties of mouse forelimb muscles. Given the prevalence of this species in biological studies, these data will be invaluable for studying the biological basis of mouse muscle structure and function. PMID:22938020

Mathewson, Margie A; Chapman, Mark A; Hentzen, Eric R; Friden, Jan; Lieber, Richard L



Muscle moment arms and function of the siamang forelimb during brachiation  

E-print Network

, 1976; Carpenter, 1976; Hollihn, 1984; Preuschoft & Demes, 1984). The gross anatomy of their forelimbs, Belgium 3 Department of Human Anatomy and Cell Biology, School of Biomedical Sciences, University biomechanics; forelimb anatomy; Symphalangus. Introduction The Hylobatidae (gibbons and siamangs) are known

D'Août, Kristiaan


Electroacupuncture Reduces Hyperalgesia after Injections of Acidic Saline in Rats  

PubMed Central

Background. Injections of acidic saline into the gastrocnemius muscle in rats produce a bilateral long-lasting hyperalgesia similar to fibromyalgia in humans. No previous study investigated the effect of electroacupuncture (EA) on this acidic saline model. This study aimed to identify the effects of EA in the hyperalgesia produced by repeated intramuscular injections of acidic saline. Methods. Rats were divided into four groups (n = 6, each group): control, acupuncture, EA 15?Hz, and 100?Hz. Left gastrocnemius muscle was injected with 100??L of pH 4.0 sterile saline twice five days apart. EA, acupuncture, or control therapy was daily administered (20?min) for 5 consecutive days under anesthesia. Needles were placed in the St36 and Sp6 acupoints. The assessment of secondary mechanical hyperalgesia, thermal hyperalgesia, and motor performance was performed before injections and before and after the treatment performed on each day. The paw withdrawal threshold was tested using the nonparametric Kruskal-Wallis test and differences within the group Wilcoxon Matched Pairs. The latency and motor performance were tested for ANOVA parametric test for independent measures, and for differences in the group, we used t-test for paired samples. Post hoc Tukey test was used for multiple corrections. P values less than 0.05 were considered statistically significant. Results. Indicate that there was a significant reduction of mechanical withdrawal threshold and paw withdrawal latency 24 hours following the second injection. Moreover, mechanical and thermal hyperalgesia were significantly reversed by EA 15, 100?Hz, and acupuncture. Conclusions. The results suggest that EA high and low frequency as well as acupuncture are effective in reducing hyperalgesia in chronic muscle pain model. PMID:24772181

Maciel, Leonardo Yung dos Santos; da Cruz, Kamilla Mayara Lucas; de Araujo, Ariane Martins; Silva, Zak Moreira de Andrade; Badaue-Passos, Daniel; Santana-Filho, Valter Joviniano; DeSantana, Josimari Melo



Rodent Model for Forelimb Neuromuscular Stimulation Based Movement Therapy  

Microsoft Academic Search

We present the development of a novel rodent model for neuromuscular stimulation assisted forelimb movement. The motor points for flexors and extensors of the shoulder, elbow, and digits were identified and the muscles were implanted with custom intramuscular stimulation electrodes. Strength-duration curves were generated to guide the choice of stimulation parameters required to produce consistent isolated contraction of each muscle

Tsukasa Kanchiku; James V Lynskey; Toshihiko Taguchi; James J. Abbas


Dimensions of forelimb muscles in orangutans and chimpanzees  

PubMed Central

Eight forelimbs of three orangutans and four chimpanzees were dissected and the muscle mass, fascicle length and physiological cross-sectional area (PCSA) of all forelimb muscles were systematically recorded to explore possible interspecies variation in muscle dimensions. Muscle mass and PCSA were divided by the total mass and total PCSA of the entire forelimb muscles for normalization. The results indicate that the mass and PCSA ratios of the monoarticular elbow flexors (M. brachialisand M. brachioradialis) are significantly larger in orangutans. In contrast, the mass ratios of the biarticular muscles in the upper arm (the short head of M. biceps brachiiand the long head of M. triceps brachii) are significantly larger in chimpanzees. For the rotator cuff muscles, the force-generating capacity of M. subscapularisis significantly larger in orangutans, whereas the opposite rotator cuff muscle, M. infraspinatus, is larger in chimpanzees. These differences in forelimb muscle dimensions of the two species may reflect functional specialization for their different positional and locomotor behaviors. PMID:19619166

Oishi, Motoharu; Ogihara, Naomichi; Endo, Hideki; Ichihara, Nobutsune; Asari, Masao



A lipid emulsion reduces mortality from clomipramine overdose in rats.  


Tricyclic antidepressants are a common cause of self poisoning. Since these drugs are highly lipid soluble, we examined the interaction between imipramine and a lipid emulsion. Rats were given an iv dose of imipramine with either normal saline or a lipid emulsion as vehicle. The rats who received the lipid emulsion had a significantly lower mortality. The role of lipid emulsions poisoning therapy is reviewed. PMID:11824772

Yoav, Goor; Odelia, Goor; Shaltiel, Cabilil; Goor, Yoav; Goor, Odelia; Cabili, Shaltiel



Reduced Metabolic Response of the Aged Rat Brain to Haloperidol  

Microsoft Academic Search

Local cerebral glucose utilization (LCGU) was determined in 49 brain regions of 3-, 12-, 24-, and 33-month-old awake Fischer-344 rats, at 30 to 120 min after administration of the dopaminergic antagonist haloperidol (HAL) at 1 mg\\/kg (i.p.). The quantitative autoradiographic ('4C)-2-deoxyglucose technique was employed. In 3-month rats, HAL produced statistically significant (p c 0.05) reductions in LCGU in 63% of



Reduced antibody responses after immunization in rat lung transplants.  


Pulmonary infections occur so frequently in recipients of lung transplants as well as of combined heart and lung transplants that it has been suggested that the function of the defense system in lung transplants is impaired. Therefore, we investigated in rats whether antibody responses against intrapulmonary antigens were impaired at various time points after transplantation. Antibody responses were induced in lungs of four experimental groups. Group 1: normal lungs (LEW); Group 2: hilar-stripped (sham-operated) lungs (LEW); Group 3: syngeneic lung transplants (LEW-to-LEW); Group 4: allogeneic lung transplants (BN-to-LEW). The operations were performed on the left lungs. All rats (including those with normal lungs) were treated with cyclosporine on Days 2 and 3 after operation, which treatment is adequate to induce permanent graft acceptance of the allografts. Rats were immunized 7, 10, 14, 21, and 28 days and at 6 months after operation with sheep red blood cells, injected selectively into the bronchus of the left lung. The resulting serum antibody titers were detected with a hemolysis assay. After immunization on Day 7, no antibody responses could be detected in all hilar-stripped and transplanted rats, whereas responses were normal in two allografted rats immunized in the nontransplanted right lung. After immunization on Day 14, responses had returned to normal in hilar-stripped rats, whereas they were still impaired in the transplanted rats. After immunization on Day 28, responses were almost normal in all rats and remained so until 6 months after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8442603

Winter, J B; Groen, M; Petersen, A H; Wildevuur, C R; Prop, J



Melatonin reduces oxidative damage induced by aluminium in rat kidney  

Microsoft Academic Search

We evaluated the effect of melatonin (Mel), in male Wistar rats which received aluminium (Al) lactate for 12 weeks (0.57mg Al\\/100g body weight (b.w.), i.p. three times per week). Moreover rats received Mel (10mg\\/kg b.w. i.p. 5 days\\/weeks) for 12 weeks. At the end of the treatment water and sodium balances were studied, and nephrogenic cyclic adenosine monophosphate (cAMP) was

Stella Mahieu; María del Carmen Contini; Marcela González; Néstor Millen



Systemic Propranolol Acts Centrally to Reduce Conditioned Fear in Rats Without Impairing Extinction  

E-print Network

Systemic Propranolol Acts Centrally to Reduce Conditioned Fear in Rats Without Impairing Extinction of conditioned fear. Less is known, however, about their role in fear expression and extinction. The -receptor in rats, we assessed the effects of systemic propranolol on the expression and extinction of two measures

Quirk, Gregory J.


Memory Retrieval before or after Extinction Reduces Recovery of Fear in Adolescent Rats  

ERIC Educational Resources Information Center

Adolescent rats exhibit impaired extinction retention compared to pre-adolescent and adult rats. A single nonreinforced exposure to the conditioned stimulus (CS; a retrieval trial) given shortly before extinction has been shown in some circumstances to reduce the recovery of fear after extinction in adult animals. This study investigated whether a…

Baker, Kathryn D.; McNally, Gavan P.; Richardson, Rick



Dietary L-arginine supplementation reduces fat mass in diet-induced obese rats  

E-print Network

-96% compared to the low-fat diet. Concentrations of serum cholesterol as well as lipids in skeletal muscle and liver were higher in obese rats than in lean rats. L-Arginine supplementation reduced white adipose tissue mass by 20-40% while increasing brown...

Jobgen, Wenjuan Shi



Endotoxin-induced mortality in rats is reduced by nitrones  

SciTech Connect

The goal of these investigations was to determine if nitrone spin-trapping agents can alter mortality associated with endotoxemia in the rat. Reactive free radicals attack nitrone spin-trapping agents forming relatively reactive, persistent free radical spin adducts. We administered 85 mM (10 ml/kg) of alpha-phenyl N-tert-butyl nitrone (PBN), alpha-4-pyridyl-N-oxide N-tert-butyl nitrone (4-POBN), 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), or vehicle (saline i.p.) 30 min before endotoxin (25 mg/kg i.p.) or vehicle to Sprague-Dawley (SD) or Holtzman virus-free (HVF) rats (n = 10-17/group). All vehicle-treated rats receiving endotoxin were dead by 1 day. At 7 days, 83% of PBN-treated SD, 42% of PBN- or POBN-treated HVF, and 25% of DMPO-treated HVF rats were alive. The difference in survival of PBN-treated animals between strains may reflect the higher susceptibility of HVF rats to endotoxin. The observed reduction in mortality may be related to the well-established capacity of spin-trapping agents to capture reactive free radicals that may be generated in target tissues in response to endotoxin, and that would otherwise react with cell components and produce tissue injury.

Hamburger, S.A.; McCay, P.B. (Oklahoma Medical Researh Foundation, Oklahoma City (USA))



Chronic carbamazepine administration reduces NMDA receptor-initiated signaling via arachidonic acid in rat brain  

PubMed Central

Background Lithium and carbamazepine (CBZ) are used to treat mania in bipolar disorder. When given chronically to rats, both agents reduce brain arachidonic acid (AA) turnover in brain phospholipids and downstream AA metabolism. Lithium administration to rats also attenuates N-methyl-D-aspartic acid receptor (NMDAR) signaling via AA. Hypothesis Chronic CBZ administration to rats, like chronic lithium, will reduce NMDAR-mediated signaling via AA. Methods We used our fatty acid method with quantitative autoradiography to image the regional brain incorporation coefficient k* of AA, a marker of AA signaling, in unanesthetized rats that had been given 25 mg/kg/day i.p. CBZ or vehicle for 30 days, then injected with NMDA (25 mg/kg i.p.) or saline. We also measured brain concentration of two AA metabolites, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). Results In chronic vehicle-treated rats, NMDA compared with saline increased k* significantly in 69 of 82 brain regions examined, but did not change k* significantly in any region in the CBZ-treated rats. In vehicle- but not CBZ-treated rats, NMDA also increased brain concentration of PGE2 and TXB2. Conclusions Chronic CBZ administration to rats blocks the brain NMDAR-mediated AA signal k* and the increments in PGE2 and TXB2 that are seen in vehicle-treated rats. The clinical action of antimanic drugs may involve inhibition of brain NMDAR-mediated signaling involving AA and its metabolites. PMID:17628508

Basselin, Mireille; Villacreses, Nelly E.; Chen, Mei; Bell, Jane M.; Rapoport, Stanley I.



Dextromethorphan reduces intravenous cocaine self-administration in the rat  

Microsoft Academic Search

Dextromethorphan is a widely used antitussive agent with non-competitive antagonistic effects at the excitatory amino acid receptors of the NMDA type. Since excitatory amino acid neurotransmission has been implicated in cocaine dependence, the aim of the present study was to evaluate the effects of acute systemic administration of dextromethorphan in rats trained to self-administer cocaine intravenously. The experiments were designed

Luigi Pulvirenti; Claudia Balducci; George F. Koob



Immunization of rats reduces nicotine distribution to brain  

Microsoft Academic Search

The effect of active immunization against nicotine on the initial distribution of nicotine to brain was studied in anesthetized\\u000a rats. Animals received nicotine 0.03?mg\\/kg nicotine (equivalent to the nicotine dose absorbed by a human smoking two cigarettes)\\u000a as a rapid injection in the jugular vein. In control animals, the arterial serum nicotine concentration initially exceeded\\u000a the venous concentration 4.6-fold, similar

Yoko Hieda; Dan E. Keyler; John T. VanDeVoort; R. Sam Niedbala; Donna E. Raphael; Cathy A. Ross; Paul R. Pentel



Dietary fish oil reduces oxidative DNA damage in rat colonocytes.  


Prolonged generation of reactive oxygen species by inflammatory mediators can induce oxidative DNA damage (8-oxodG formation), potentially resulting in intestinal tumorigenesis. Fish oil (FO), compared to corn oil (CO), has been shown to downregulate inflammation and upregulate apoptosis targeted at damaged cells. We hypothesized FO could protect the intestine against 8-oxodG formation during dextran sodium sulfate- (DSS-) induced inflammation. We provided 60 rats with FO- or CO-supplemented diets for 2 weeks with or without 3% DSS in drinking water for 48 h. Half the treated rats received 48 additional h of untreated water before termination. Due to DSS treatment, the intestinal epithelium had higher levels of 8-oxodG (p =.04), induction of repair enzyme OGG1 mRNA (p =.02), and higher levels of apoptosis at the top of colonic crypts (p =.01) and in surface cells (p <.0001). FO-fed rats, compared to CO, had lower levels of 8-oxodG (p =.05) and increased apoptosis (p =.04) in the upper crypt region; however, FO had no significant effect on OGG1 mRNA. We conclude that FO protects intestinal cells against oxidative DNA damage in part via deletion mechanisms. PMID:12853071

Bancroft, Laura K; Lupton, Joanne R; Davidson, Laurie A; Taddeo, Stella S; Murphy, Mary E; Carroll, Raymond J; Chapkin, Robert S



Blood-brain barrier transport of choline is reduced in the aged rat.  


An age-related impairment in choline transport across the blood-brain barrier (BBB) may contribute to the cholinergic mechanisms of geriatric memory dysfunction. To test this hypothesis, the brain choline uptake in male Fisher 344 rats at 2, 18 and 24 months of age was studied using the Oldendorf technique. The Vmax of choline transport in the 24-month-old rats (0.05 +/- 0.04 nmol/min/g) was significantly lower than that in the 2-month-old rat (2.5 +/- 1.0 nmol/min/g) (P less than 0.05). The Km of transport in old rats (13 +/- 35 microM) was also significantly smaller than the value in 24-month-old rats (450 +/- 195 microM), while the constant of the non-saturable component of the transport, Kd, was not significantly different in older rats (1.2 +/- 0.3 vs 0.6 +/- 0.1 microliter/min/g). These results indicate that the carrier in old rats has reduced capacity and increased affinity to choline. The reduced choline carrier capacity explains the significant decrease in BBB choline transport in aged rats. PMID:3359216

Mooradian, A D



Subdiaphragmatic vagotomy reduces intake of sweet-tasting solutions in rats.  


Studies have shown that there are strong interactions between gustatory and visceral sensations in the central nervous system when rats ingest sweet foods or solutions. To investigate the role of the subdiaphragmatic vagi in transmitting general visceral information during the process of drinking sweet-tasting solutions, we examined the effects of subdiaphragmatic vagotomy on the intake of 0.5 mol/L sucrose, 0.005 mol/L saccharin or distilled water over the course of 1 hour in rats deprived of water. Results showed no significant difference in consumption of these three solutions in vagotomized rats. However, rats in the sham-surgery group drank more saccharin solution than sucrose solution or distilled water. Moreover, the intake of distilled water was similar between vagotomized rats and sham-surgery group rats, but significantly less sucrose and saccharin were consumed by vagotomized rats compared with rats in the sham-surgery group. These findings indicate that subdiaphragmatic vagotomy reduces intake of sweet-tasting solution in rats, and suggest that vagal and extravagal inputs play a balanced role in the control of the intake of sweet-tasting solutions. They also suggest that subdiaphragmatic vagotomy eliminates the difference in hedonic perception induced by sweet-tasting solutions compared with distilled water. PMID:25206451

Jiang, Enshe; Yu, Dongming; Feng, Zhifen



Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats.  


Effect of metformin treatment on blood pressure, endothelial function and oxidative stress in streptozotocin (STZ)-induced diabetes in rats was studied. In vitro effect of metformin on vascular reactivity to various agonist in the presence of metformin in untreated nondiabetic and STZ-diabetic rats were also studied. Sprague-Dawley rats were randomized into nondiabetic and STZ-diabetic groups. Rats were further randomized to receive metformin (150 mg/kg) or vehicle for 4 weeks. Metformin treatment reduced blood pressure without having any significant effect on blood glucose level in STZ-diabetic rats. Enhanced phenylephrine (PE)-induced contraction and impaired acetylcholine (Ach)-induced relaxation in STZ-diabetic rats were restored to normal by metformin treatment. Enhanced Ach-induced relaxation in metformin-treated STZ-diabetic rats was blocked due to pretreatment with 100 microM of Nomega-nitro-L-arginine-methyl ester (L-NAME) or 10 microM of methylene blue but not 10 microM of indomethacin. Metformin treatment significantly increased antioxidant enzymes and reduced lipid peroxidation in STZ-diabetic rats. In vitro studies in aortic rings of untreated nondiabetic and STZ-diabetic rats showed that the presence of higher concentration of metformin (1 mM and 10 mM) significantly reduced PE-induced contraction and increased Ach-induced relaxation. Metformin per se relaxed precontracted aortic rings of untreated nondiabetic and STZ-diabetic rats in a dose-dependent manner. Pretreatment with L-NAME or removal of endothelium blocked metformin-induced relaxation at lower concentration (up to 30 microM) but not at higher concentration (above 30 microM). Metformin-induced relaxation was blocked in the presence of 1 mM of 4-aminopyridine, or 1 mM of tetraethylammonium but not in the presence of 100 microM of barium ion or 10 microM of glybenclamide. The restored endothelial function along with direct effect of metformin on aortic rings and reduced oxidative stress contributes to reduced blood pressure in STZ-diabetic rats. From the present study, it can be concluded that metformin administration to STZ-diabetic rats lowers blood pressure, and restores endothelial function. PMID:16318863

Majithiya, Jayesh B; Balaraman, R



Coordination strategies for limb forces during weight-bearing locomotion in normal rats, and in rats spinalized as neonates  

PubMed Central

Some rats spinally transected as neonates (ST rats) achieve weight-supporting independent locomotion. The mechanisms of coordinated hindlimb weight support in such rats are not well understood. To examine these in such ST rats and normal rats, rats with better than 60% of weight supported steps on a treadmill as adults were trained to cross an instrumented runway. Ground reaction forces, coordination of hindlimb and forelimb forces and the motions of the center of pressure were assessed. Normal rats crossed the runway with a diagonal trot. On average hindlimbs bore about 80% of the vertical load carried by forelimbs, although this varied. Forelimbs and hindlimb acted synergistically to generate decelerative and propulsive rostrocaudal forces, which averaged 15% of body weight with maximums of 50% . Lateral forces were very small (<8% of body weight). Center of pressure progressed in jumps along a straight line with mean lateral deviations <1 cm. ST rats hindlimbs bore about 60% of the vertical load of forelimbs, significantly less compared to intact (p<0.05). ST rats showed similar mean rostrocaudal forces, but with significantly larger maximum fluctuations of up to 80% of body weight (p<0.05). Joint force-plate recordings showed forelimbs and hindlimb rostrocaudal forces in ST rats were opposing and significantly different from intact rats (p<0.05). Lateral forces were ~20% of body weight and significantly larger than in normal rats (p<0.05). Center of pressure zig-zagged, with mean lateral deviations of ~ 2cm and a significantly larger range (p<0.05). The haunches were also observed to roll more than normal rats. The locomotor strategy of injured rats using limbs in opposition was presumably less efficient but their complex gait was statically stable. Because forelimbs and hindlimbs acted in opposition, the trunk was held compressed. Force coordination was likely managed largely by the voluntary control in forelimbs and trunk. PMID:18612631

Giszter, Simon F; Davies, Michelle R; Graziani, Virginia



The Novel Antiobesic HMR1426 Reduces Food Intake without Affecting Energy Expenditure in Rats  

Microsoft Academic Search

Objective: To determine the effect of acute and chronic administration of a new food intake-reducing compound (HMR1426) with novel mode of action (retardation of gastric emptying) on body weight development, food intake, and energy metabolism in rats.Research Methods and Procedures: Adult male Shoe-Wistar rats were implanted with transponders allowing registration of body temperature (Tb) and locomotor activity. HMR1426 (10 or

Sylvia Ortmann; Juliane Kampe; Matthias Gossel; Martin Bickel; Karl Geisen; Gerhard Jähne; Hans Jochen Lang; Susanne Klaus



Polyethylene glycol reduces inflammation and aberrant crypt foci in carcinogen-initiated rats.  


Polyethylene glycol 8000 inhibits the formation of tumors and of aberrant crypt foci (ACF) in carcinogen-initiated rats. We asked: is the inhibition associated with a reduction of colonic inflammation and an increase in colonic cell permeability? Twenty-eight, male F 344 rats were divided into two groups, 10 control animals and 18 animals initiated with azoxymethane. Nine of the rats in the carcinogen-initiated group were given a diet with 5% PEG 8000 in an AIN-93 based, high fat diet. The other nine, and the control group received the diet without the addition of PEG. Nine weeks later, the rats receiving the diet containing PEG had a 43% reduction in ACF (P<0.001) compared with the carcinogen-initiated rats on the control diet, a result confirming earlier observations that PEG inhibits colon carcinogenesis. The animals receiving the diet containing PEG also had a 10-fold reduction in fecal granulocyte marker protein (GMP) (P<0.001) compared with both the carcinogen-treated and the control animals. PEG reduced inflammation below the levels of carcinogen-treated and of untreated animals. Fecal water from the rats receiving PEG did not reduce transepithelial resistance of, or manitol flux through, human Caco-cells grown as monolayers in vitro. PEG may reduce colon carcinogenesis through a mechanism involving colonic inflammation. PMID:15896454

Karlsson, Pernilla C; Hughes, Roisin; Rafter, Joseph J; Bruce, W Robert



Sildenafil and glyceryl trinitrate reduce tactile allodynia in streptozotocin-injected rats.  


The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide donor glyceryl trinitrate as well as the changes in phosphodiesterase 5A2 mRNA expression in dorsal root ganglion and spinal cord of allodynic diabetic rats was assessed. Diabetes was induced by streptozotocin (50mg/kg, i.p.) in male Wistar rats. Streptozotocin injection produced hyperlglycemia, polydipsia, polyphagia and polyuria as well as long-term tactile allodynia (12 weeks) and a reduction of phosphodiesterase 5A2 mRNA expression in spinal cord of diabetic rats. Systemic administration of sildenafil (1-5.6 mg/kg, i.p.) reduced tactile allodynia in a dose-dependent manner in diabetic rats. Likewise, glyceryl trinitrate patches (0.2mg/h) also reduced tactile allodynia in diabetic rats. Moreover, both drugs reversed streptozotocin-induced phosphodiesterase 5A2 mRNA expression reduction. Our results indicate that glyceryl trinitrate and sildenafil reduce tactile allodynia in diabetic rats suggesting that nitric oxide and cyclic GMP supply is an important step in their mechanism of action of these drugs in diabetic animals. Data suggest that nitric oxide donors (as glyceryl trinitrate) and drugs which increase cyclic GMP levels (as sildenafil) could have a role in the pharmacotherapy of tactile allodynia in diabetic patients. PMID:20079349

Araiza-Saldaña, Claudia I; Rocha-González, Héctor I; Ambriz-Tututi, Mónica; Castañeda-Corral, Gabriela; Caram-Salas, Nadia L; Hong, Enrique; Granados-Soto, Vinicio



Amphetamine promotes task-dependent recovery following focal cortical ischaemic lesions in the rat  

Microsoft Academic Search

This study investigated the effect of amphetamine (AMP) on skilled forelimb use following focal cortical ischaemic lesions in the rat. Unilateral lesions were produced by a novel method of intracortical microinjection of endothelin-1 (ET-1), intended to principally target the forelimb representation zone in primary motor–primary somatosensory cortex. Lesions were placed in the hemisphere contralateral to the preferred limb and produced

Gary Gilmour; Susan D. Iversen; Michael F. O’Neill; Michael J. O’Neill; Mark A. Ward; David M. Bannerman



Minocycline reduces reactive gliosis in the rat model of hydrocephalus  

PubMed Central

Background Reactive gliosis had been implicated in injury and recovery patterns associated with hydrocephalus. Our aim is to determine the efficacy of minocycline, an antibiotic known for its anti-inflammatory properties, to reduce reactive gliosis and inhibit the development of hydrocephalus. Results The ventricular dilatation were evaluated by MRI at 1-week post drugs treated, while GFAP and Iba-1were detected by RT-PCR, Immunohistochemistry and Western blot. The expression of GFAP and Iba-1 was significantly higher in hydrocephalic group compared with saline control group (p < 0.05). Minocycline treatment of hydrocephalic animals reduced the expression of GFAP and Iba-1 significantly (p < 0.05). Likewise, the severity of ventricular dilatation is lower in minocycline treated hydrocephalic animals compared with the no minocycline group (p < 0.05). Conclusion Minocycline treatment is effective in reducing the gliosis and delaying the development of hydrocephalus with prospective to be the auxiliary therapeutic method of hydrocephalus. PMID:23217034



Insulin and losartan reduce proteinuria and renal hypertrophy in the pregnant diabetic rat.  


This study was designed to investigate the effect of hyperglycemia and angiotensin II (AngII) on renal hypertrophy and proteinuria in the pregnant diabetic rat. Secondary objectives were to evaluate changes in components of the renin-angiotensin axis and the effects of administration of losartan on pregnancy outcome. Fifty-three pregnant rats were allocated to 6 groups (1) nondiabetic controls (n = 12), (2) nondiabetic controls administered losartan (70-80 mg/kg/day; n = 10), (3) rats in which intravenous streptozotocin (STZ) was used to induce diabetes (55 mg/kg on day 10 of pregnancy; n = 10), (4) diabetic rats treated with losartan (n = 7), (5) diabetic rats treated with insulin (4 U/day; n = 7), and (6) diabetic rats treated with insulin and losartan (n = 7). Urinary protein excretion measured 4 days after STZ was 4 times greater in the rats with STZ-induced diabetes and significantly less in diabetic rats given losartan, insulin, or both. Postpartum kidney weight was greater in the rats with STZ-induced diabetes (2.04 +/- 0.21 g) than in the controls (1.37 +/- 0.14 g; P <.05) and reduced in the diabetic rats given losartan, insulin, or both (1.57 +/- 0.22, 1.73 +/- 0.13, and 1.51 +/- 0.14 g, respectively; P <.05). Plasma levels of angiotensin II in rats given losartan were more than 3.5 times greater than those in controls (749 +/- 436, 596 +/- 323, 567 +/- 349, and 159 +/- 28 pg/mL; P <.001). Postpartum activity of angiotensin-converting enzyme was increased in the untreated diabetic rats compared with that in control rats (162 +/- 12 vs 117 +/- 16 nmol/mL/min; P <.05). This increase was abolished by treatment with losartan or insulin. The number of newborns and mean weight of each newborn was similar in all groups. In summary, administration of losartan or insulin prevented, in part, kidney hypertrophy and protein excretion in the diabetic pregnant rat. Losartan did not affect the number or weight of newborns. Because angiotensin II receptor-blockers are contraindicated in pregnancy, good control of diabetes through the use of insulin should be advantageous. PMID:14532904

Natif, Noam; Sclarovsky-Benjaminov, Fabiana; Van Dijk, David Jonathan; Sulkes, Jacklin; Gafter, Uzi; Boner, Geoffrey; Erman, Arie



A Three-Dimensional Analysis of Morphological Evolution and Locomotor Performance of the Carnivoran Forelimb  

PubMed Central

In this study, three-dimensional landmark-based methods of geometric morphometrics are used for estimating the influence of phylogeny, allometry and locomotor performance on forelimb shape in living and extinct carnivorans (Mammalia, Carnivora). The main objective is to investigate morphological convergences towards similar locomotor strategies in the shape of the major forelimb bones. Results indicate that both size and phylogeny have strong effects on the anatomy of all forelimb bones. In contrast, bone shape does not correlate in the living taxa with maximum running speed or daily movement distance, two proxies closely related to locomotor performance. A phylomorphospace approach showed that shape variation in forelimb bones mainly relates to changes in bone robustness. This indicates the presence of biomechanical constraints resulting from opposite demands for energetic efficiency in locomotion –which would require a slender forelimb– and resistance to stress –which would be satisfied by a robust forelimb–. Thus, we interpret that the need of maintaining a trade-off between both functional demands would limit shape variability in forelimb bones. Given that different situations can lead to one or another morphological solution, depending on the specific ecology of taxa, the evolution of forelimb morphology represents a remarkable “one-to-many mapping” case between anatomy and ecology. PMID:24454891

Martin-Serra, Alberto; Figueirido, Borja; Palmqvist, Paul



Red maca (Lepidium meyenii) reduced prostate size in rats  

Microsoft Academic Search

BACKGROUND: Epidemiological studies have found that consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer. This effect seems to be due to aromatic glucosinolate content. Glucosinolates are known for have both antiproliferative and proapoptotic actions. Maca is a cruciferous cultivated in the highlands of Peru. The absolute content of glucosinolates in Maca hypocotyls is relatively higher

Gustavo F Gonzales; Sara Miranda; Jessica Nieto; Gilma Fernández; Sandra Yucra; Julio Rubio; Pedro Yi; Manuel Gasco



K(v) 7 Positive Modulators Reduce Detrusor Overactivity and Increase Bladder Capacity in Rats.  


? The effects of the K(v) 7 channel modulators retigabine (opener) and XE991 (blocker) on rat bladder function were investigated ex vivo and in vivo to assess the potential of K(v) 7 openers for the treatment of overactive bladder. In organ bath studies, capsaicin-stimulated rat urinary bladder rings were exposed to retigabine and XE991 and the effect on tension and amplitude was evaluated. In anaesthetized rats, retigabine (0.01-1?mg/kg, i.v.) effects on bladder function, in which overactivity was induced by continuous infusion of 0.5% acetic acid, were assessed. The effect of retigabine (10?mg/kg, p.o.) on cystometric parameters was also measured in conscious rats with capsaicin-induced irritated bladders. Localization of K(v) 7 subunits within bladder tissue was analysed by RT-qPCR and western blotting. In organ bath studies, retigabine robustly reduced capsaicin-induced contractility of bladder rings and this effect was blocked by XE991 confirming the specificity of action via K(v) 7 channels. In anaesthetized rats with acetic acid-irritated bladders, retigabine markedly increased bladder capacity with no concomitant reduction in blood pressure. Retigabine also reduced bladder pressure and delayed voiding in conscious rats with capsaicin-irritated bladders. K(v) 7.1, K(v) 7.4 and K(v) 7.5 subunit mRNA transcripts were detected in rat bladder. Western blot analysis confirmed that K(v) 7.4 subunit protein was expressed in rat bladder. These results suggest that retigabine and other K(v) 7 channel positive modulators may have beneficial effects on bladder overactivity partly via activation of K(v) 7 channels expressed in bladder tissue. PMID:21895977

Svalø, Julie; Hansen, Henrik H; Rønn, Lars Christian B; Sheykhzade, Majid; Munro, Gordon; Rode, Frederik



Glucose transport is reduced in the blood-brain barrier of aged rats.  


To determine the biochemical basis of decreased brain uptake of glucose with age, the brain influx of 3-O-methylglucose (3-O-MG) was measured in male Fischer 344 rats at various ages using the arterial injection-tissue sampling technique of Oldendorf. The Vmax of 3-O-MG transport in the 24-month-old rats (0.22 +/- 0.14 mumol/min/g) was significantly lower than that in 3-month-old rats (0.88 +/- 0.18 mumol/min/g) (P less than 0.05). The Km of transport in aged rats (10.1 +/- 4.8 mM) was not different from that in young rats (8.1 +/- 2.5 mM). The cytochalasin B binding sites in cerebral microvessels isolated from aged rats (13.9 +/- 0.9 pmol/mg) compared to the binding sites in cerebral microvessels of young rats (21.9 +/- 1.4 pmol/mg) were significantly reduced (P less than 0.001). However, the immunoreactive mass of glucose transporter of cerebral microvessels was not altered with age. The enrichment of capillary preparations with gamma-glutamyl transpeptidase activity, a marker of endothelial cells, was not altered in aged rats, suggesting that the reduced blood-brain barrier transport of glucose is due to specific reduction in glucose binding sites of the transporter rather than secondary to a non-specific age-related effect of endothelial cell drop-out. PMID:1913147

Mooradian, A D; Morin, A M; Cipp, L J; Haspel, H C



Swim therapy reduces mechanical allodynia and thermal hyperalgesia induced by chronic constriction nerve injury in rats  

PubMed Central

Objective Neuropathic pain is common and often difficult to treat because it generally does not respond well to the currently available pain medications or nerve blocks. Recent studies in both humans and animals have suggested that exercise may induce a transient analgesia and reduce acute pain in normal healthy individuals. We examined whether swim therapy could alleviate neuropathic pain in rats. Design Rats were trained to swim over a two week period in warm water. After the rats were trained, neuropathic pain was induced by constricting the right sciatic nerve and regular swimming was resumed. The sensitivity of each hind paw was monitored using the Hargreaves test and von Frey test to evaluate the withdrawal response thresholds to heat and touch. Results The paw ipsilateral to the nerve ligation expressed pain-like behaviors including thermal hyperalgesia and mechanical allodynia. Regular swim therapy sessions significantly reduced the mechanical allodynia and thermal hyperalgesia. Swim therapy had little effect on the withdrawal thresholds for the contralateral paw. In addition, swim therapy alone did not alter the thermal or mechanical thresholds of normal rats. Conclusions The results suggest that regular exercise, including swim therapy, may be an effective treatment for neuropathic pain caused by nerve injuries. This study, showing that swim therapy reduces neuropathic pain behavior in rats, provides a scientific rationale for clinicians to test the efficacy of exercise in the management of neuropathic pain. It may prove to be a safe and cost-effective therapy in a variety of neuropathic pain states. PMID:23438327

Shen, Jun; Fox, Lyle E.; Cheng, Jianguo



Hyperbaric oxygen therapy fails to reduce hydrocephalus formation following subarachnoid hemorrhage in rats  

PubMed Central

Background & purpose Approximately 40% of hemorrhagic stroke survivors develop hydrocephalus. Hyperbaric oxygen (HBO) has been shown to be anti-inflammation following experimental stroke; however, its effect upon post-hemorrhagic hydrocephalus formation is not known. The objective of this study is to investigate whether HBO therapy can effectively reduce hydrocephalus formation and improve neurobehavioral functions in a rat model of subarachnoid hemorrhage (SAH). Method Thirty-eight male Sprague–Dawley rats (300-320 g) rats survived for 21 days from SAH by endovascular perforation or sham surgery were used. At 24 hours after SAH, HBO (3 atmospheres absolute) or normobaric oxygen (NBO) administrated for 1 hour once daily for a total of 7 days. Wire hanging and rotarod testing were conducted at 14 days after SAH, and cognitive functions were evaluated via the Morris water maze, between day 17 to day 21 after surgery. At day 21, rats were sacrificed and cerebroventricular volumes were measured histologically. Results Hydrocephalus exacerbated neurological deficits after SAH, and HBO multiple treatment tendentially improved the neurobehavioral functions. Spatial learning and memory deficits were noticed after SAH, and rats with hydrocephalus showed worse learning and memory abilities and HBO treatment showed a minor improvement. In the SAH group (room air) 4 rats showed an increased ventricular volume at day 21 after SAH-induction (n?=?10). HBO or NBO therapy did not alter the occurrence of hydrocephalus after SAH, as 4 rats in each of these groups showed an increased ventricular volume (n?=?10 per group). Conclusion Multiple HBO therapy does not ameliorate hydrocephalus formation in a rat model of SAH; however, HBO tendentially improved the neurological functions and spatial learning and memory abilities in rats with hydrocephalus. PMID:25132956



Amniotic membrane application reduces liver fibrosis in a bile duct ligation rat model.  


Biliary fibrosis and resultant cirrhosis are among the most common outcomes of chronic liver diseases. Currently, liver transplantation remains the only effective treatment. In seeking alternative therapeutic approaches, we focused on the potential use of the human amniotic membrane (AM). Indeed, AM has gained increasing importance for its antiscarring, anti-inflammatory, and wound-healing properties, as well as for the multipotent differentiation ability and immunomodulatory features of AM-derived cells. Intriguingly, we have recently demonstrated that placenta-derived cells reduce lung fibrosis in bleomycin-treated mice, and that AM patches reduce postischemic cardiac injury in rats. Hence, we have now investigated the effects of human AM on biliary fibrosis induced in rats through the bile duct ligation (BDL) procedure. A fragment of human AM was applied onto the liver surface after BDL and the effects on fibrosis establishment and progression were evaluated at different time points in comparison with fibrosis progression in control BDL rats. The degree of liver fibrosis was first assessed by the semiquantitative Knodell scoring system and, thereafter, by digital image morphometric analysis to quantify the area occupied by ductular reaction, activated myofibroblasts, and collagen deposition. We demonstrated a significant reduction in the severity of BDL-induced fibrosis in AM-treated rats. Indeed, while fibrosis progressed rapidly in control BDL rats, leading to cirrhosis within 6 weeks, AM-treated rats showed confined fibrosis at the portal/periportal area with no signs of cirrhosis, and a reduction in collagen deposition to about 50% of levels observed in control BDL rats. In addition, the AM was able to significantly slow the gradual progression of the ductular reaction and reduce, at all time points, the area occupied by activated myofibroblasts. These findings suggest that human AM, when applied as a patch onto the liver surface, might inhibit fibrosis progression in BDL-injured livers, and could protect against hepatic damage associated with fibrotic degeneration. PMID:20719087

Sant'Anna, Luciana B; Cargnoni, Anna; Ressel, Lorenzo; Vanosi, Graziella; Parolini, Ornella



Curcuma Oil Reduces Endothelial Cell-mediated Inflammation in Postmyocardial Ischemia/Reperfusion in Rats.  


: Endothelial cells initiated inflammation persisting in postmyocardial infarction needs to be controlled and moderated for avoiding fatal complications. Curcuma oil (C.oil, Herbal Medicament), a standardized hexane soluble fraction of Curcuma longa has possessed neuroprotective effect. However, its effect on myocardial ischemia/reperfusion (MI/RP) and endothelial cells remains incompletely defined. Here, using in vivo rat MI/RP injury model and in vitro cellular approaches using EA.hy926 endothelial cells, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and myograph, we provide evidence that with effective regimen and preconditioning of rats with C.oil (250 mg/kg, PO), before and after MI/RP surgery protects rats from MI/RP-induced injury. C.oil treatment reduces left ventricular ischemic area and endothelial cell-induced inflammation, specifically in the ischemic region (*P < 0.0001) and improved endothelial function by reducing the expression of proinflammatory genes and adhesion factors on endothelial cells both in vitro and in vivo. Furthermore, mechanistic studies have revealed that C.oil reduced the expression of adhesion factors like E-selectin (#P = 0.0016) and ICAM-1 ($P = 0.0069) in initiating endothelial cells-induced inflammation. In line to the real-time polymerase chain reaction expression data, C.oil reduced the adhesion of inflammatory cells to endothelial cells as assessed by the interaction of THP-1 monocytes with the endothelial cells using flow-based adhesion and under inflammatory conditions. These studies provide evidence that salutary effect of C.oil on MI/RP could be achieved with pretreatment and posttreatment of rats, C.oil reduced MI/RP-induced injury by reducing the endothelial cell-mediated inflammation, specifically in the ischemic zone of MI/RP rat heart. PMID:24853488

Manhas, Amit; Khanna, Vivek; Prakash, Prem; Goyal, Dipika; Malasoni, Richa; Naqvi, Arshi; Dwivedi, Anil K; Dikshit, Madhu; Jagavelu, Kumaravelu



Humoral immunity and reduced periodontal bone loss in Eikenella corrodens-monoassociated rats.  

PubMed Central

Germfree Sprague-Dawley rats monoassociated with Eikenella corrodens exhibited alveolar bone loss. This progressive bone loss occurred over a period of weeks, during which time the hosts developed an immune response toward the infective microorganism. By means of repeated bacterial vaccination resulting in elevated serum antibody titers, reduced bone loss was observed. PMID:7026446

Behling, U H; Sallay, C; Sanavi, F; Pham, P H; Nowotny, A



Decreased brain zinc availability reduces hippocampal neurogenesis in mice and rats  

Microsoft Academic Search

In the adult brain, neurogenesis occurs in the subgranular zone of the dentate gyrus (DG), where high levels of vesicular zinc are localized in the presynaptic terminals. To determine whether zinc has a role in modulating hippocampal neurogenesis under normal or pathologic conditions, we manipulated the level of vesicular zinc experimentally. To reduce hippocampal vesicular zinc, rats were either fed

Sang Won Suh; Seok Joon Won; Aaron M Hamby; Byung Hoon Yoo; Yang Fan; Christian T Sheline; Haruna Tamano; Atsushi Takeda; Jialing Liu



Glomerular capillary network of cortical nephrons is reduced in male but not in female aging rats.  


The gender differences in the age-related changes of glomerular structures were determined in 10- and 30-month-old rats. In adult animals, glomerular volume, urinary space, capillary lumen area and mesangial domains of deep and superficial nephrons were larger in males than in females. Glomerular hypertrophy was evidenced with age in both males and females. This hypertrophy was greater in female (+70%) than in male (+20%) rats. Age-related hypertrophy concerned equally the urinary space and the glomerular tuft. The mesangial domain, however, increased more markedly than glomerular volume (+400%). As a result, the ratio of mesangial domain to glomerular section area was more than doubled between 10 and 30 months. In females, the age-related renal hypertrophy was associated with a constant total capillary lumen area in cortical nephrons. In contrast, the total capillary lumen area of male rats was reduced by 20% in superficial glomeruli and by 36% in deep glomeruli between 10 and 30 months. These morphological changes are in good agreement with the maintained glomerular filtration rate reported in old female rats and the decrease in renal blood flow and filtration rate reported in male rats. They suggest that the aging process does not similarly affect the vascular system of the kidney of male and female rats, although their mean blood pressure was comparable. PMID:8910256

Francois, V; Heudes, D; Bariety, J; Bruneval, P; Corman, B



Reduced L-Carnitine Transport in Aortic Endothelial Cells from Spontaneously Hypertensive Rats  

PubMed Central

Impaired L-carnitine uptake correlates with higher blood pressure in adult men, and L-carnitine restores endothelial function in aortic rings from spontaneously hypertensive rat (SHR). Thus, endothelial dysfunction in hypertension could result from lower L-carnitine transport in this cell type. L-Carnitine transport is mainly mediated by novel organic cation transporters 1 (Octn1, Na+-independent) and 2 (Octn2, Na+-dependent); however, their kinetic properties and potential consequences in hypertension are unknown. We hypothesize that L-carnitine transport kinetic properties will be altered in aortic endothelium from spontaneously hypertensive rats (SHR). L-Carnitine transport was measured at different extracellular pH (pHo 5.5–8.5) in the absence or presence of sodium in rat aortic endothelial cells (RAECs) from non-hypertensive Wistar-Kyoto (WKY) rats and SHR. Octn1 and Octn2 mRNA relative expression was also determined. Dilation of endothelium-intact or denuded aortic rings in response to calcitonine gene related peptide (CGRP, 0.1–100 nmol/L) was measured (myography) in the absence or presence of L-carnitine. Total L-carnitine transport was lower in cells from SHR compared with WKY rats, an effect due to reduced Na+-dependent (Na+dep) compared with Na+-independent (Na+indep) transport components. Saturable L-carnitine transport kinetics show maximal velocity (Vmax), without changes in apparent Km for Na+indep transport in SHR compared with WKY rats. Total and Na+dep component of transport were increased, but Na+indep transport was reduced by extracellular alkalization in WKY rats. However, alkalization reduced total and Na+indep transport in cells from SHR. Octn2 mRNA was higher than Octn-1 mRNA expression in cells from both conditions. Dilation of artery rings in response to CGRP was reduced in vessels from SHR compared with WKY rats. CGRP effect was endothelium-dependent and restored by L-carnitine. All together these results suggest that reduced L-carnitine transport (likely via Na+-dependent Octn2) could limit this compound's potential beneficial effects in RAECs from SHR. PMID:24587332

Salsoso, Rocio; Guzman-Gutierrez, Enrique; Arroyo, Pablo; Salomon, Carlos; Zambrano, Sonia; Ruiz-Armenta, Maria Victoria; Blanca, Antonio Jesus; Pardo, Fabian; Leiva, Andrea; Mate, Alfonso; Sobrevia, Luis; Vazquez, Carmen Maria



The ?2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats.  


Evidence suggests that noradrenergic signaling may play a role in mediating alcohol-drinking behavior in both rodents and humans. We have investigated this possibility by administering clonidine to alcohol-drinking rats selectively bred for alcohol preference (P line). Clonidine is an ?2-adrenergic receptor agonist which, at low doses, inhibits noradrenergic signaling by decreasing norepinephrine release from presynaptic noradrenergic neurons. Adult male P rats were given 24 h access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 h daily. Rats received intra-peritoneal (IP) injections with clonidine (0, 10, 20, 40, or 80 ?g/kg body weight [BW], 10-11 rats/treatment group) once/day at 30 min prior to onset of the daily 2 h alcohol access period for 2 consecutive days. Clonidine, in doses of 40 or 80 ?g/kg BW, significantly reduced alcohol intake on both days of treatment (p < 0.001). Two weeks later, rats were treated with clonidine for 5 consecutive days and clonidine, in doses of 40 or 80 ?g/kg BW, reduced alcohol intake on all 5 treatment days (p < 0.001). Clonidine did not alter water consumption during the daily 2 h free-choice between alcohol and water. In a separate group of male P rats, clonidine (40 ?g/kg BW) suppressed intake of a saccharin solution (0.04 g/L). These results are consistent with and complement our previous findings that the ?1-adrenergic receptor antagonist, prazosin, decreases voluntary alcohol drinking in alcohol-preferring rats, but suggests that effects of clonidine may not be specific for alcohol. The results suggest that although activation of the noradrenergic system plays an important role in mediating voluntary alcohol drinking, care is needed in selecting which drugs to use to suppress central noradrenergic signaling in order to maximize the selectivity of the drugs for treating alcohol-use disorders. PMID:25085719

Rasmussen, Dennis D; Alexander, Laura; Malone, Julia; Federoff, David; Froehlich, Janice C



Reduced hindbrain and enteric neuronal response to intestinal oleate in rats maintained on high-fat diet  

Microsoft Academic Search

Rats maintained on a high-fat diet (HF) reduce their food intake less in response to intestinal infusion of oleic acid than rats maintained on a low-fat diet (LF). Inhibition of gastric emptying by intestinal infusion of oleate also is attenuated in rats fed a high-fat diet. It is well documented that intestinal oleate reduces food intake and inhibits gastric emptying

Mihai Covasa; Jennifer Grahn; Robert C. Ritter



Serotonin transporter knockout rats show improved strategy set-shifting and reduced latent inhibition.  


Behavioral flexibility is a cognitive process depending on prefrontal areas allowing adaptive responses to environmental changes. Serotonin transporter knockout (5-HTT(-/-)) rodents show improved reversal learning in addition to orbitofrontal cortex changes. Another form of behavioral flexibility, extradimensional strategy set-shifting (EDSS), heavily depends on the medial prefrontal cortex. This region shows functional changes in 5-HTT(-/-) rodents as well. Here we subjected 5-HTT(-/-) rats and their wild-type counterparts to an EDSS paradigm and a supplementary latent inhibition task. Results indicate that 5-HTT(-/-) rats also show improved EDSS, and indicate that reduced latent inhibition may contribute as an underlying mechanism. PMID:22505721

Nonkes, Lourens J P; van de Vondervoort, Ilse I G M; de Leeuw, Mark J C; Wijlaars, Linda P; Maes, Joseph H R; Homberg, Judith R



d Lysine reduces the non-enzymatic glycation of proteins in experimental diabetes mellitus in rats  

Microsoft Academic Search

Summary  \\u000ad-Lysine, the non-physiological isomer of l-lysine, can competitively reduce protein non-enzymatic glycation in vitro. To study the effect of d-lysine in vivo, 6–8-week old Sprague-Dawley rats with streptozotocin-induced diabetes mellitus were treated from diagnosis for 45 days with two daily subcutaneous injections of d-lysine (0.5 g·ml–1·day–1). Another group of diabetic rats was only injected with equal volumes of physiological

M. Sensi; M. G. De Rossi; F. S. Celi; A. Cristina; C. Rosati; D. Perrett; D. Andreani; U. Di Mario



Forelimb skeletal morphology and flight mode evolution in pelecaniform birds.  


The total length and mid-shaft diameters of wing elements of 50 species of pelecaniform birds were examined to investigate how forelimb skeletal morphology varies with body size and flight mode within this group. Pelecaniforms were assigned to flight mode categories based on primary habitual behaviors (soar, flap-glide, continuous flap). Allometric and discriminant function analyses were conducted on wing element variables in both historical (using independent contrasts) and ahistorical contexts. Results of this study indicate that when phylogenetic relationships are taken into account, only the length of the ulna scales with positive allometry, whereas all other variables exhibit isometry. These results differ from the ahistorical allometric analysis. Discriminant function analysis (DFA) significantly separated the flight mode groups (Wilk's lambda=0.002, p<0.00001), with only six individuals from two species (out of n=284) misclassified. Results of historical canonical variates analysis supported the ahistorical DFA and identified two carpometacarpal (CMC) variables as important for separating the flight mode groups: dorsoventral CMC diameter and total CMC length. The carpometacarpus is that portion of the forelimb skeleton that serves as the attachment point for the primary flight feathers, and thus, that portion of the airfoil surface that mediates detailed flight control. Its morphology, more than any other element, reflects differences in flight mode in pelecaniforms. Results of this study indicate that, in pelecaniforms, wing bones generally exhibit isometry (with the exception of the ulna) and do possess specific morphologies reflective of the demands associated with different types of aerial locomotor specialization. PMID:20071157

Simons, Erin L R



Amelioration of azoxymethane induced-carcinogenesis by reducing oxidative stress in rat colon by natural extracts  

PubMed Central

Background Azoxymethane (AOM) is a potent carcinogenic agent commonly used to induce colon cancer in rats; the cytotoxicity of AOM is considered to mediate oxidative stress. This study investigated the chemopreventive effect of three natural extracts [pomegranate peel extract (PomPE), papaya peel extract (PapPE) and seaweed extract (SE)] against AOM-induced oxidative stress and carcinogenesis in rat colon. Methods Eighty Sprague–Dawley rats (aged 4 weeks) were randomly divided into 8 groups (10 rats/group). Control group was fed a basal diet; AOM-treated group was fed a basal diet and received AOM intraperitonial injections for two weeks at a dose of 15 mg/kg bodyweight, whereas the other six groups were received oral supplementation of PomPE, PapPE or SE, in the presence or absence of AOM injection. All animals were continuously fed ad-libitum until aged 16 weeks, then all rats were sacrificed and the colon tissues were examined microscopically for pathological changes and aberrant crypt foci (ACF) development, genotoxicity (induced micronuclei (MN) cells enumeration), and glutathione and lipid peroxidation. Results Our results showed that AOM-induced ACF development and pathological changes in the colonic mucosal tissues, increased bone marrow MN cells and oxidative stress (glutathione depletion, lipid peroxidation) in rat colonic cells. The concomitant treatment of AOM with PomPE, PapPE or SE significantly ameliorated the cytotoxic effects of AOM. Conclusions The results of this study provide in-vivo evidence that PomPE, PapPE and SE reduced the AOM-induced colon cancer in rats, through their potent anti-oxidant activities. PMID:24533833



Dexamethasone reduces brain cell apoptosis and inhibits inflammatory response in rats with intracerebral hemorrhage.  


Spontaneous intracerebral hemorrhage (ICH) is associated with high rates of mortality and morbidity. Thus, the identification of novel therapeutic agents for preventing strokes and attenuating poststroke brain damage is crucial. Dexamethasone (DEX) is used clinically to reduce edema formation in patients with spinal cord injury and brain tumors. In this study, we sought to elucidate the effects of DEX treatment on apoptosis and inflammation following ICH in rats. A high dose of DEX (15 mg/kg) was administered immediately following ICH induction and again 3 days later. The inflammatory and apoptotic responses in the rat brains were evaluated by using hematoxylin-eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, Nissl, and neurofilament-H staining. Levels of phosphorylated neurofilaments and apoptosis-related proteins such as B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), caspase-3, and P53 were analyzed by Western blotting. This study shows that rats without ICH that received DEX treatment had a fourfold higher expression of Bcl-2 than sham-operated rats. ICH causes an increase in Bax, cleaved caspase-3, and P53 proteins from 4 hr to 7 days following ICH induction. In comparison with the ICH rats, the ICH/DEX rats showed significantly decreased apoptotic cell death and increased neuron survival and maintained neurofilament integrity in the perihematomal region. DEX increased the Bcl-2/Bax ratio and lowered the expression of cleaved caspase-3 at 12 hr and 5 days. The ICH rats were accompanied by activation of the inflammatory response, and DEX treatment modulated the expression of a variety of cell types and then decreased ICH-induced apoptosis. © 2014 Wiley Periodicals, Inc. PMID:25042403

Lee, I-Neng; Cheng, Wan-Chun; Chung, Chiu-Yen; Lee, Ming-Hsueh; Lin, Martin Hsiu-Chu; Kuo, Chia-Hui; Weng, Hsu-Huei; Yang, Jen-Tsung



Green Tea Polyphenols Reduce Body Weight in Rats by Modulating Obesity-Related Genes  

PubMed Central

Beneficial effects of green tea polyphenols (GTP) against obesity have been reported, however, the mechanism of this protection is not clear. Therefore, the objective of this study was to identify GTP-targeted genes in obesity using the high-fat-diet-induced obese rat model. A total of three groups (n?=?12/group) of Sprague Dawley (SD) female rats were tested, including the control group (rats fed with low-fat diet), the HF group (rats fed with high-fat diet), and the HF+GTP group (rats fed with high-fat diet and GTP in drinking water). The HF group increased body weight as compared to the control group. Supplementation of GTP in the drinking water in the HF+GTP group reduced body weight as compared to the HF group. RNA from liver samples was extracted for gene expression analysis. A total of eighty-four genes related to obesity were analyzed using PCR array. Compared to the rats in the control group, the rats in the HF group had the expression levels of 12 genes with significant changes, including 3 orexigenic genes (Agrp, Ghrl, and Nr3c1); 7 anorectic genes (Apoa4, Cntf, Ghr, IL-1?, Ins1, Lepr, and Sort); and 2 genes that relate to energy expenditure (Adcyap1r1 and Adrb1). Intriguingly, the HF+GTP group restored the expression levels of these genes in the high-fat-induced obese rats. The protein expression levels of IL-1? and IL-6 in the serum samples from the control, HF, and HF+GTP groups confirmed the results of gene expression. Furthermore, the protein expression levels of superoxide dismutase-1 (SOD1) and catechol-O-methyltransferase (COMT) also showed GTP-regulated protective changes in this obese rat model. Collectively, this study revealed the beneficial effects of GTP on body weight via regulating obesity-related genes, anti-inflammation, anti-oxidant capacity, and estrogen-related actions in high-fat-induced obese rats. PMID:22715380

Lu, Chuanwen; Zhu, Wenbin; Shen, Chwan-Li; Gao, Weimin



Environmental enrichment reduces the impact of novelty and motivational properties of ethanol in spontaneously hypertensive rats.  


The present study investigated the consequences of environmental enrichment on the impact of novelty and motivational properties of ethanol in spontaneously hypertensive rats (SHR), a validated model of attention deficit hyperactivity disorder (ADHD). This rat strain displays increased sensitivity to distinct classes of abused drugs, which makes it an interesting model for the study of the association between ADHD and drug abuse. Female SHR reared from weaning to adulthood in standard (SE) or enriched (EE) environment were tested on novelty-induced locomotion, saccharin consumption, ethanol consumption (forced and free-choice schedules) and ethanol-induced conditioned place preference (CPP). SHR reared in an EE showed reduced novelty-induced locomotion, consumed less saccharin and ethanol in a forced schedule and showed less ethanol preference in a free-choice schedule compared to SE rats. Moreover, EE rats did not develop CPP, whereas SE rats developed preference for ethanol (1.2g/kg). These results show that exposure to stimuli mimicking positive life experiences (environmental enrichment) induces persistent changes in the reward/motivational system of female SHR, suggesting an important role of the familiar environment during early stages of the neurodevelopment on the co-morbidity of ADHD and drug abuse. PMID:19962407

de Carvalho, Cristiane Ribeiro; Pandolfo, Pablo; Pamplona, Fabrício Alano; Takahashi, Reinaldo Naoto



Pulsed electromagnetic field stimulates osteoprotegerin and reduces RANKL expression in ovariectomized rats.  


Pulsed electromagnetic field (PEMF) has been shown to increase bone mineral density in osteoporosis patients and prevent bone loss in ovariectomized rats. But the mechanisms through which PEMF elicits these favorable biological responses are still not fully understood. Receptor activator of nuclear factor ?B ligand (RANKL) and osteoprotegerin (OPG) are cytokines predominantly secreted by osteoblasts and play a central role in differentiation and functional activation of osteoclasts. The purpose of this study was to investigate the effects of PEMF on RANKL and OPG expression in ovariectomized rats. Thirty 3-month-old female Sprague-Dawley rats were randomly divided into three groups: sham-operated control (Sham), ovariectomy control (OVX), and ovariectomy with PEMF treatment (PEMF). After 12-week interventions, the results showed that PEMF increased serum 17?-estradiol level, reduced serum tartrate-resistant acid phosphatase level, increased bone mineral density, and inhibited deterioration of bone microarchitecture and strength in OVX rats. Furthermore, PEMF could suppress RANKL expression and improve OPG expression in bone marrow cells of OVX rats. In conclusion, this study suggests that PEMF can prevent ovariectomy-induced bone loss through regulating the expression of RANKL and OPG. PMID:22948539

Zhou, Jun; Chen, Shiju; Guo, Hua; Xia, Lu; Liu, Huifang; Qin, Yuxi; He, Chengqi



Reduced expression of IA channels is associated with postischemic seizures in hyperglycemic rats.  


Poststroke seizures are considered to be the major cause of epilepsy in the elderly. The mechanisms of poststroke seizures remain unclear. A history of diabetes mellitus has been identified as an independent predictor of acute poststroke seizures in stroke patients. The present study sought to reveal the mechanisms for the development of postischemic seizures under hyperglycemic conditions. Transient forebrain ischemia was produced in adult Wistar rats by using the four-vessel occlusion method. At the normal blood glucose level, seizures occurred in ?50% of rats after 25 min of ischemia. However, in rats with hyperglycemia, the incidence rate of postischemic seizures was significantly increased to 100%. The occurrence of postischemic seizures was not correlated with the severity of brain damage in hyperglycemic rats. Mannitol, an osmotic diuretic agent, could neither prevent postischemic seizures nor alleviate the exacerbated brain damage in the presence of hyperglycemia. K(+) channels play a critical role in controlling neuronal excitability. The expression of A-type K(+) channel subunit Kv4.2 in the hippocampus and the cortex was significantly reduced in hyperglycemic rats with seizures compared with those without seizures. These results suggest that the reduction of Kv4.2 expression could contribute to the development of postischemic seizures in hyperglycemia. © 2014 Wiley Periodicals, Inc. PMID:25043828

Lei, Zhigang; Zhang, Hui; Liang, Yanling; Cui, Qiliang; Xu, Zhiqiang; Xu, Zao C



Reduced sympathetic neurite outgrowth on uterine tissue sections from rats treated with estrogen.  


In order to evaluate the contribution of substrate-bound factors to the extent and patterning of the sympathetic innervation of rat uterus following estrogen treatment, superior cervical ganglion explants from neonatal and adult ovariectomized rats were cultured on tissue sections of fresh frozen uterus from adult ovariectomized rats treated with estrogen or a vehicle. The main findings were: (1) neurite growth was greatly influenced by histological features of the underlying section; (2) on myometrial sections, neurites followed the orientation of the main axis of the longitudinally sectioned muscle cells; (3) neurites showed limited growth on transversally sectioned smooth muscle; (4) neuritic patterning was unaffected by a reduction in migrating ganglionic non-neuronal cells; (5) neurite outgrowth, but not non-neural cell migration, was markedly reduced on myometrial sections from rats treated with estrogen. These results suggest that adult myometrium continues to provide signals allowing the organotypic patterning and growth of sympathetic axons, that estrogen treatment modifies myometrial substrate properties so that it is less supportive for sympathetic neurite growth, and that adult sympathetic neurons retain their ability to recognize substrate-bound cues present in the myometrium. On endometrial sections, neurites formed radially symmetric halos, which were reduced in size on estrogen-treated endometrial substrates. Thus, changes in the neuritogenic capacity of the uterus underlie plasticity in uterine sympathetic nerves, and alterations in substrate-bound factors contribute to the diminished receptivity of the estrogenized uterus to its sympathetic innervation. PMID:20387079

Richeri, Analía; Bianchimano, Paola; Crutcher, Keith A; Brauer, M Mónica



Distal forelimb representations in primary motor cortex are redistributed after forelimb restriction: a longitudinal study in adult squirrel monkeys.  


Primary motor cortex (M1) movement representations reflect acquired motor skills. Representations of muscles and joints used in a skilled task expand. However, it is unknown whether motor restriction in healthy individuals results in complementary reductions in M1 representations. With the use of intracortical microstimulation techniques in squirrel monkeys, detailed maps of movement representations in M1 were derived before and up to 35 wk after restriction of the preferred distal forelimb (DFL) by use of a soft cast. Although total DFL area and movement threshold remained constant, casting resulted in a redistribution of digit and wrist/forearm representations. Digit representations progressively decreased, whereas wrist/forearm representations progressively increased in areal extent. In three of four monkeys, hand preference returned to normal by the end of the postcast recovery period, and postrecovery maps demonstrated reversal of restriction-induced changes. However, in one monkey, a chronic motor impairment occurred in the casted limb. Rehabilitation via a forced-use paradigm resulted in recovery in use and skill of the impaired limb, as well as restoration of normal motor maps. These results demonstrate that plasticity in motor representations can be induced by training or restricting movements of the limb. Physiological changes induced by restriction appear to be reversible, even in the case of adverse motor outcomes. The respective contributions of both disuse and lost motor skills are discussed. These results have relevance for clinical conditions requiring forelimb casting as well as interpreting the differential effects of injury and disuse that are necessarily intertwined after cortical injury, as occurs in stroke. PMID:23236004

Milliken, Garrett W; Plautz, Erik J; Nudo, Randolph J



Dynamic motor compensations with permanent, focal loss of forelimb force after cervical spinal cord injury.  


Incomplete cervical lesion is the most common type of human spinal cord injury (SCI) and causes permanent paresis of arm muscles, a phenomenon still incompletely understood in physiopathological and neuroanatomical terms. We performed spinal cord hemisection in adult rats at the caudal part of the segment C6, just rostral to the bulk of triceps brachii motoneurons, and analyzed the forces and kinematics of locomotion up to 4 months postlesion to determine the nature of motor function loss and recovery. A dramatic (50%), immediate and permanent loss of extensor force occurred in the forelimb but not in the hind limb of the injured side, accompanied by elbow and wrist kinematic impairments and early adaptations of whole-body movements that initially compensated the balance but changed continuously over the follow-up period to allow effective locomotion. Overuse of both contralateral legs and ipsilateral hind leg was evidenced since 5 days postlesion. Ipsilateral foreleg deficits resulted mainly from interruption of axons that innervate the spinal cord segments caudal to the lesion, because chronic loss (about 35%) of synapses was detected at C7 while only 14% of triceps braquii motoneurons died, as assessed by synaptophysin immunohistochemistry and retrograde neural tracing, respectively. We also found a large pool of propriospinal neurons projecting from C2-C5 to C7 in normal rats, with topographical features similar to the propriospinal premotoneuronal system of cats and primates. Thus, concurrent axotomy at C6 of brain descending axons and cervical propriospinal axons likely hampered spontaneous recovery of the focal neurological impairments. PMID:23249275

López-Dolado, Elisa; Lucas-Osma, Ana M; Collazos-Castro, Jorge E



Rats maintained on high-fat diets exhibit reduced satiety in response to CCK and bombesin  

Microsoft Academic Search

Rats maintained on high-fat diets often exhibit increased food intake and weight gain. We hypothesized that high-fat diets might result in reduced sensitivity to hormonal signals responsible for terminating food intake—satiety signals. The intestinal hormone cholecystokinin (CCK) and the gastrointestinal neuropeptide, bombesin (BBS) both have been proposed as satiety signals. To determine whether maintenance on high-fat diets alters sensitivity to

Mihai Covasa; Robert C Ritter



Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats  

Microsoft Academic Search

Ultra-low-dose opioid antagonists have been shown to enhance opioid analgesia and alleviate opioid tolerance and dependence. Our present studies in male Sprague–Dawley rats assessed the abuse potential of oxycodone+ultra-low-dose naltrexone (NTX) versus oxycodone alone. The lowest NTX dose (1 pg\\/kg\\/infusion), but not slightly higher doses (10 and 100 pg\\/kg\\/infusion), enhanced oxycodone (0.1 mg\\/kg\\/infusion) intravenous self-administration, suggesting a reduced rewarding potency

Francesco Leri; Lindsay H. Burns



Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity  

Microsoft Academic Search

High-fat, energy-dense diets promote weight gain and obesity in humans and other animals, but the mechanisms underlying such diet-induced obesity remain elusive. To determine whether a reduced capacity to oxidize fat is involved in the etiology of diet-induced obesity, we examined different measures of fatty acid oxidation in rats selectively bred for susceptibility (DIO) or resistance (DR) to dietary obesity

Hong Ji; Mark I. Friedman



Mitochondrials complex I activity is reduced in latent adriamycin-induced cardiomyopathy of rat  

Microsoft Academic Search

We previously reported on the use of enzymatic analysis to impair fatty acid metabolism followed by reduced myocardial energy content, leading to severe heart failure in adriamycin (ADR)-treated rats. The aim of this study is to investigate whether impaired myocardial energy metabolism can also be detected by other methods; i.e. measuring mitochondrial complex I activity and myocardial 125I-15-(p-iodophenyl)-3-(R,S)- methylpentadecanoic acid

Kiyotaka Ohkura; Jong-Dae Lee; Hiromasa Shimizu; Akira Nakano; Hiroyasu Uzui; Motosaburo Horikoshi; Yasuhisa Fujibayashi; Yoshiharu Yonekura; Takanori Ueda



Hyperammonemia Reduces Water Immersion–Restraint Stress Gastric Ulcers in Rats  

Microsoft Academic Search

1.The influence of hyperammonemia (produced by the continuous intraperitoneal infusion of ammonium acetate for 6 days) on stress-induced gastric ulcer formation was investigated in conscious rats.2.Continuous ammonium acetate infusion significantly reduced stress-induced gastric ulceration concomitant with an increase in gastric blood flow, as determined using radioactive microspheres. The serum levels of L-arginine as well as nitrite and nitrate (oxidative byproducts

Takashi Ishihara; Tatsuyoshi Takada; Yoshikazu Shoji; Yasunari Uedono; Naoshi Takeyama; Takaya Tanaka



Forelimb regeneration from different levels of amputation in the newt, Notophthalmus viridescens : Length, rate, and stages  

Microsoft Academic Search

1.Some aspects of the influence of position on regeneration have been examined by comparing regeneration from two different levels along the newt forelimb.2.We have defined a series of stages of forelimb regeneration in the newt,Notophthalmus viridescens, in order to facilitate this study.3.Limbs amputated at either a proximal level (through the humerus) or a distal level (through the radius and ulna)

Laurie E. Iten; Susan V. Bryant



Scapula Movements and Their Contribution to Three-Dimensional Forelimb Excursions in Quadrupedal Primates  

Microsoft Academic Search

\\u000a Primates are endowed with a great repertoire of locomotor and nonlocomotor abilities, for which they rely on their powerful\\u000a prehensile hind limbs and their skilled and mobile forelimbs. The overall mobility of the forelimb depends to a considerable\\u000a degree on structure and function of the shoulder region but only scant information about the detailed motion of the primate\\u000a shoulder is

Manuela Schmidt; Cornelia Krause


Deep brain stimulation of the nucleus accumbens reduces ethanol consumption in rats.  


Recent studies have shown that deep brain stimulation (DBS) of the nucleus accumbens (NAcc) has an inhibitory effect on drug-seeking behaviors including reinstatement responding for cocaine. The objective of the present study was to expand on these findings by assessing the effects of DBS on behaviors related to alcohol consumption. The specific aim of this study was to determine whether DBS delivered to either the shell or core of the NAcc would reduce ETOH intake in rats using a two-bottle choice limited access procedure. Long Evans rats were induced to drink a 10% ethanol solution using a saccharin fading procedure. Bipolar electrodes were implanted bilaterally into either the core or shell of the NAcc. During testing animals received DBS 5 min prior to and during a 30-minute test session in which both ETOH and water bottles were accessible. Current was delivered at amplitudes ranging from 0 to 150 microA. ETOH consumption was significantly reduced from baseline levels at the 150 microA current for both shell and core electrode placements. A significant current effect was not found for water consumption for either site. These results provide evidence that DBS delivered either to the nucleus accumbens core or shell subregions can significantly reduce ethanol intake in the rat. PMID:19463262

Knapp, Clifford M; Tozier, Lisa; Pak, Arlene; Ciraulo, Domenic A; Kornetsky, Conan



Low-Anxiety Rat Phenotypes Can Be Further Reduced through Genetic Intervention  

PubMed Central

Background A previous study using an intercross between the inbred rat strains Lewis (LEW) and Spontaneously Hypertensive Rats (SHR) identified a locus on chromosome 4, named Anxrr16, influencing an experimental index of anxiety and showing a transgressive effect, with alleles from the LEW strain (more anxious) decreasing rather than increasing anxiety. Objective To confirm the location and isolate the effect of a rat genome region named Anxrr16 through a planned genomic recombination strategy, where the target locus in SHR rats was replaced with LEW genetic material. Methods A new congenic strain, named SHR.LEW-Anxrr16 (SLA16), was developed from a cross between LEW (donor) and SHR (receptor) rats and then evaluated in several anxiety-related tests. The activity and attention levels of the new strain were also evaluated, since hyperactivity was observed during its construction and because SHR is a model of attention deficit hyperactivity disorder. Results Significant effects of Anxrr16 were found for open field central locomotion, as well as for other indices of anxiety from the light/dark box, triple test and T-maze. In all cases, the low-anxiety levels of SHR rats were further reduced by the insertion of LEW alleles. Differences in locomotor activity were found only in unfamiliar (hence stressful) environments and no genetic effects were observed in indices of attention. Conclusion The SLA16 strain can help in the identification of the molecular pathways involved in experimental anxiety and it demonstrates how apparently extreme phenotypes sometimes hide major opposite-acting genes. PMID:24386249

Granzotto, Natalli; Ramos, Andre



Comparative kinematics of the forelimb during swimming in red-eared slider (Trachemys scripta) and spiny softshell (Apalone spinifera) turtles.  


Softshell turtles (Family Trionychidae) possess extensive webbing between the digits of the manus, suggesting that the forelimb may serve as an effective thrust generator during aquatic locomotion. However, the hindlimb has previously been viewed as the dominant propulsive organ in swimming freshwater turtles. To evaluate the potential role of the forelimb in thrust production during swimming in freshwater turtles, we compared the forelimb morphology and three-dimensional forelimb kinematics of a highly aquatic trionychid turtle, the spiny softshell Apalone spinifera, and a morphologically generalized emydid turtle, the red-eared slider Trachemys scripta. Spiny softshells possess nearly twice as much forelimb surface area as sliders for generating drag-based thrust. In addition, although both species use drag-based propulsion, several aspects of forelimb kinematics differ significantly between these species. During the thrust phase of the forelimb cycle, spiny softshells hold the elbow and wrist joints significantly straighter than sliders, thereby further increasing the surface area of the limb that can move water posteriorly and increasing the velocity of the distal portion of the forelimb. These aspects of swimming kinematics in softshells should increase forelimb thrust production and suggest that the forelimbs make more substantial contributions to forward thrust in softshell turtles than in sliders. Spiny softshells also restrict forelimb movements to a much narrower dorsoventral and anteroposterior range than sliders throughout the stroke, thereby helping to minimize limb movements potentially extraneous to forward thrust production. These comparisons demonstrate considerable diversity in the forelimb kinematics of turtles that swim using rowing motions of the limbs and suggest that the evolution of turtle forelimb mechanics produced a variety of contrasting solutions for aquatic specialization. PMID:11606600

Pace, C M; Blob, R W; Westneat, M W



Abnormally rapid reversal learning and reduced response to antipsychotic drugs following ovariectomy in female rats.  


Epidemiological and clinical life cycle studies indicate that favorable illness course and better response to antipsychotic drugs (APDs) in women with schizophrenia are positively correlated with estrogen levels. Accordingly, the estrogen hypothesis of schizophrenia proposes a neuroprotective role of estrogen in women vulnerable to schizophrenia. Previously we demonstrated in the rat that low levels of estrogen induced by ovariectomy led to disruption of latent inhibition (LI) reflecting impairment of selective attention, a core deficit of schizophrenia. LI disruption was reversed by 17?-estradiol and the atypical APD clozapine, whereas the typical APD haloperidol was ineffective unless co-administered with 17?-estradiol. Here we aimed to extend these findings by testing ovariectomized rats in another selective attention task, discrimination reversal. Ovariectomy led to a loss of selective attention as manifested in abnormally rapid reversal. The latter was normalized by high dose of 17?-estradiol (150 ?g/kg) and clozapine (2.5mg/kg), but not by haloperidol (0.1mg/kg) or lower doses of 17?-estradiol (10 and 50 ?g/kg). However, co-administration of haloperidol with 17?-estradiol (50 ?g/kg) was effective. In sham rats low 17?-estradiol (10 ?g/kg) produced rapid reversal, while high 17?-estradiol (150 ?g/kg), haloperidol alone, or haloperidol-17?-estradiol combination reduced reversal speed. Clozapine did not affect reversal speed in sham rats. These results strengthen our previous results in suggesting that schizophrenia-like attentional abnormalities as well as reduced response to APDs in female rats are associated with low level of gonadal hormones. In addition, they support the possibility that estrogen may have an antipsychotic-like action in animal models. PMID:21723667

Arad, Michal; Weiner, Ina



Captopril reduces collagen and mast cell accumulation in irradiated rat lung  

SciTech Connect

The angiotensin converting enzyme inhibitor captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats. The present study determined whether captopril also reduces collagen (hydroxyproline) accumulation in the lungs of rats sacrificed 2 months after a range of single doses (0-30 Gy) of 60Co gamma rays to the right hemithorax. Captopril was administered in the feed at a regimen of 0, 25, or 50 mg/kg/day continuously after irradiation. Mast cell counts also were obtained from lungs of all animals exposed to 30 Gy. In rats receiving no captopril, there was a radiation dose-dependent increase in right lung hydroxyproline (HP) content and in HP concentration per g wet weight. Captopril produced a drug dose-dependent suppression in this radiation-induced HP accumulation. At a dose of 50 mg/kg/d, captopril reduced the slope of the radiation dose response curve for lung HP content by a factor of 1.7, and completely prevented the increase in HP concentration. At an isoeffect level of 550 micrograms HP per right superior lobe, this dose of captopril exhibited a DRF of 1.7 +/- 0.2. In rats exposed to 30 Gy, moreover, the number of mast cells per mm2 of alveolar cross-sectional surface area decreased from 105 +/- 8 to 100 +/- 7 and 59 +/- 5 in the groups given 0, 25 or 50 mg/kg/d of captopril, respectively, (vs none in sham-irradiated rats). These data are the first to demonstrate that the ACE inhibitor captopril might provide a novel intervention in the pathogenesis of radiation fibrosis.

Ward, W.F.; Molteni, A.; Ts'ao, C.H.; Hinz, J.M. (Northwestern Univ. Medical School, Chicago, IL (USA))



Nuclear factor ?B inhibition reduces lung vascular lumen obliteration in severe pulmonary hypertension in rats.  


NF-?B and IL-6, a NF-?B downstream mediator, play a central role in the inflammatory response of tissues. We aimed to determine the role of the classical NF-?B pathway in severe pulmonary arterial hypertension (PAH) induced by SU5416 and chronic hypoxia (SuHx) in rats. Tissue samples from patients with idiopathic PAH (iPAH) and control subjects were investigated. SuHx rats were treated from Days 1 to 3, 1 to 21, and 29 to 42 with the NF-?B inhibitor pyrrolidine dithiocarbamate (PDTC) and/or from Days 1 to 21 with anti-IL-6 antibody. Nuclear staining for NF-?B, an indicator of the activation of the classical NF-?B pathway, was detected in pulmonary arterial lesions of patients with iPAH and SuHx rats. NF-?B inhibition with PDTC prevented and reduced pulmonary arterial obliteration without reducing muscularization. However, the elevated lung levels of IL-6 were not reduced in PDTC-treated SuHx animals. PDTC treatment prevented or reduced apoptosis of pulmonary artery wall cells and pulmonary arterial obliteration. IL-6 inhibition had only a partial effect on apoptosis and obliteration. Pulmonary arterial media wall thickness was not affected by any of these treatments. Preventive and therapeutic PDTC treatment promoted immune regulation by increasing the number of perivascular CD4(+) T cells, in particular regulatory T cells (early treatment), and by reducing the number of perivascular CD8(+) T lymphocytes and CD45RA(+) B lymphocytes. Therapeutic PDTC treatment further preserved right ventricular function in SuHx animals. Inhibition of NF-?B may represent a therapeutic option for pulmonary arterial obliteration via reduced vessel wall cell apoptosis and improved regulation of the immune system. PMID:24684441

Farkas, Daniela; Alhussaini, Aysar A; Kraskauskas, Donatas; Kraskauskiene, Vita; Cool, Carlyne D; Nicolls, Mark R; Natarajan, Ramesh; Farkas, Laszlo



Electro-acupuncture attenuates behavioral hyperalgesia and selectively reduces spinal Fos protein expression in rats with persistent inflammation.  


This study examined the effect of electro-acupuncture (EA) on persistent inflammatory hyperalgesia in a rat model. Inflammation and hyperalgesia were induced by injecting complete Freund's adjuvant (CFA) into one hindpaw of the rat. Hyperalgesia was determined by a decrease in paw withdrawal latencies (PWL) to a noxious thermal stimulus. EA was applied bilaterally at the acupuncture point Huantiao (G30) at the rat's hindlimbs. EA-treated rats (n = 11) had significantly longer PWLs as compared with placebo control rats (n = 7) in the inflamed paw at 2.5 hours and 5 days after injection of CFA (P <.05) and longer PWLs as compared to sham control rats (n = 9) at 2.5 hours (P >.05). Paw edema was significantly reduced in EA-treated rats versus placebo controls at 24 hours after inflammation (P <.01). Inflammation-induced spinal Fos expression in the medial half of laminae I-II in EA-treated rats versus placebo rats (n = 5 per group) was significantly reduced (P <.01). These data showed that EA delayed the onset and facilitated the recovery of inflammatory hyperalgesia and suppressed the inflammation-induced spinal Fos expression in neurons (laminae I-II) involved in receiving noxious stimulation. This rat model of persistent pain and inflammation seems to be an ideal animal model for studying the effect of acupuncture. PMID:14622832

Lao, L; Zhang, G; Wei, F; Berman, B M; Ren, K



Chronic administration of valproic acid reduces brain NMDA signaling via arachidonic acid in unanesthetized rats  

PubMed Central

Evidence that brain glutamatergic activity is pathologically elevated in bipolar disorder suggests that mood stabilizers are therapeutic in the disease in part by downregulating glutamatergic activity. Such activity can involve the second messenger, arachidonic acid (AA, 20:4n-6). We tested this hypothesis with regard to valproic acid (VPA), when stimulating glutamatergic N-methyl-D-aspartate (NMDA) receptors in rat brain and measuring AA and related responses. An acute subconvulsant dose of NMDA (25 mg/kg i.p.) or saline was administered to unanesthetized rats that had been treated i.p. daily with VPA (200 mg/kg) or vehicle for 30 days. Quantitative autoradiography following intravenous [1-14C]AA infusion was used to image regional brain AA incorporation coefficients k*, markers of AA signaling. In chronic vehicle-pretreated rats, NMDA compared with saline significantly increased k* in 41 of 82 examined brain regions, many of which have high NMDA receptor densities, and also increased brain concentrations of the AA metabolites, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). VPA pretreatment reduced baseline concentrations of PGE2 and TXB2, and blocked the NMDA induced increases in k* and in eicosanoid concentrations. These results, taken with evidence that carbamazepine and lithium also block k* responses to NMDA in rat brain, suggest that mood stabilizers act in bipolar disorder in part by downregulating glutamatergic signaling involving AA. PMID:18461450

Basselin, Mireille; Chang, Lisa; Chen, Mei; Bell, Jane M.; Rapoport, Stanley I.



A Magnesium Based Phosphate Binder Reduces Vascular Calcification without Affecting Bone in Chronic Renal Failure Rats  

PubMed Central

The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover. PMID:25229549

Neven, Ellen; De Schutter, Tineke M.; Dams, Geert; Gundlach, Kristina; Steppan, Sonja; Buchel, Janine; Passlick-Deetjen, Jutta; D'Haese, Patrick C.; Behets, Geert J.



Comparative study on the efficacy of allium sativum (garlic) in reducing some heavy metal accumulation in liver of wistar rats  

Microsoft Academic Search

Scope: Heavy metals are known to cause damage through indirect oxidative effects. This study was undertaken to compare the therapeutic efficacy and protective ability of garlic extracts on reducing toxicity induced by mercury, lead and cadmium in the liver.Methods and results: Rats were fed with rat chow mixed with raw garlic (7% w\\/w) while mercury (10 ppm), cadmium (200 ppm)

Chukwuemeka R. Nwokocha; Daniel U. Owu; Magdalene I. Nwokocha; Chibueze S. Ufearo; Moses O. E. Iwuala


The Serotonin Reuptake Inhibitor Fluoxetine Reduces Sex Steroid-Related Aggression in Female Rats: An Animal Model of Premenstrual Irritability?  

Microsoft Academic Search

The aggressive behavior displayed by some (but not all) female Wistar rats when an unfamiliar rat is being introduced into their home cage (the resident intruder paradigm) was found to be higher in non-receptive phases (metestrus, diestrus) than in the receptive phases (proestrus, estrus) of the estrus cycle, and effectively reduced by ovariectomy. When removal of the ovaries was followed

Hoi-Por Ho; Marie Olsson; M Pharm; Lars Westberg; Jonas Melke; Elias Eriksson



Tributyltin contributes in reducing the vascular reactivity to phenylephrine in isolated aortic rings from female rats.  


Organotin compounds such as tributyltin (TBT) are used as antifouling paints by shipping companies. TBT inhibits the aromatase responsible for the transformation of testosterone into estrogen. Our hypothesis is that TBT modulates the vascular reactivity of female rats. Female Wistar rats were treated daily (Control; CONT) or TBT (100 ng/kg) for 15 days. Rings from thoracic aortas were incubated with phenylephrine (PHE, 10(-10)-10(-4) M) in the presence and absence of endothelium, and in the presence of N(G)-Nitro-L-Arginine Methyl Ester (L-NAME), tetraethylammonium (TEA) and apocynin. TBT decreased plasma levels of estrogen and the vascular response to PHE. In the TBT group, the vascular reactivity was increased in the absence of endothelium, L-NAME and TEA. The decrease in PHE reactivity during incubation with apocynin was more evident in the TBT group. The sensitivity to acetylcholine (ACh) and sodium nitroprusside (SNP) was reduced in the TBT group. TBT increased collagen, reduced ?1-smooth muscle actin. Female rats treated with TBT for 15 days showed morphology alteration of the aorta and decreased their vascular reactivity, probably due to mechanisms dependent on nitric oxide (NO) bioavailability, K(+) channels and an increase in oxidative stress. PMID:24468273

Rodrigues, Samya Mere L; Ximenes, Carolina F; de Batista, Priscila R; Simões, Fabiana V; Coser, Pedro Henrique P; Sena, Gabriela C; Podratz, Priscila L; de Souza, Leticia N G; Vassallo, Dalton V; Graceli, Jones B; Stefanon, Ivanita



Propolis reduces oxidative stress in l-NAME-induced hypertension rats.  


The inhibition in the synthesis or bioavailability of nitric oxide (NO) has an important role in progress of hypertension. The blocking of nitric oxide synthase activity may cause vasoconstriction with the formation of reactive oxygen species (ROS). Propolis is a resinous substance collected by honey bees from various plants. Propolis has biological and pharmacological properties. The aim of this study was to examine the effect of propolis on catalase (CAT) activity, malondialdehyde (MDA) and NO levels in the testis tissues of hypertensive rats by N?-nitro-l-arginine methyl ester (l-NAME). Rats have received nitric oxide synthase inhibitor (l-NAME, 40 mg kg(-1) , intraperitoneally) for 15 days to produce hypertension and propolis (200 mg kg(-1) , by gavage) during the last 5 days. MDA level in l-NAME-treated group significantly increased compared with control group (P < 0.01). MDA level of l-NAME + propolis-treated rats significantly reduced (P < 0.01) compared with l-NAME-treated group. CAT activity and NO level significantly reduced (P < 0.01) in l-NAME group compared with control group. There were no statistically significant increases in the CAT activity and NO level of the l-NAME + propolis group compared with the l-NAME-treated group (P > 0.01). These results suggest that propolis changes CAT activity, NO and MDA levels in testis of l-NAME-treated animals, and so it may modulate the antioxidant system. PMID:23788129

Selamoglu Talas, Zeliha



Activation of PPAR-? inhibits differentiation of rat osteoblasts by reducing expression of connective tissue growth factor.  


Long-term treatment with an agonist of peroxisome proliferator-activated receptor (PPAR)-? is associated with bone fractures in the clinical practice. However, the mechanisms underlying the fractures are not fully understood. This study was aimed to examine the effect of rosiglitazone (an agonist of PPAR-?) of different doses on the proliferation, differentiation, and transforming growth factor beta 1 (TGF-?1)-induced expression of connective tissue growth factor (CTGF) in primary rat osteoblasts in vitro. Osteoblasts were isolated from newly born SD rats and treated with different doses of rosiglitazone (0-20 ?mol/L). The proliferation and differentiation of osteoblasts were measured by MTT assay and NPP assay, respectively. The expression of CTGF was determined by RT-PCR and Western blotting. The results showed that most isolated osteoblasts displayed strong alkaline phosphatase (ALP) activity and treatment with different doses of rosiglitazone did not affect their proliferation, but significantly inhibited the differentiation of osteoblasts in a dose-dependent manner. Moreover, treatment with different doses of rosiglitazone significantly reduced the TGF-?1-induced CTGF mRNA transcription and protein expression in a dose-dependent manner in rat osteoblasts. It was concluded that the activation of PPAR-? may inhibit the differentiation of osteoblasts by reducing the TGF-?1-induced CTGF expression in vitro. PMID:25318873

Yu, Wei-Wei; Xia, Qin; Wu, Yan; Bu, Qiao-Yun



Botulinum toxin in gastric submucosa reduces stimulated HCl production in rats  

PubMed Central

Background Botulinum toxin blocks acetylcholine release from nerve endings and acts as a long term, reversible inhibitor of muscle contraction as well as of salivary, sweat gland, adrenal and prostatic secretions. The aim of the present study is to investigate whether gastric submucosal injection of botulinum toxin type A reduces stimulated gastric production of HCl. Methods Sixty-four rats were randomized in two groups and laparotomized. One group was treated with botulinum toxin-A 10 U by multiple submucosal gastric injections, while the second group was injected with saline. Two weeks later, acid secretion was stimulated by pyloric ligation and acid output was measured. Body weight, food and water intake were also recorded daily. Results HCl production after pyloric ligation was found to be significantly lower in botulinum toxin-treated rats (657 ± 90.25 micromol HCl vs. 1247 ± 152. P = 0.0017). Botulinum toxin-treated rats also showed significantly lower food intake and weight gain. Conclusions Botulinum toxin type A reduces stimulated gastric acidity. This is likely due either to inhibition of the cholinergic stimulation of gastric parietal cells, or to an action on the myenteric nervous plexuses. Reduction of growth and food intake may reflect both impaired digestion and decreased gastric motility. PMID:12964945

Runfola, Matteo; Rossi, Simone; Panunzi, Simona; Spada, Pier Luigi; Gui, Daniele



Rifaximin, but not growth factor 1, reduces brain edema in cirrhotic rats  

PubMed Central

AIM: To compare rifaximin and insulin-like growth factor (IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion. METHODS: Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups: Cirrhosis; Cirrhosis + IGF-1; Cirrhosis + rifaximin; Controls; Controls + IGF-1; and Controls + rifaximin. An oral glutamine-challenge test was performed, and plasma and cerebral ammonia, glucose, bilirubin, transaminases, endotoxemia, brain water content and ileocecal cultures were measured and liver histology was assessed. RESULTS: Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups, and improved some liver function parameters (bilirubin, alanine aminotransferase and aspartate aminotransferase). These effects were associated with a significant reduction in cerebral water content. Blood and cerebral ammonia levels, and area-under-the-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals. By contrast, IGF-1 administration failed to improve most alterations observed in cirrhosis. CONCLUSION: By reducing gut bacterial overgrowth, only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema, alterations associated with hepatic encephalopathy. PMID:22563196

Òdena, Gemma; Miquel, Mireia; Serafín, Anna; Galan, Amparo; Morillas, Rosa; Planas, Ramon; Bartolí, Ramon



Hoxb5b acts downstream of retinoic acid signaling in the forelimb field to restrict heart field potential in zebrafish  

PubMed Central

SUMMARY How adjacent organ fields communicate during development is not understood. Here, we identify a mechanism in which signaling within the forelimb field restricts the potential of the neighboring heart field. In zebrafish embryos deficient in retinoic acid (RA) signaling, the pectoral fins (forelimbs) are lost while both chambers of the heart are enlarged. We provide evidence that both of these phenotypes are due to RA signaling acting directly within the forelimb field. hoxb5b, an RA-responsive gene expressed within the forelimb field, is required to restrict the number of atrial cells arising from the adjacent heart field, although its function is dispensable for forelimb formation. Together, these data indicate non-autonomous influences downstream of RA signaling that act to limit individual chamber size. Therefore, our results offer new perspectives on the mechanisms regulating organ size and the possible causes of congenital syndromes affecting both the heart and forelimb. PMID:19081079

Waxman, Joshua S.; Keegan, Brian R.; Roberts, Richard W.; Poss, Kenneth D.; Yelon, Deborah



Ancestry of motor innervation to pectoral fin and forelimb  

PubMed Central

Motor innervation to the tetrapod forelimb and fish pectoral fin is assumed to share a conserved spinal cord origin, despite major structural and functional innovations of the appendage during the vertebrate water-to-land transition. In this paper, we present anatomical and embryological evidence showing that pectoral motoneurons also originate in the hindbrain among ray-finned fish. New and previous data for lobe-finned fish, a group that includes tetrapods, and more basal cartilaginous fish showed pectoral innervation that was consistent with a hindbrain-spinal origin of motoneurons. Together, these findings support a hindbrain–spinal phenotype as the ancestral vertebrate condition that originated as a postural adaptation for pectoral control of head orientation. A phylogenetic analysis indicated that Hox gene modules were shared in fish and tetrapod pectoral systems. We propose that evolutionary shifts in Hox gene expression along the body axis provided a transcriptional mechanism allowing eventual decoupling of pectoral motoneurons from the hindbrain much like their target appendage gained independence from the head. PMID:20975699

Ma, Leung-Hang; Gilland, Edwin; Bass, Andrew H.; Baker, Robert



Perinatal cocaine exposure reduces myocardial norepinephrine transporter function in the neonatal rat.  


Norepinephrine transporter (NET) mediates the active removal of norepinephrine (NE) released from sympathetic nerve terminals via reuptake, and NET function and expression can be regulated by cocaine. NET expression and its regulation by cocaine in the developing sympathetic nervous system during early postnatal period, however, have not been examined. We quantified immunodetectable NET protein expression in the neonatal rat heart to examine the developmental pattern of myocardial NET during the first 2 weeks after birth. To assess sympathetic innervations, we simultaneously quantified the expression of myocardial tyrosine hydroxylase (TH). Timed pregnant rats received daily intragastric treatment with saline (CTL) or cocaine at 60 mg/kg (Coc) from Gestational Day 2 until parturition. After birth, nursing mothers continued to receive the same treatment. The expression of myocardial TH and NET in neonatal rats were then studied at 1 day (Postnatal Day 1, PD1), 7 days (PD7) or 14 days (PD14) of age. We observed a similar age-dependent increase in the expression for myocardial NET and TH during the first 2 weeks of postnatal life, in both CTL and Coc animals. While myocardial TH was significantly up-regulated following perinatal cocaine exposure, no significant change in immunodetectable myocardial NET protein was evident. To further examine whether NET function might be affected by perinatal cocaine exposure, we performed NE uptake in myocardial membranes from PD14 CTL and Coc rats. We found that NE uptake was reduced at PD14 in the cocaine-treated group. Our results indicate that myocardial NET and TH are both developmentally regulated. Furthermore, our results indicate that perinatal exposure to cocaine did not change NET protein expression but impaired myocardial NET function in the neonatal rat. PMID:15113605

Zhao, Yejun; Sun, Lena



Gestational or acute restraint in adulthood reduces levels of 5?-reduced testosterone metabolites in the hippocampus and produces behavioral inhibition of adult male rats  

PubMed Central

Stressors, during early life or adulthood, can alter steroid-sensitive behaviors, such as exploration, anxiety, and/or cognitive processes. We investigated if exposure to acute stressors in adulthood may alter behavioral and neuroendocrine responses of male rats that were exposed to gestational stress or not. We hypothesized that rats exposed to gestational and acute stress may show behavioral inhibition, increased corticosterone, and altered androgen levels in the hippocampus. Subjects were adult, male offspring of rat dams that were restrained daily on gestational days 14–20, or did not experience this manipulation. Immediately before testing, rats were restraint stressed for 20 min or not. During week 1, rats were tested in a battery of tasks, including the open field, elevated plus maze, social interaction, tailflick, pawlick, and defensive burying tasks. During week 2, rats were trained and tested 24 h later in the inhibitory avoidance task. Plasma corticosterone and androgen levels, and hippocampal androgen levels, were measured in all subjects. Gestational and acute restraint stress increased plasma levels of corticosterone, and reduced levels of testosterone's 5?-reduced metabolites, dihydrotestosterone (DHT) and 3?-androstanediol (3?-diol), but not the aromatized metabolite, estradiol (E2), in plasma or the hippocampus. Gestational and acute restraint stress reduced central entries made in the open field, and latencies to enter the shock-associated side of the inhibitory avoidance chamber during testing. Gestational stress reduced time spent interacting with a conspecific. These data suggest that gestational and acute restraint stress can have actions to produce behavioral inhibition coincident with increased corticosterone and decreased 5?-reduced androgens of adult male rats. Thus, gestational stress altered neural circuits involved in the neuroendocrine response to acute stress in early adulthood. PMID:23264760

Walf, Alicia A.; Frye, Cheryl A.



Aqueous extract of Ficus religiosa linn. reduces oxidative stress in experimentally induced type 2 diabetic rats.  


One of the major etiologies in pathogenesis of type 2 diabetes especially complications is oxidative stress. Aqueous extract of Ficus religiosa at a dose of 100 and 200 mg/kg orally decreased the fasting blood glucose in streptozotocin induced type 2 diabetic rats. The drug had enzyme induction effect with respect to catalase (CAT) and glutathione peroxidase (GSH-Px) activity, however decreased the exaggerated activity of superoxide dismutase (SOD) in type 2 diabetic rats. F. religiosa modulated the enzymes of antioxidant defence system to combat oxidative stress. As a result, glutathione (GSH-reduced form) was restored and inhibited the formation of malondialdehyde. Drug at higher dose (200 mg/kg) had more pronounced effect. F. religiosa, a rasayana group of plant drug having anti-diabetic activity along with antioxidant potential was beneficial in treatment of type 2 diabetes. PMID:20112810

Kirana, H; Agrawal, S S; Srinivasan, B P



Effectiveness of topical anesthetics on reducing tactile sensitivity in the paws of newborn rats.  


The aim of this study was to evaluate the effectiveness of three local, topical anesthetics on touch response thresholds of the paws of 1-day-old rats. Touch response thresholds were measured using Semmes Weinstein monofilaments after treatment of the paws with EMLA (2.5% lidocaine and 2.5% prilocaine), alcaine (.5% proparacaine), triocaine (20% benzocaine, 6% lidocaine, and 4% tetracaine), or petroleum jelly (treatment control). Touch thresholds significantly increased after treatment with EMLA 18% of the time, and there was no evidence of a systemic effect. Touch thresholds were not significantly altered after treatment with alcaine, triocaine, or petroleum jelly. Therefore, EMLA appears to be a slightly effective topical anesthetic for reducing tactile sensitivity in newborn rats. PMID:23254968

Strain, Misty M; Vineyard, Mary Ann; Roberto, Megan E; Brumley, Michele R



Inhaled Lactonase Reduces Pseudomonas aeruginosa Quorum Sensing and Mortality in Rat Pneumonia  

PubMed Central

Rationale The effectiveness of antibiotic molecules in treating Pseudomonas aeruginosa pneumonia is reduced as a result of the dissemination of bacterial resistance. The existence of bacterial communication systems, such as quorum sensing, has provided new opportunities of treatment. Lactonases efficiently quench acyl-homoserine lactone-based bacterial quorum sensing, implicating these enzymes as potential new anti-Pseudomonas drugs that might be evaluated in pneumonia. Objectives The aim of the present study was to evaluate the ability of a lactonase called SsoPox-I to reduce the mortality of a rat P. aeruginosa pneumonia. Methods To assess SsoPox-I-mediated quorum quenching, we first measured the activity of the virulence gene lasB, the synthesis of pyocianin, the proteolytic activity of a bacterial suspension and the formation of biofilm of a PAO1 strain grown in the presence of lactonase. In an acute lethal model of P. aeruginosa pneumonia in rats, we evaluated the effects of an early or deferred intra-tracheal treatment with SsoPox-I on the mortality, lung bacterial count and lung damage. Measurements and Primary Results SsoPox-I decreased PAO1 lasB virulence gene activity, pyocianin synthesis, proteolytic activity and biofilm formation. The early use of SsoPox-I reduced the mortality of rats with acute pneumonia from 75% to 20%. Histological lung damage was significantly reduced but the lung bacterial count was not modified by the treatment. A delayed treatment was associated with a non-significant reduction of mortality. Conclusion These results demonstrate the protective effects of lactonase SsoPox-I in P. aeruginosa pneumonia and open the way for a future therapeutic use. PMID:25350373

Lafleur, John; Lepidi, Hubert; Papazian, Laurent; Rolain, Jean-Marc; Raoult, Didier; Elias, Mikael; Silby, Mark W.; Bzdrenga, Janek; Bregeon, Fabienne; Chabriere, Eric



Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat.  


High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1?/?, peroxisome proliferator-activated receptor (PPAR)-?, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-?, fatty acid synthase (FAS) and PPAR? genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-?] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1?/? and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury. PMID:24486395

Prakash, Prem; Singh, Vishal; Jain, Manish; Rana, Minakshi; Khanna, Vivek; Barthwal, Manoj Kumar; Dikshit, Madhu



Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass.  

PubMed Central

The effects of angiotensin II (AII) blockade were compared with the effects of angiotensin converting enzyme inhibition in rats with reduced nephron number. Rats were subjected to five-sixths renal ablation and divided into four groups with similar values for blood pressure and serum creatinine after 2 wk. Group 1 then served as untreated controls, while group 2 received the AII receptor antagonist MK954 (which has previously been designated DuP753), group 3 received the converting enzyme inhibitor enalapril, and group 4 received a combination of reserpine, hydralazine, and hydrochlorothiazide. Micropuncture and morphologic studies were performed 10 wk later. Converting enzyme inhibition, AII receptor blockade, and the combination regimen were equally effective in reversing systemic hypertension (time-averaged systolic blood pressure: group 1, 185 +/- 5 mmHg; group 2, 125 +/- 2 mmHg; group 3, 127 +/- 2 mmHg; group 4, 117 +/- 4 mmHg). Micropuncture studies showed that glomerular transcapillary pressure was reduced significantly by converting enzyme inhibition and by AII blockade but not by the combination regimen (delta P: group 1, 49 +/- 1 mmHg; group 2, 42 +/- 1 mmHg; group 3, 40 +/- 2 mmHg, group 4, 47 +/- 1 mmHg). Reduction of systemic blood pressure was associated with the development of markedly less proteinuria and segmental glomerular sclerosis in rats receiving enalapril and MK954 but not in rats receiving the combination regimen (prevalence of glomerular sclerotic lesions: group 1, 41 +/- 4%; group 2, 9 +/- 1%; group 3, 9 +/- 1%; group 4, 33 +/- 6%). These results indicate that the effects of converting enzyme inhibition on remnant glomerular function and structure depend on reduction in AII activity and are not attributable simply to normalization of systemic blood pressure. PMID:1522231

Lafayette, R A; Mayer, G; Park, S K; Meyer, T W



Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.  


Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1. PMID:12191973

Gueler, Faikah; Rong, Song; Park, Joon-Keun; Fiebeler, Anette; Menne, Jan; Elger, Marlies; Mueller, Dominik N; Hampich, Franziska; Dechend, Ralf; Kunter, Uta; Luft, Friedrich C; Haller, Hermann



Comparative study of the forelimbs of the semifossorial prairie dog, Cynomys gunnisoni, and the scansorial fox squirrel, Sciurus niger.  


A comparative study of the forelimbs of the semifossorial prairie dog, Cynomys gunnisoni , and the scansorial tree squirrel, Sciurus niger, was focused on the musculoskeletal design for digging in the former and climbing in the latter. Based on lever arm mechanics, it was expected that the forelimb of the prairie dog would show features appropriate to the production of relatively large forces and that of the fox squirrel to relatively great velocity. Force and lever arm measurements were made of select forelimb muscles at the shoulder, elbow, and wrist joints for a series of angles in both species. Contraction time and fatigue indexes were determined for the same forelimb muscles. Contrary to expectation, in the few cases in which significant (P less than .05) differences were found, the forces, lever arms, and torques (force times its lever arm) were greater in the smaller fox squirrel. The observed variation in the torques produced fits the demands on the forelimb during climbing and digging as estimated from films. Several forelimb muscles of the fox squirrel show significantly higher mean contraction times than do the homologous muscles of the prairie dog. There were no significant differences between the two species in the fatigability of the selected forelimb muscles, although the mean fatigue index was always higher (less fatigable muscle) in the prairie dog. Similarities in the forelimbs of these two sciurids suggest that only minor modifications may have been required of the ancestral forelimb in order for descendent forms to operate successfully as climbers and diggers . PMID:6726818

Stalheim-Smith, A



Evidence for reduced cancellous bone mass in the spontaneously hypertensive rat  

NASA Technical Reports Server (NTRS)

The histomorphometric changes in the proximal tibial metaphysis and epiphyseal growth plate and midtibial shaft of 26-week-old spontaneously hypertensive rats (SHR) compared with those of the corresponding normotensive Wistar-Kyoto (WKY) rats were studied. A decrease in body weight, growth plate thickness, and longitudinal growth rate of the proximal tibial epiphysis, trabecular bone volume, trabecular thickness and number, the number of osteoblasts and osteoprogenitor cells per millimeter square surface of the proximal tibial metaphysis, periosteal and endocortical apposition rate and bone formation rate of the tibial diaphysis were observed in the SHR. Additionally, systolic blood pressure, the number of osteoclasts per millimeter square surface and average number of nuclei per osteoclast of the proximal tibial metaphysis were significantly increased. Thus, osteoclastic activity is dominant over osteoblastic and chondroblastic activity in the SHR that results in a cancellous bone deficit in the skeleton. It will require additional work to ascertain the underlying cause for this condition as several factors in the SHR with a potential for causing this change are present, including elevated parathyroid hormone (PTH), depressed 1,25-(OH)2D3, low calcium absorption, reduced body weight (reduced loading) elevated blood pressure and possibly other direct cell differences in the mutant strain. At present elevated PTH and adaptation to underloading from reduced weight are postulated to be a likely cause, but additional studies are required to test this interpretation.

Wang, T. M.; Hsu, J. F.; Jee, W. S.; Matthews, J. L.



BPC-15 reduces trinitrobenzene sulfonic acid-induced colonic damage in rats.  


The effect of BPC-15 (Booly Protection Compound-15) was evaluated in a rat model of colonic injury. A single intracolonic administration of trinitrobenzene sulfonic acid (TNBS) dissolved in ethanol induces severe colonic damage, which is characterized by areas of necrosis surrounded by areas of acute inflammation. The damage is associated with high myeloperoxidase (MPO) activity, mainly as a reflection of neutrophilic infiltration into the damaged tissue. In this study, 1 hr before a single intracolonic administration of 50 mg/kg of TNBS in 50% ethanol, the animals were treated with one of the following doses of BPC-15: 0.0001, 0.001, 0.01, 0.1, 1 or 10 nmol/kg administered i.p. or with a dose of 10 nmol/kg administered intracolonically. The animals were sacrificed 3 days later and the extent of colonic necrosis and hyperemia was measured with an image analyzer. The i.p. administration of BPC-15 significantly reduced the extent of TNBS-induced colonic damage in a dose-dependent manner. This was associated with a statistically significant and dose-dependent reduction in colonic tissue MPO activity. At the dose tested (10 nmol/kg), intracolonic administration of BPC-15 did not significantly reduce either the extent of the colonic damage or the increase in MPO activity induced by TNBS. In conclusion, this study showed that i.p. administration of BPC-15 reduced TNBS-induced colonic damage in rats. PMID:7815358

Veljaca, M; Lesch, C A; Pllana, R; Sanchez, B; Chan, K; Guglietta, A



Vagus Nerve Stimulation Reduces Body Weight and Fat Mass in Rats  

PubMed Central

Among the manifold effects of vagus nerve stimulation (VNS) delivered as an add-on treatment to patients with drug-resistant epilepsy, a moderate loss of body weight has been observed in some individuals. We have now investigated this effect in rats. Exposure of rats to VNS for 4 weeks reduced feed conversion efficiency as well as body weight gain (by ?25%) and the amount of mesenteric adipose tissue (by ?45%) in comparison with those in sham-operated control animals. A pair-fed experiment showed that both lower dietary intake and increase energy expenditure independently contributed to the reduction of body weight and mesenteric adipose tissue. Moreover, VNS increased the level of non-esterified fatty acids in plasma and mesenteric adipose tissue by ?50 and 80%, respectively, without affecting that in the liver. In addition, VNS reduced the amounts of endocannabinoids and increased N-palmitoylethanolamide, an endogenous ligand of the transcription factor PPAR? (peroxisome proliferator–activated receptor ?) in mesenteric adipose tissue but not in the hypothalamus. These effects were accompanied by increased expression of the gene for brain-derived neurotrophic factor (BDNF) in the hypothalamus and up-regulation of the abundance of PPAR? in the liver. Our results suggest that the reduction in body fat induced by VNS in rats may result from the action of both central and peripheral mediators. The reduced feed conversion efficiency associated with VNS may be mediated by hypothalamic BDNF, down-regulation of endocannabinoid tone in mesenteric adipose tissue and a PPAR?-dependent increase in fatty acid oxidation in the liver, which in concerted action may account for the anorexic effect and increased energy expenditure. PMID:23028630

Banni, Sebastiano; Carta, Gianfranca; Murru, Elisabetta; Cordeddu, Lina; Giordano, Elena; Marrosu, Francesco; Puligheddu, Monica; Floris, Gabriele; Asuni, Gino Paolo; Cappai, Angela Letizia; Deriu, Silvia; Follesa, Paolo



Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus  

PubMed Central

BACKGROUND AND PURPOSE We evaluated the anti-emetic and anti-nausea properties of the acid precursor of ?9-tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), and determined its mechanism of action in these animal models. EXPERIMENTAL APPROACH We investigated the effect of THCA on lithium chloride- (LiCl) induced conditioned gaping (nausea-induced behaviour) to a flavour, and context (a model of anticipatory nausea) in rats, and on LiCl-induced vomiting in Suncus murinus. Furthermore, we investigated THCA's ability to induce hypothermia and suppress locomotion [rodent tasks to assess cannabinoid1 (CB1) receptor agonist-like activity], and measured plasma and brain THCA and THC levels. We also determined whether THCA's effect could be blocked by pretreatment with SR141716 (SR, a CB1 receptor antagonist). KEY RESULTS In rats, THCA (0.05 and/or 0.5 mg·kg?1) suppressed LiCl-induced conditioned gaping to a flavour and context; the latter effect blocked by the CB1 receptor antagonist, SR, but not by the 5-hydroxytryptamine-1A receptor antagonist, WAY100635. In S. murinus, THCA (0.05 and 0.5 mg·kg?1) reduced LiCl-induced vomiting, an effect that was reversed with SR. A comparatively low dose of THC (0.05 mg·kg?1) did not suppress conditioned gaping to a LiCl-paired flavour or context. THCA did not induce hypothermia or reduce locomotion, indicating non-CB1 agonist-like effects. THCA, but not THC was detected in plasma samples. CONCLUSIONS AND IMPLICATIONS THCA potently reduced conditioned gaping in rats and vomiting in S. murinus, effects that were blocked by SR. These data suggest that THCA may be a more potent alternative to THC in the treatment of nausea and vomiting. PMID:23889598

Rock, E M; Kopstick, R L; Limebeer, C L; Parker, L A



Cognitive decline is associated with reduced reelin expression in the entorhinal cortex of aged rats.  


Brain regions and neural circuits differ in their vulnerability to changes that occur during aging and in age-related neurodegenerative diseases. Among the areas that comprise the medial temporal lobe memory system, the layer II neurons of the entorhinal cortex, which form the perforant path input to the hippocampal formation, exhibit early alterations over the course of aging Reelin, a glycoprotein implicated in synaptic plasticity, is expressed by entorhinal cortical layer II neurons. Here, we report that an age-related reduction in reelin expression in the entorhinal cortex is associated with cognitive decline. Using immunohistochemistry and in situ hybridization, we observed decreases in the number of Reelin-immunoreactive cells and reelin messenger RNA expression in the lateral entorhinal cortex of aged rats that are cognitively impaired relative to young adults and aged rats with preserved cognitive abilities. The lateral entorhinal cortex of aged rats with cognitive impairment also exhibited changes in other molecular markers, including increased accumulation of phosphorylated tau and decreased synaptophysin immunoreactivity. Taken together, these findings suggest that reduced reelin expression, emanating from layer II entorhinal neurons, may contribute to network dysfunction that occurs during memory loss in aging. PMID:20538740

Stranahan, Alexis M; Haberman, Rebecca P; Gallagher, Michela



The edible brown seaweed Ecklonia cava reduces hypersensitivity in postoperative and neuropathic pain models in rats.  


The current study was designed to investigate whether edible brown seaweed Ecklonia cava extracts exhibits analgesic effects in plantar incision and spared nerve injury (SNI) rats. To evaluate pain-related behavior, we performed the mechanical withdrawal threshold (MWT) and thermal hypersensitivity tests measured by von Frey filaments and a hot/cold plate analgesia meter. Pain-related behavior was also determined through analysis of ultrasonic vocalization. The results of experiments showed MWT values of the group that was treated with E. cava extracts by 300 mg/kg significantly increased; on the contrary, number of ultrasonic distress vocalization of the treated group was reduced at 6 h and 24 h after plantar incision operation (62.8%, p < 0.05). Moreover, E. cava 300 mg/kg treated group increased the paw withdrawal latency in hot-and cold-plate tests in the plantar incision rats. After 15 days of continuous treatment with E. cava extracts at 300 mg/kg, the treated group showed significantly alleviated SNI-induced hypersensitivity response by MWT compared with the control group. In conclusion, these results suggest that E. cava extracts have potential analgesic effects in the case of postoperative pain and neuropathic pain in rats. PMID:24918539

Kim, Jae Goo; Lim, Dong Wook; Cho, Suengmok; Han, Daeseok; Kim, Yun Tai



A1 Noradrenergic Neurons Lesions Reduce Natriuresis and Hypertensive Responses to Hypernatremia in Rats  

PubMed Central

Noradrenergic neurons in the caudal ventrolateral medulla (CVLM; A1 group) contribute to cardiovascular regulation. The present study assessed whether specific lesions in the A1 group altered the cardiovascular responses that were evoked by hypertonic saline (HS) infusion in non-anesthetized rats. Male Wistar rats (280–340 g) received nanoinjections of antidopamine-?-hydroxylase-saporin (A1 lesion, 0.105 ng.nL?1) or free saporin (sham, 0.021 ng.nL?1) into their CVLMs. Two weeks later, the rats were anesthetized (2% halothane in O2) and their femoral artery and vein were catheterized and led to exit subcutaneously between the scapulae. On the following day, the animals were submitted to HS infusion (3 M NaCl, 1.8 ml • kg?1, b.wt., for longer than 1 min). In the sham-group (n?=?8), HS induced a sustained pressor response (?MAP: 35±3.6 and 11±1.8 mmHg, for 10 and 90 min after HS infusion, respectively; P<0.05 vs. baseline). Ten min after HS infusion, the pressor responses of the anti-D?H-saporin-treated rats (n?=?11)were significantly smaller(?MAP: 18±1.4 mmHg; P<0.05 vs. baseline and vs. sham group), and at 90 min, their blood pressures reached baseline values (2±1.6 mmHg). Compared to the sham group, the natriuresis that was induced by HS was reduced in the lesioned group 60 min after the challenge (196±5.5 mM vs. 262±7.6 mM, respectively; P<0.05). In addition, A1-lesioned rats excreted only 47% of their sodium 90 min after HS infusion, while sham animals excreted 80% of their sodium. Immunohistochemical analysis confirmed a substantial destruction of the A1 cell group in the CVLM of rats that had been nanoinjected withanti-D?H-saporin. These results suggest that medullary noradrenergic A1 neurons are involved in the excitatory neural pathway that regulates hypertensive and natriuretic responses to acute changes in the composition of body fluid. PMID:24039883

da Silva, Elaine Fernanda; Freiria-Oliveira, Andre Henrique; Custodio, Carlos Henrique Xavier; Ghedini, Paulo Cesar; Bataus, Luiz Artur Mendes; Colombari, Eduardo; de Castro, Carlos Henrique; Colugnati, Diego Basile; Rosa, Daniel Alves; Cravo, Sergio L. D.; Pedrino, Gustavo Rodrigues



A1 noradrenergic neurons lesions reduce natriuresis and hypertensive responses to hypernatremia in rats.  


Noradrenergic neurons in the caudal ventrolateral medulla (CVLM; A1 group) contribute to cardiovascular regulation. The present study assessed whether specific lesions in the A1 group altered the cardiovascular responses that were evoked by hypertonic saline (HS) infusion in non-anesthetized rats. Male Wistar rats (280-340 g) received nanoinjections of antidopamine-?-hydroxylase-saporin (A1 lesion, 0.105 ng.nL(-1)) or free saporin (sham, 0.021 ng.nL(-1)) into their CVLMs. Two weeks later, the rats were anesthetized (2% halothane in O2) and their femoral artery and vein were catheterized and led to exit subcutaneously between the scapulae. On the following day, the animals were submitted to HS infusion (3 M NaCl, 1.8 ml • kg(-1), b.wt., for longer than 1 min). In the sham-group (n?=?8), HS induced a sustained pressor response (?MAP: 35±3.6 and 11±1.8 mmHg, for 10 and 90 min after HS infusion, respectively; P<0.05 vs. baseline). Ten min after HS infusion, the pressor responses of the anti-D?H-saporin-treated rats (n?=?11)were significantly smaller(?MAP: 18±1.4 mmHg; P<0.05 vs. baseline and vs. sham group), and at 90 min, their blood pressures reached baseline values (2±1.6 mmHg). Compared to the sham group, the natriuresis that was induced by HS was reduced in the lesioned group 60 min after the challenge (196±5.5 mM vs. 262±7.6 mM, respectively; P<0.05). In addition, A1-lesioned rats excreted only 47% of their sodium 90 min after HS infusion, while sham animals excreted 80% of their sodium. Immunohistochemical analysis confirmed a substantial destruction of the A1 cell group in the CVLM of rats that had been nanoinjected withanti-D?H-saporin. These results suggest that medullary noradrenergic A1 neurons are involved in the excitatory neural pathway that regulates hypertensive and natriuretic responses to acute changes in the composition of body fluid. PMID:24039883

da Silva, Elaine Fernanda; Freiria-Oliveira, André Henrique; Custódio, Carlos Henrique Xavier; Ghedini, Paulo César; Bataus, Luiz Artur Mendes; Colombari, Eduardo; de Castro, Carlos Henrique; Colugnati, Diego Basile; Rosa, Daniel Alves; Cravo, Sergio L D; Pedrino, Gustavo Rodrigues



Reduced glutathione protects cultured gastric mucosal cells from suckling rats against acid.  


We examined the role of reduced glutathione as a defense mechanism against acid-induced gastric mucosal cell damage in vitro. Cellular stores of reduced glutathione were depleted by reaction with diethyl maleate (DEM) or 1-chloro-2,4-dinitrobenzene (CDNB) and increased by reaction with L-cysteine. Depletion of cellular glutathione by reaction with DEM or CDNB potentiated gastric mucosal cell lysis by acid. Increase of cellular glutathione by L-cysteine decreased cell lysis by acid. Altering the cellular reduced-to-oxidized glutathione ratio by tert-butyl hydroperoxide or diamide increased cellular susceptibility to acid. Reduced glutathione is essential for glutathione peroxidase to catalyze hydrogen peroxide. We further studied whether oxygen free radicals were involved in the pathogenesis of acid-induced gastric mucosal injury in vitro. Neither superoxide dismutase, catalase, nor dimethyl sulfoxide decreased acid-induced gastric mucosal cell damage. We conclude that reduced glutathione plays an important role as a defense mechanism against acid-induced injury in cultured rat gastric mucosal cells. Production of oxygen radical in response to acid exposure may occur intracellularly, since exogenous oxygen radical scavengers, which do not gain access to the interior of cells, had no protective effect. Reduced glutathione might protect gastric mucosal cells by mechanisms other than the elimination of oxygen free radicals. PMID:1858888

Mutoh, H; Ota, S; Hiraishi, H; Ivey, K J; Terano, A; Sugimoto, T



Resistance Exercise Restores Endothelial Function and Reduces Blood Pressure in Type 1 Diabetic Rats  

PubMed Central

Background Resistance exercise effects on cardiovascular parameters are not consistent. Objectives The effects of resistance exercise on changes in blood glucose, blood pressure and vascular reactivity were evaluated in diabetic rats. Methods Wistar rats were divided into three groups: control group (n = 8); sedentary diabetic (n = 8); and trained diabetic (n = 8). Resistance exercise was carried out in a squat device for rats and consisted of three sets of ten repetitions with an intensity of 50%, three times per week, for eight weeks. Changes in vascular reactivity were evaluated in superior mesenteric artery rings. Results A significant reduction in the maximum response of acetylcholine-induced relaxation was observed in the sedentary diabetic group (78.1 ± 2%) and an increase in the trained diabetic group (95 ± 3%) without changing potency. In the presence of NG-nitro-L-arginine methyl ester, the acetylcholine-induced relaxation was significantly reduced in the control and trained diabetic groups, but not in the sedentary diabetic group. Furthermore, a significant increase (p < 0.05) in mean arterial blood pressure was observed in the sedentary diabetic group (104.9 ± 5 to 126.7 ± 5 mmHg) as compared to that in the control group. However, the trained diabetic group showed a significant decrease (p < 0.05) in the mean arterial blood pressure levels (126.7 ± 5 to 105.1 ± 4 mmHg) as compared to the sedentary diabetic group. Conclusions Resistance exercise could restore endothelial function and prevent an increase in arterial blood pressure in type 1 diabetic rats. PMID:25120082

Mota, Marcelo Mendonca; da Silva, Tharciano Luiz Teixeira Braga; Fontes, Milene Tavares; Barreto, Andre Sales; Araujo, Joao Eliakim dos Santos; de Oliveira, Antonio Cesar Cabral; Wichi, Rogerio Brandao; Santos, Marcio Roberto Viana



Systemic Bisperoxovanadium Activates Akt/mTOR, Reduces Autophagy, and Enhances Recovery following Cervical Spinal Cord Injury  

PubMed Central

Secondary damage following primary spinal cord injury extends pathology beyond the site of initial trauma, and effective management is imperative for maximizing anatomical and functional recovery. Bisperoxovanadium compounds have proven neuroprotective effects in several central nervous system injury/disease models, however, no mechanism has been linked to such neuroprotection from bisperoxovanadium treatment following spinal trauma. The goal of this study was to assess acute bisperoxovanadium treatment effects on neuroprotection and functional recovery following cervical unilateral contusive spinal cord injury, and investigate a potential mechanism of the compound's action. Two experimental groups of rats were established to 1) assess twice-daily 7 day treatment of the compound, potassium bisperoxo (picolinato) vanadium, on long-term recovery of skilled forelimb activity using a novel food manipulation test, and neuroprotection 6 weeks following injury and 2) elucidate an acute mechanistic link for the action of the drug post-injury. Immunofluorescence and Western blotting were performed to assess cellular signaling 1 day following SCI, and histochemistry and forelimb functional analysis were utilized to assess neuroprotection and recovery 6 weeks after injury. Bisperoxovanadium promoted significant neuroprotection through reduced motorneuron death, increased tissue sparing, and minimized cavity formation in rats. Enhanced forelimb functional ability during a treat-eating assessment was also observed. Additionally, bisperoxovanadium significantly enhanced downstream Akt and mammalian target of rapamycin signaling and reduced autophagic activity, suggesting inhibition of the phosphatase and tensin homologue deleted on chromosome ten as a potential mechanism of bisperoxovanadium action following traumatic spinal cord injury. Overall, this study demonstrates the efficacy of a clinically applicable pharmacological therapy for rapid initiation of neuroprotection post-spinal cord injury, and sheds light on the signaling involved in its action. PMID:22253859

Walker, Chandler L.; Walker, Melissa J.; Liu, Nai-Kui; Risberg, Emelie C.; Gao, Xiang; Chen, Jinhui; Xu, Xiao-Ming



Saffron Reduced Toxic Effects of its Constituent, Safranal, in Acute and Subacute Toxicities in Rats  

PubMed Central

Background: Saffron and its constituents are widely used around the world as a spice and medicinal plant. Different constituents in medicinal herbs are thought to have the potential to induce useful and/or adverse effects. So, efforts have been made to find the best and most valuable tools to reduce their adverse effects. Objectives: According to Iranian traditional medicine (ITM), it is believed that administration of whole herbs exhibits more activity and fewer side effects than isolated constituents. Since toxicological studies have indicated that safranal is more toxic than other active components in saffron stigma, thus this study was undertaken to evaluate the effect of co-administration of saffron extract and safranal in acute and sub-acute toxicities in rats. Materials and Methods: In acute toxicity, rats received safranal (1.2 mL/kg, IP) plus saffron aqueous extract (25-100 mg/kg, IP). One and four days after the treatment, percentage of mortality was assessed. In subacute toxicity, rats were randomly divided into six groups. Group 1) safranal (0.2 mL/kg, IP), Groups 2, 3 and 4) safranal plus saffron aqueous extract (5, 10 and 20 mg/kg, IP) Groups 5 and 6) Paraffin and normal saline, as solvents of safranal and saffron aqueous extract, respectively. Treatments were continued for 21 days. For sub-acute toxicity, the percentages of lethality as well as some biochemical parameters were evaluated. Results: Our results showed that four days co-treatment of safranal and saffron significantly reduced mortality, so that the effect was more obvious in lower doses. Sub-acute toxicity studies showed that saffron could increase survival in rats so that no mortality was observed at dose of 10 mg/kg. Our data also indicated that the levels of triglyceride, BUN and ALT significantly increased after sub-acute interaperitoneal (IP) administration of safranal (0.2 mL/kg/day) and co-treatment of saffron aqueous extract (5 and 10 mg/kg) plus safranal significantly improved all toxic effects of safranal on biochemical parameters. Conclusions: The co-administration of saffron aqueous extract and safranal reduced toxic effects of safranal in acute and sub-acute toxicities. PMID:24644432

Ziaee, Toktam; Razavi, Bibi Marjan; Hosseinzadeh, Hossein



Amlodipine Reduces Inflammation despite Promoting Albuminuria in the Streptozotocin-Induced Diabetic Rat  

PubMed Central

Amlodipine reduces blood pressure; however, its effect in the diabetic kidney irrespective of its blood pressure-lowering effects is unclear. This study examined the effects of amlodipine (0, 5, 10 and 20 mg/kg; DA0, DA5, DA10 and DA20, respectively) for 12 weeks on renal functional and structural changes in the streptozotocin-induced diabetic rat, a nonhypertensive model of diabetes-associated hyperfiltration. Compared with nondiabetic rats, diabetes (D) was associated with increased urine albumin excretion (UAE, 12.6 ± 3.40 vs. 3.73 ± 1.14 mg/day), glomerular filtration rate (2.17 ± 0.09 vs. 1.64 ± 0.12 ml/min/g kidney weight), glomerulosclerosis (0.21 ± 0.03 vs. 0.05 ± 0.01 AU) and infiltration of inflammatory cells (18.5 ± 2.78 vs. 6.92 ± 0.70 cells/cm2), but did not affect mean arterial pressure (MAP, 110 ± 4.70 vs. 109 ± 5.33 mm Hg). While DA20 abolished glomerular hyperfiltration (1.49 ± 0.05 ml/min/g kidney weight) and inflammatory cell abundance (6.0 ± 0.79 cells/cm2), it exacerbated UAE (43.5 ± 8.49 mg/day) and increased MAP (132 ± 3.76 mm Hg), but had no effect on renal pathology. These data suggest that amlodipine reduces renal inflammation and abolished glomerular hyperfiltration, but increases blood pressure and exacerbates albuminuria in the rat model of normotensive diabetic kidney disease. We conclude that amlodipine may have limited renoprotective effects in the face of hyperfiltration and absence of elevated blood pressure. PMID:22811694

Flynn, Elizabeth R.; Marbury, David C.; Sawyer, R. Taylor; Lee, Jonathan; Teutsch, Christine; Kauser, Katalin; Maric-Bilkan, Christine



Alcohol Binge Drinking during Adolescence or Dependence during Adulthood Reduces Prefrontal Myelin in Male Rats.  


Teen binge drinking is associated with low frontal white matter integrity and increased risk of alcoholism in adulthood. This neuropathology may result from alcohol exposure or reflect a pre-existing condition in people prone to addiction. Here we used rodent models with documented clinical relevance to adolescent binge drinking and alcoholism in humans to test whether alcohol damages myelinated axons of the prefrontal cortex. In Experiment 1, outbred male Wistar rats self-administered sweetened alcohol or sweetened water intermittently for 2 weeks during early adolescence. In adulthood, drinking behavior was tested under nondependent conditions or after dependence induced by 1 month of alcohol vapor intoxication/withdrawal cycles, and prefrontal myelin was examined 1 month into abstinence. Adolescent binge drinking or adult dependence induction reduced the size of the anterior branches of the corpus callosum, i.e., forceps minor (CCFM), and this neuropathology correlated with higher relapse-like drinking in adulthood. Degraded myelin basic protein in the gray matter medial to the CCFM of binge rats indicated myelin was damaged on axons in the mPFC. In follow-up studies we found that binge drinking reduced myelin density in the mPFC in adolescent rats (Experiment 2) and heavier drinking predicted worse performance on the T-maze working memory task in adulthood (Experiment 3). These findings establish a causal role of voluntary alcohol on myelin and give insight into specific prefrontal axons that are both sensitive to alcohol and could contribute to the behavioral and cognitive impairments associated with early onset drinking and alcoholism. PMID:25355229

Vargas, Wanette M; Bengston, Lynn; Gilpin, Nicholas W; Whitcomb, Brian W; Richardson, Heather N



Yellow pea fiber improves glycemia and reduces Clostridium leptum in diet-induced obese rats.  


Numerous studies have demonstrated the impact of functional fibers on gut microbiota and metabolic health, but some less well-studied fibers and/or fractions of foods known to be high in fiber still warrant examination. The aim of this study was to assess the effect of yellow pea-derived fractions varying in fiber and protein content on metabolic parameters and gut microbiota in diet-induced obese rats. We hypothesized that the yellow pea fiber (PF) fraction would improve glycemia and alter gut microbiota. Rats were randomized to 1 of 5 isoenergetic dietary treatments for 6 weeks: (1) control; (2) oligofructose (OFS); (3) yellow PF; (4) yellow pea flour (PFL); or (5) yellow pea starch (PS). Glycemia, plasma gut hormones, body composition, hepatic triglyceride content, gut microbiota, and messenger RNA expression of genes related to hepatic fat metabolism were examined. Pea flour attenuated weight gain compared with control, PF, and PS (P < .05). Pea flour, PS, and OFS had significantly lower final percent body fat compared with control. Oligofructose but not the pea fraction diets reduced food intake compared with control (P < .05). Pea fiber resulted in lower fasting glucose and glucose area under the curve compared with control. Changes in gut microbiota were fraction specific and included a decrease in Firmicutes (percent) for OFS, PF, and PFL compared with control (P < .05). The Firmicutes/Bacteroidetes ratio was reduced with OFS, PF, and PFL when compared with PS (P < .05). Taken together, this work suggests that yellow pea-derived fractions are able to distinctly modulate metabolic parameters and gut microbiota in obese rats. PMID:25156790

Eslinger, Amanda J; Eller, Lindsay K; Reimer, Raylene A



Studies on cigarette smoke induced oxidative DNA damage and reduced spermatogenesis in rats.  


In the present work, the effect of exposure to cigarette smoke on male fertility in rats, as characterized by changes in the relative weight of sex organs, epididymal sperm count, activity of marker enzymes and DNA damage was evaluated. Exposure of rats to cigarette smoke caused a gradual decrease in total body weight gain and relative weight of the epididymis and seminal vesicles by 30 and 40% respectively. Epididymal sperm count was reduced significantly by 25% (P 0.05) after 2 weeks and by 41% (P 0.001) after 4 weeks of exposure. Exposure to cigarette smoke had reduced the activity of sorbitol dehydogenase by 18% (P < or = 0.05) and increased the activity of lactate dehydrogenase by 28% (P < or = 0.05). The changes in both key enzymes were significant, which reflected the inhibitory effect of cigarette smoke on spermatogenesis and sperm maturation. The toxic effect of exposure could be explained partially due to induction of DNA damage and oxidative stress as shown by the significant increase in serum 8-hydroxy-2'-deoxyguanosine from 22.83 to 37.33 ng ml(-1) blood. PMID:25204071

Abdul-Ghani, Rula; Qazzaz, Munir; Dabdoub, Nabil; Muhammad, Rateb; Abdul-Ghani, A S



A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model  

PubMed Central

Preeclampsia is defined as new-onset hypertension with proteinuria after 20 wk gestation and is hypothesized to be due to shallow trophoblast invasion in the spiral arteries thus resulting in progressive placental ischemia as the fetus grows. Many animal models have been developed that mimic changes in maternal circulation or immune function associated with preeclampsia. The model of reduced uterine perfusion pressure in pregnant rats closely mimics the hypertension, immune system abnormalities, systemic and renal vasoconstriction, and oxidative stress in the mother, and intrauterine growth restriction found in the offspring. The model has been successfully used in many species; however, rat and primate are the most consistent in comparison of characteristics with human preeclampsia. The model suffers, however, from lack of the ability to study the mechanisms responsible for abnormal placentation that ultimately leads to placental ischemia. Despite this limitation, the model is excellent for studying the consequences of reduced uterine blood flow as it mimics many of the salient features of preeclampsia during the last weeks of gestation in humans. This review discusses these features. PMID:22523250

Li, Jing; LaMarca, Babbette



Red yeast rice repairs kidney damage and reduces inflammatory transcription factors in rat models of hyperlipidemia  

PubMed Central

Xuezhikang (XZK), an extract of red yeast rice, has been widely used for the management of hyperlipidemia and coronary heart disease (CHD); however, the effects of XZK treatment on kidney injury have not yet been fully identified. The aim of the current study was to evaluate the effects of XZK on the kidneys and investigate the related mechanisms in a rat model of hyperlipidemia. Thus, the effect on inflammatory transcription factors and kidney damage was investigated with in vitro and in vivo experiments on hyperlipidemic rats following XZK treatment. The results revealed that the plasma levels of total cholesterol (TC), triglycerides (TG) and low-density lipoprotein-cholesterol (LDL-C) were significantly decreased, while the levels of high-density lipoprotein-cholesterol (HDL-C) were significantly upregulated in the XZK treatment group, as compared with those in the hyperlipidemia group (P<0.05). In addition, the results demonstrated that XZK was able to repair the kidney damage caused by hyperlipidemia. Furthermore, the expression levels of the inflammatory transcription factors, tumor necrosis factor-? and interleukin-6, were shown to be reduced in the XZK group when compared with the hyperlipidemia group. In summary, XZK reduces kidney injury, downregulates the levels of TG, TC and LDL-C, as well as the expression levels of inflammatory transcription factors, and upregulates HDL-C. These results further the understanding of the molecular pathogenic mechanisms underlying hyperlipidemia and aid the development of XZK as an effective therapeutic agent for hyperlipidemia. PMID:25371725




Goat milk fat naturally enriched with conjugated linoleic acid increased lipoproteins and reduced triacylglycerol in rats.  


Goat milk is source of different lipids, including conjugated linoleic acid (CLA). CLA reduces body fat and protect against cardiovascular diseases. In the present study fat from goat milk naturally enriched with CLA was used. Male Wistar rats were divided into three groups that received during a 10 week diet with different lipid sources: soybean oil (CON), coconut oil (CO) and goat milk fat naturally enriched with CLA (GM-CLA). We evaluated the effects of a GM-CLA on biochemistry parameters--high density lipoprotein (HDL), triacylglycerol (TAG), TAG/HDL ratio, total cholesterol and glucose, body weight and histopathological aspects of the intestine and liver. GM-CLA increased body weight from the second to the fifth week of the experiment compared to CON. Feed intake differed between the CON group and GM-CLA early in the first to third week of the experiments and later between the ninth and tenth week. The CLA-diet group showed increased levels of HDL, reduced levels of TAG and TAG/HDL ratio and no effect on LDL, but enhanced total cholesterol. Serum glucose of the GM-CLA group showed no difference from the control group. Thus, a GM-CLA diet promoted growth in young rats and acted as protector of cardiovascular function, but further studies are still needed to clarify these effects. PMID:24662092

Rodrigues, Raphaela; Soares, Juliana; Garcia, Hugo; Nascimento, Claudenice; Medeiros, Maria; Bomfim, Marco; Medeiros, Maria Carmo; Queiroga, Rita



Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism  

SciTech Connect

Glomerular angiotensin II receptors are reduced in number in early diabetes mellitus, which may contribute to hyperfiltration and glomerular injury. The time course and role of the renin-angiotensin-aldosterone system in the pathogenesis of the receptor abnormality were studied in male Sprague-Dawley rats made diabetic with streptozotocin (65 mg, iv). Glomerular angiotensin II receptors were measured by Scatchard analysis; insulin, renin activity, angiotensin II, and aldosterone were measured by RIA. Diabetes mellitus was documented at 24 h by a rise in plasma glucose (vehicle-injected control, 133 +/- 4; diabetic, 482 +/- 22 mg/dl and a fall in plasma insulin (control, 53.1 +/- 5.7; diabetic, 35.6 +/- 4.0 microIU/ml. At 24 h glomerular angiotensin II receptor density was decreased by 26.5% in diabetic rats (control, 75.5 +/- 9.6 X 10(6); diabetic, 55.5 +/- 8.3 X 10(6) receptors/glomerulus. Receptor occupancy could not explain the defect, because there was reduced binding in diabetic glomeruli after pretreatment with 3 M MgCl/sub 2/, a maneuver that caused dissociation of previously bound hormone. There was a progressive return of the receptor density toward normal over the 60 days following induction of diabetes, with diabetic glomeruli measuring 22.7%, 14.8%, and 3.7% fewer receptors than age-matched controls at 11 days, 1 month, and 2 months, respectively.

Wilkes, B.M.



Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis  

PubMed Central

Background Sepsis-induced organ failure is the major cause of death in critical care units, and is characterized by a massive dysregulated inflammatory response and oxidative stress. We investigated the effects of treatment with antioxidants that protect mitochondria (MitoQ, MitoE, or melatonin) in a rat model of lipopolysaccharide (LPS) plus peptidoglycan (PepG)-induced acute sepsis, characterized by inflammation, mitochondrial dysfunction and early organ damage. Methods Anaesthetized and ventilated rats received an i.v. bolus of LPS and PepG followed by an i.v. infusion of MitoQ, MitoE, melatonin, or saline for 5 h. Organs and blood were then removed for determination of mitochondrial and organ function, oxidative stress, and key cytokines. Results MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P<0.002), reduced oxidative stress (P<0.02), and decreased interleukin-6 levels (P=0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P=0.02) and creatinine concentrations (P<0.0001). Conclusions Antioxidants that act preferentially in mitochondria reduce mitochondrial damage and organ dysfunction and decrease inflammatory responses in a rat model of acute sepsis. PMID:23381720

Lowes, D. A.; Webster, N. R.; Murphy, M. P.; Galley, H. F.



Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes.  


Islet-level oxidative stress has been proposed as a trigger for type 1 diabetes (T1D), and release of cytokines by infiltrating immune cells further elevates reactive oxygen species (ROS), exacerbating ? cell duress. To identify genes/mechanisms involved with diabetogenesis at the ? cell level, gene expression profiling and targeted follow-up studies were used to investigate islet activity in the biobreeding (BB) rat. Forty-day-old spontaneously diabetic lymphopenic BB DRlyp/lyp rats (before T cell insulitis) as well as nondiabetic BB DR+/+ rats, nondiabetic but lymphopenic F344lyp/lyp rats, and healthy Fischer (F344) rats were examined. Gene expression profiles of BB rat islets were highly distinct from F344 islets and under-expressed numerous genes involved in ROS metabolism, including glutathione S-transferase (GST) family members (Gstm2, Gstm4, Gstm7, Gstt1, Gstp1, and Gstk1), superoxide dismutases (Sod2 and Sod3), peroxidases, and peroxiredoxins. This pattern of under-expression was not observed in brain, liver, or muscle. Compared with F344 rats, BB rat pancreata exhibited lower GST protein levels, while plasma GST activity was found significantly lower in BB rats. Systemic administration of the antioxidant N-acetyl cysteine to DRlyp/lyp rats altered abundances of peripheral eosinophils, reduced severity of insulitis, and significantly delayed but did not prevent diabetes onset. We find evidence of ? cell dysfunction in BB rats independent of T1D progression, which includes lower expression of genes related to antioxidative defense mechanisms during the pre-onset period that may contribute to overall T1D susceptibility. PMID:23111281

Bogdani, Marika; Henschel, Angela M; Kansra, Sanjay; Fuller, Jessica M; Geoffrey, Rhonda; Jia, Shuang; Kaldunski, Mary L; Pavletich, Scott; Prosser, Simon; Chen, Yi-Guang; Lernmark, Ake; Hessner, Martin J



Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin  

Microsoft Academic Search

Recently, in rat abdominal aorta terminoterminal-anastomosis the stable gastric pentadecapeptide BPC 157 prevents obstructive thrombus formation and rapidly destroys already formed obstructive thrombus. Also, BPC 157 wound healing may signify the clot as conductive matrix or “scaffold” to speed up wound healing process, and decrease bleeding. Here, in rats, BPC 157 (10?g\\/kg, 10ng\\/kg) improved always reduced bleeding time and amount

Mirjana Stupnisek; Sandra Franjic; Domagoj Drmic; Masa Hrelec; Danijela Kolenc; Bozo Radic; Davor Bojic; Aleksandar Vcev; Sven Seiwerth; Predrag Sikiric


Histological analysis of forelimb regeneration in the California newt Taricha granulosa.  


The regenerative ability of the forelimbs of the California rough-skinned newt, Taricha granulosa was determined and compared to the same ability of the adult Mexican axolotl, Ambystoma mexicanum. Forelimbs were amputated distally at the wrist and limbs removed at 1, 2, 3, 4, 5 and 6 weeks post-amputation were examined by histological analysis. Since vitamin A and its derivatives cause extreme changes in pattern formation in the regenerating amphibian limb, we decided to study the ability of retinoic acid to proximalize the distal amputation. Animals injected with RA displayed apparent proximalization of the distal amputation. PMID:1525332

Washabaugh, C H; Tsonis, P A



Ultra-low-dose naltrexone reduces the rewarding potency of oxycodone and relapse vulnerability in rats.  


Ultra-low-dose opioid antagonists have been shown to enhance opioid analgesia and alleviate opioid tolerance and dependence. Our present studies in male Sprague-Dawley rats assessed the abuse potential of oxycodone+ultra-low-dose naltrexone (NTX) versus oxycodone alone. The lowest NTX dose (1 pg/kg/infusion), but not slightly higher doses (10 and 100 pg/kg/infusion), enhanced oxycodone (0.1 mg/kg/infusion) intravenous self-administration, suggesting a reduced rewarding potency per infusion. During tests of reinstatement performed in extinction conditions, co-self-administration of any of these three NTX doses significantly reduced drug-seeking precipitated by priming injections of oxycodone (0.25 mg/kg, s.c.), a drug-conditioned cue, or foot-shock stress. During self-administration on a progressive-ratio schedule, animals self-administering oxycodone (0.1 mg/kg/infusion)+NTX (1 pg/kg/infusion) reached a "break-point" sooner and showed a trend toward less responding compared to rats self-administering oxycodone alone (0.1 mg/kg/infusion). In the final experiment, the addition of ultra-low-dose NTX (10 pg/kg, s.c.) enhanced the acute stimulatory effect of oxycodone (1 mg/kg, s.c.), as well as locomotor sensitization produced by repeated oxycodone administration (7 x 1 mg/kg, s.c.). In summary, this work shows that ultra-low-dose NTX co-treatment augments the locomotor effects of oxycodone as it enhances opioid analgesia, but reduces oxycodone's rewarding potency and subsequent vulnerability to relapse. PMID:16182352

Leri, Francesco; Burns, Lindsay H



Extract of Adenanthera pavonina L. seed reduces development of diabetic nephropathy in streptozotocin-induced diabetic rats  

PubMed Central

Objective: The aim of the present study was to investigate the renal protective effect of Adenanthera pavonina (A. pavonina) seed aqueous extract (APSAE), in streptozotocin (STZ)-induced diabetic rats. Materials and Methods: The renal protective effect of A. pavonina seed aqueous extract (APSAE) was studied in STZ-induced diabetic rats. APSAE (50, 100 and 200 mg/kg per day) was given daily to diabetic rats for 13 weeks. Blood glucose, serum parameters such as albumin, creatinine, total protein, urea, lipid profile, glycated haemoglobin (HbA1c), and urine parameters such as urine protein and albumin were examined. Kidney histopathology was also done. Results: After 13 weeks of treatment, in STZ-induced diabetic rats, severe hyperglycemia was developed, with marked increase in proteinuria and albuminuria. However, APSAE treatment significantly reduced proteinuria, albuminuria, lipid levels, and HbA1c deposition in diabetic rats. Conclusion: These results suggested that APSAE has reduced development of diabetic nephropathy in streptozotocin-induced diabetic rats and could have beneficial effect in reducing the progression of diabetic nephropathy. PMID:25050253

Pandhare, Ramdas; Sangameswaran, Balakrishnan



Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-?  

PubMed Central

Background Tumor necrosis factor-alpha (TNF-?) is elevated early in injured brain after traumatic brain injury (TBI), in humans and in animals. Etanercept (a TNF-? antagonist with anti-inflammatory effects) attenuates TBI in rats by reducing both microglial and astrocytic activation and increased serum levels of TNF-?. However, it is not known whether etanercept improves outcomes of TBI by attenuating microglia-associated, astrocytes-associated, and/or neurons-associated TNF-? expression in ischemic brain. A well clinically relevant rat model, where a lateral fluid percussion is combined with systemic administration of etanercept immediately after TBI, was used. The neurological severity score and motor function was measured on all rats preinjury and on day 3 after etanercept administration. At the same time, the neuronal and glial production of TNF-? was measured by Immunofluorescence staining. In addition, TNF? contents of ischemic cerebral homogenates was measured using commercial enzyme-linked immunosorbent assay kits. Results In addition to inducing brain ischemia as well as neurological and motor deficits, TBI caused significantly higher numbers of microglia-TNF-? double positive cells, but not neurons-TNF-? or astrocytes-TNF-? double positive cells in the injured brain areas than did the sham operated controls, when evaluated 3 days after TBI. The TBI-induced cerebral ischemia, neurological motor deficits, and increased numbers of microglia-TNF-? double positive cells and increased TNF-? levels in the injured brain were all significantly attenuated by etanercept therapy. Conclusion This finding indicates that early microglia overproduction of TNF-? in the injured brain region after TBI contributes to cerebral ischemia and neurological motor deficits, which can be attenuated by etanercept therapy. Studies in this model could provide insight into the mechanisms underlying neurological motor disturbance in brain-injured patients. PMID:23496862



Indomethacin administered early in the postnatal period results in reduced glomerular number in the adult rat.  


Indomethacin and ibuprofen are administered to close a patent ductus arteriosus (PDA) during active glomerulogenesis. Light and electron microscopic glomerular changes with no change in glomerular number were seen following indomethacin and ibuprofen treatment during glomerulogenesis at 14 days after birth in a neonatal rat model. This present study aimed to determine whether longstanding renal structural changes are present at 30 days and 6 mo (equivalent to human adulthood). Rat pups were administered indomethacin or ibuprofen antenatally on days 18-20 (0.5 mg·kg(-1)·dose(-1) indomethacin; 10 mg·kg(-1)·dose(-1) ibuprofen) or postnatally intraperitoneally from day 1 to 3 or day 1 to 5 (0.2 mg·kg(-1)·dose(-1) indomethacin; 10 mg·kg(-1)·dose(-1) ibuprofen). Control groups received no treatment or normal saline intraperitoneally. Pups were killed at 30 days of age and 6 mo of age. Tissue blocks from right kidneys were prepared for light and electron microscopic examination, while total glomerular number was determined in left kidneys using unbiased stereology. Eight pups were included in each group from 14 maternal rats. At 30 days and 6 mo, there were persistent electron microscopy abnormalities of the glomerular basement membrane in those receiving postnatal indomethacin and ibuprofen. There were no significant light microscopy findings at 30 days or 6 mo. At 6 mo, there were significantly fewer glomeruli in those receiving postnatal indomethacin but not ibuprofen (P = 0.003). In conclusion, indomethacin administered during glomerulogenesis appears to reduce the number of glomeruli in adulthood. Alternative options for closing a PDA should be considered including ibuprofen as well as emerging therapies such as paracetamol. PMID:25186294

Kent, A L; Koina, M E; Gubhaju, L; Cullen-McEwen, L A; Bertram, J F; Lynnhtun, J; Shadbolt, B; Falk, M C; Dahlstrom, J E



Preconditioning somatothermal stimulation on Qimen (LR14) reduces hepatic ischemia/reperfusion injury in rats  

PubMed Central

Background In human beings or animals, ischemia/reperfusion (I/R) injury of the liver may occur in many clinical conditions, such as circulating shock, liver transplantation and surgery and several other pathological conditions. I/R injury has a complex pathophysiology resulting from a number of contributing factors. Therefore, it is difficult to achieve effective treatment or protection by individually targeting the mediators. This study aimed at studying the effects of local somatothermal stimulation preconditioning on the right Qimen (LR14) on hepatic I/R injury in rats. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups. The rats were preconditioned with thermal tolerance study, which included one dose of local somatothermal stimulation (LSTS) on right Qimen (LR14) at an interval of 12 h, followed by hepatic ischemia for 60 min and then reperfusion for 60 min. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) have been used to assess the liver functions, and liver tissues were taken for the measurements such as malondialdehyde (MDA), glutathione (GSH), catalase (CAT), superoxidase dismutase (SOD), and myeloperoxidase (MPO). Results The results show that the plasma ALT and AST activities were higher in the I/R group than in the control group. In addition, the plasma ALT and AST activities decreased in the groups that received LSTS. The hepatic SOD levels reduced significantly by I/R injury. Moreover, the hepatic MPO activity significantly increased by I/R injury while it decreased in the groups given LSTS. Conclusions Our findings show that LSTS provides a protective effects on the liver from the I/R injury. Therefore, LSTS might offer an easy and inexpensive intervention for patients who have suffered from I/R of the liver especially in the process of hepatotomy and hepatic transplantation. PMID:24417801



Glycyrrhizinate reduces portal hypertension in isolated perfused rat livers with chronic hepatitis  

PubMed Central

AIM: To investigate the effects of diammonium glycyrrhizinate (Gly) on portal hypertension (PHT) in isolated portal perfused rat liver (IPPRL) with carbon tetrachloride (CCl4)-induced chronic hepatitis. METHODS: PHT model was replicated with CCl4 in rats for 84 d. Model was identified by measuring the ascetic amounts, hepatic function, portal pressure in vivo, splenic index, and pathological alterations. Inducible nitric oxide synthase (iNOS) in liver was assessed by immunohistochemistry. IPPRLs were performed at d0, d28, d56, and d84. After phenylephrine-induced constriction, Gly was geometrically used to reduce PHT. Gly action was expressed as median effective concentration (EC50) and area under the curve (AUC). Underlying mechanism was exploited by linear correlation between AUC values of Gly and existed iNOS in portal triads. RESULTS: PHT model was confirmed with ascites, splenomegaly, serum biomarkers of hepatic injury, and elevated portal pressure. Pathological findings had shown normal hepatic structure at d0, degenerations at d28, fibrosis at d56, cirrhosis at d84 in PHT rats. Pseudo lobule ratios decreased and collagen ratios increased progressively along with PHT development. Gly does dose-dependently reduce PHT in IPPRLs with CCl4-induced chronic hepatitis. Gly potencies were increased gradually along with PHT development, characterized with its EC50 at 2.80 × 10-10, 3.03 × 10-11, 3.77 × 10-11 and 4.65×10-11 mol/L at d0, d28, d56 and d84, respectively. Existed iNOS was located at hepatocyte at d0, stellate cells at d28, stellate cells and macrophages at d56, and macrophages in portal triads at d84. Macrophages infiltrated more into portal triads and expressed more iNOS along with PHT development. AUC values of Gly were positively correlated with existed iNOS levels in portal triads. CONCLUSION: Gly reduces indirectly PHT in IPPRL with CCl4-induced chronic hepatitis. The underlying mechanisms may relate to rescue NO bioavailability from macrophage-derived peroxynitrite in portal triads. PMID:24106408

Zhao, Xin; Deng, Bo; Xu, Xue-Yan; Yang, Shi-Jun; Zhang, Tao; Song, Yi-Jun; Liu, Xiao-Ting; Wang, Yue-Qi; Cai, Da-Yong



A Novel Chemically Modified Curcumin Reduces Severity of Experimental Periodontal Disease in Rats: Initial Observations  

PubMed Central

Tetracycline-based matrix metalloproteinase- (MMP-) inhibitors are currently approved for two inflammatory diseases, periodontitis and rosacea. The current study addresses the therapeutic potential of a novel pleiotropic MMP-inhibitor not based on an antibiotic. To induce experimental periodontitis, endotoxin (LPS) was repeatedly injected into the gingiva of rats on one side of the maxilla; the contralateral (control) side received saline injections. Two groups of rats were treated by daily oral intubation with a chemically modified curcumin, CMC 2.24, for two weeks; the control groups received vehicle alone. After sacrifice, gingiva, blood, and maxilla were collected, the jaws were defleshed, and periodontal (alveolar) bone loss was quantified morphometrically and by ?-CT scan. The gingivae were pooled per experimental group, extracted, and analyzed for MMPs (gelatin zymography; western blot) and for cytokines (e.g., IL-1?; ELISA); serum and plasma samples were analyzed for cytokines and MMP-8. The LPS-induced pathologically excessive bone loss was reduced to normal levels based on either morphometric (P = 0.003) or ?-CT (P = 0.008) analysis. A similar response was seen for MMPs and cytokines in the gingiva and blood. This initial study, on a novel triketonic zinc-binding CMC, indicates potential efficacy on inflammatory mediators and alveolar bone loss in experimental periodontitis and warrants future therapeutic and pharmacokinetic investigations. PMID:25104884

Elburki, Muna S.; Rossa, Carlos; Guimaraes, Morgana R.; Goodenough, Mark; Lee, Hsi-Ming; Curylofo, Fabiana A.; Zhang, Yu; Johnson, Francis; Golub, Lorne M.



SDF-1? in Glycan Nanoparticles Exhibits Full Activity and Reduces Pulmonary Hypertension in Rats  

PubMed Central

In order to establish a homing signal in the lung to recruit circulating stem cells for tissue repair, we formulated a nanoparticle, SDF-1? NP, by complexing SDF-1? with dextran sulfate and chitosan. The data show that SDF-1? was barely released from the nanoparticles over an extended period of time in vitro (3% in 7 days at 37°C); however, incorporated SDF-1? exhibited full chemotactic activity and receptor activation compared to its free form. The nanoparticles were not endocytosed after incubation with Jurkat cells. When aerosolized into the lungs of rats, SDF-1? NP displayed a greater retention time compared to free SDF-1? (64% vs. 2% remaining at 16 hr). In a rat model of monocrotaline-induced lung injury, SDF-1? NP, but not free form SDF-1?, was found to reduce pulmonary hypertension. These data suggest that the nanoparticle formulation protected SDF-1? from rapid clearance in the lung and sustained its biological function in vivo. PMID:24059347

Yin, Tao; Bader, Andrew R.; Hou, Tim K.; Maron, Bradley A.; Kao, Derrick D.; Qian, Ray; Kohane, Daniel S.; Handy, Diane E.; Loscalzo, Joseph; Zhang, Ying-Yi



Decreased adrenoceptor stimulation in heart failure rats reduces NGF expression by cardiac parasympathetic neurons.  


Postganglionic cardiac parasympathetic and sympathetic nerves are physically proximate in atrial cardiac tissue allowing reciprocal inhibition of neurotransmitter release, depending on demands from central cardiovascular centers or reflex pathways. Parasympathetic cardiac ganglion (CG) neurons synthesize and release the sympathetic neurotrophin nerve growth factor (NGF), which may serve to maintain these close connections. In this study we investigated whether NGF synthesis by CG neurons is altered in heart failure, and whether norepinephrine from sympathetic neurons promotes NGF synthesis. NGF and proNGF immunoreactivity in CG neurons in heart failure rats following chronic coronary artery ligation was investigated. NGF immunoreactivity was decreased significantly in heart failure rats compared to sham-operated animals, whereas proNGF expression was unchanged. Changes in neurochemistry of CG neurons included attenuated expression of the cholinergic marker vesicular acetylcholine transporter, and increased expression of the neuropeptide vasoactive intestinal polypeptide. To further investigate norepinephrine's role in promoting NGF synthesis, we cultured CG neurons treated with adrenergic receptor (AR) agonists. An 82% increase in NGF mRNA levels was detected after 1h of isoproterenol (?-AR agonist) treatment, which increased an additional 22% at 24h. Antagonist treatment blocked isoproterenol-induced increases in NGF transcripts. In contrast, the ?-AR agonist phenylephrine did not alter NGF mRNA expression. These results are consistent with ?-AR mediated maintenance of NGF synthesis in CG neurons. In heart failure, a decrease in NGF synthesis by CG neurons may potentially contribute to reduced connections with adjacent sympathetic nerves. PMID:24332566

Hasan, Wohaib; Smith, Peter G



Molecular cloning of the Notophthalmus viridescens radical fringe cDNA and characterization of its expression during forelimb development and adult forelimb regeneration.  


Larval and adult newts provide important experimental models to study limb development and regeneration. These animals have exceptional ability to regenerate their appendages, as well as other vital structures. Our research examines the role of the fringe gene (fng) in the developing and regenerating adult newt forelimb. Fringe codes for a secretory protein. It was first discovered in Drosophila, and later homologues were isolated in Xenopus laevis, chick and mouse. This gene has been highly conserved throughout evolution, indicating its crucial role in vertebrate and invertebrate development. We have isolated, cloned, and sequenced the full length of the Notophthalmus viridescens radical fringe cDNA (nrFng) by screening a newt forelimb blastema cDNA library with a 500-bp fragment of the Xenopus lunatic fringe cDNA. The newt fringe cDNA codes for a 396 amino acid protein with a predicted N-terminal signal sequence. Newt fringe shows high homology with radical fringe homologues of many species. Whole mount mRNA in situ hybridization on several stages of newt limb development reveals that nrFng is first expressed in the limb field, with intense expression as the limb bud develops. However, gene expression diminishes with more advanced digit development. A significant role in adult forelimb regeneration is also evident, as we isolated the cDNA from a regeneration-specific library and found it highly expressed during the regenerative phases of active cell division and then down regulated at sites undergoing differentiation and morphogenesis. PMID:10090152

Cadinouche, M Z; Liversage, R A; Muller, W; Tsilfidis, C



Reduced brown adipose tissue thermogenesis during environmental interactions in transgenic rats with ataxin-3-mediated ablation of hypothalamic orexin neurons.  


Thermogenesis in brown adipose tissue (BAT) contributes to substantial increases in body temperature evoked by threatening or emotional stimuli. BAT thermogenesis also contributes to increases in body temperature that occur during active phases of the basic rest-activity cycle (BRAC), as part of normal daily life. Hypothalamic orexin-synthesizing neurons influence many physiological and behavioral variables, including BAT and body temperature. In conscious unrestrained animals maintained for 3 days in a quiet environment (24-26°C) with ad libitum food and water, we compared temperatures in transgenic rats with ablation of orexin neurons induced by expression of ataxin-3 (Orx_Ab) with wild-type (WT) rats. Both baseline BAT temperature and baseline body temperature, measured at the onset of BRAC episodes, were similar in Orx_Ab and WT rats. The time interval between BRAC episodes was also similar in the two groups. However, the initial slopes and amplitudes of BRAC-related increases in BAT and body temperature were reduced in Orx_Ab rats. Similarly, the initial slopes and amplitudes of the increases in BAT temperatures induced by sudden exposure to an intruder rat (freely moving or confined to a small cage) or by sudden exposure to live cockroaches were reduced in resident Orx_Ab rats. Constriction of the tail artery induced by salient alerting stimuli was also reduced in Orx_Ab rats. Our results suggest that orexin-synthesizing neurons contribute to the intensity with which rats interact with the external environment, both when the interaction is "spontaneous" and when the interaction is provoked by threatening or salient environmental events. PMID:25324552

Mohammed, Mazher; Ootsuka, Youichirou; Yanagisawa, Masashi; Blessing, William



Calcium montmorillonite clay reduces urinary biomarkers of fumonisin B1 exposure in rats and humans  

PubMed Central

Fumonisin B1 (FB1) is often a co-contaminant with aflatoxin (AF) in grains and may enhance AF’s carcinogenicity by acting as a cancer promoter. Calcium montmorillonite (i.e. NovaSil, NS) is a possible dietary intervention to help decrease chronic aflatoxin exposure where populations are at risk. Previous studies show that an oral dose of NS clay was able to reduce AF exposure in a Ghanaian population. In vitro analyses from our laboratory indicated that FB1 (like aflatoxin) could also be sorbed onto the surfaces of NS. Hence, our objectives were to evaluate the efficacy of NS clay to reduce urinary FB1 in a rodent model and then in a human population highly exposed to AF. In the rodent model, male Fisher rats were randomly assigned to either, FB1 control, FB1 + 2% NS or absolute control group. FB1 alone or with clay was given as a single dose by gavage. For the human trial, participants received NS (1.5 or 3 g day?1) or placebo (1.5 g day?1) for 3 months. Urines from weeks 8 and 10 were collected from the study participants for analysis. In rats, NS significantly reduced urinary FB1 biomarker by 20% in 24 h and 50% after 48 h compared to controls. In the humans, 56% of the urine samples analyzed (n = 186) had detectable levels of FB1. Median urinary FB1 levels were significantly (p < 0.05) decreased by > 90% in the high dose NS group (3 g day?1) compared to the placebo. This work indicates that our study participants in Ghana were exposed to FB1 (in addition to AFs) from the diet. Moreover, earlier studies have shown conclusively that NS reduces the bioavailability of AF and the findings from this study suggest that NS clay also reduces the bioavailability FB1. This is important since AF is a proven dietary risk factor for hepatocellular carcinoma (HCC) in humans and FB1 is suspected to be a dietary risk factor for HCC and esophageal cancer in humans. PMID:22324939

Robinson, A.; Johnson, N.M.; Strey, A.; Taylor, J.F.; Marroquin-Cardona, A.; Mitchell, N.J.; Afriyie-Gyawu, E.; Ankrah, N.A.; Williams, J.H.; Wang, J.S.; Jolly, P.E.; Nachman, R.J.; Phillips, T.D.



Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats.  


The aim of this study was to obtain evidences of a possible analgesic role for palmitoylethanolamide (PEA) in chronic granulomatous inflammation sustained by mast cell (MC) activation in rats at 96 hours. PEA (200-400-800 ?g/mL), locally administered at time 0, reduced in a concentration-dependent manner the expression and release of NGF in comparison with saline-treated controls. PEA prevented nerve formation and sprouting, as shown by histological analysis, reduced mechanical allodynia, evaluated by Von Frey filaments, and inhibited dorsal root ganglia activation. These results were supported by the evidence that MCs in granuloma were mainly degranulated and closely localized near nerve fibres and PEA significantly reduced MC degranulation and nerves fibre formation. These findings are the first evidence that PEA, by the modulation of MC activation, controls pain perception in an animal model of chronic inflammation, suggesting its potential use for the treatment of all those painful conditions in which MC activation is an initial key step. PMID:21219627

De Filippis, Daniele; Luongo, Livio; Cipriano, Mariateresa; Palazzo, Enza; Cinelli, Maria Pia; de Novellis, Vito; Maione, Sabatino; Iuvone, Teresa



Ebselen alters mitochondrial physiology and reduces viability of rat hippocampal astrocytes.  


The seleno-organic compound and radical scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) have been extensively employed as an anti-inflammatory and neuroprotective compound. However, its glutathione peroxidase activity at the expense of cellular thiols groups could underlie certain deleterious actions of the compound on cell physiology. In this study, we have analyzed the effect of ebselen on rat hippocampal astrocytes in culture. Cellular viability, the intracellular free-Ca(2+) concentration ([Ca(2+)]c), the mitochondrial free-Ca(2+) concentration ([Ca(2+)]m), and mitochondrial membrane potential (?m) were analyzed. The caspase-3 activity was also assayed. Our results show that cell viability was reduced by treatment of cells with ebselen, depending on the concentration employed. In the presence of ebselen, we observed an initial transient increase in [Ca(2+)]c that was then followed by a progressive increase to an elevated plateau. We also observed a transient increase in [Ca(2+)]m in the presence of ebselen that returned toward a value over the prestimulation level. The compound induced depolarization of ?m and altered the permeability of the mitochondrial membrane. Additionally, a disruption of the mitochondrial network was observed. Finally, we did not detect changes in caspase-3 activation in response to ebselen treatment. Collectively, these data support the likelihood of ebselen, depending on the concentration employed, reduces viability of rat hippocampal astrocytes via its action on the mitochondrial activity. These may be early effects that do not involve caspase-3 activation. We conclude that, depending on the concentration used, ebselen might exert deleterious actions on astrocyte physiology that could compromise cell function. PMID:23496767

Santofimia-Castaño, Patricia; Salido, Ginés M; González, Antonio



Ulinastatin reduces pathogenesis of phosgene-induced acute lung injury in rats.  


Phosgene (CG) is an industrial chemical used to make plastics, rubbers, dyestuff, and pesticides. Although the inhalation of CG is relatively uncommon, its accidental exposure can lead to acute lung injury (ALI). Ulinastatin, a urinary trypsin inhibitor, has been emerged to use for the treatment of acute inflammatory state of a number of organs including the lung. In this study, we examined the pathogenic changes in the lungs after the inhalation of CG gas and also examined the effect of ulinastatin treatment in reversing these changes in rats. We found that the rats exposed to CG gas at a dose of 5.0 g/m(3) for 5 min led to ALI after 6 h. The signs of lung injury include pulmonary edema, hemorrhage, and cellular infiltration in pulmonary alveoli. In addition, interleukin-15 (IL-15) and intercellular adhesion molecule-1 (ICAM-1) were significantly increased in CG-inhaled animals. Ulinastatin administration at 1 h postexposure significantly reduced the intensity of all the pathological changes in the lungs of these CG-exposed animals. Ulinastatin at a dose of 400 U/g was shown to decrease the total number of cells in bronchoalveolar lavage fluid and the levels of IL-15 and ICAM-1 in the serum. We also found that the structure of the lung was protected by ulinastatin treatment. Thus, our data suggest that ulinastatin can be used as an effective drug for the treatment of CG-induced ALI. The serum levels of IL-15 and ICAM-1 can be used as the markers of lung injury after exposure to CG and may also serve as useful therapeutic targets at an early stage. The effects of long-term treatment of ulinastatin and the mechanisms by which ulinastatin decreases the infiltration of blood cells and reduces cytokines need further investigation. PMID:23075575

Shen, Jie; Gan, Zhengyi; Zhao, Jie; Zhang, Liming; Xu, Guoxiong



Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat  

SciTech Connect

In type 2 diabetes (T2DM) {beta}-cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) is reduced. In a model of T2DM, the VDF Zucker rat, GIP receptor mRNA and protein levels were shown to be down-regulated. Possible restoration of responsiveness to GIP in Zucker rats by reducing hyperglycemia has been examined. ZDF rats with extreme hyperglycemia demonstrated greater islet GIP receptor mRNA down-regulation (94.3 {+-} 3.8%) than ZF rats (48.8 {+-} 22.8%). GIP receptor mRNA levels in ZDF rats returned to 83.0 {+-} 17.9% of lean following normalization of hyperglycemia by phlorizin treatment and pancreas perfusions demonstrated markedly improved GIP responsiveness. Treatment of VDF rats with a DP IV inhibitor (P32/98) resulted in improved glucose tolerance and restored sensitivity to GIP in isolated pancreata. These findings support the proposal that GIP receptor down-regulation in rodent T2DM is secondary to chronic hyperglycemia and that normalization of glycemia can restore GIP sensitivity.

Piteau, Shalea; Olver, Amy; Kim, Su-Jin; Winter, Kyle [University of British Columbia, Department of Cellular and Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC (Canada); Pospisilik, John Andrew [Institute of Molecular Biotechnology, Vienna (Austria); Lynn, Francis [HRI, Diabetes Center, University of California San Francisco, CA (United States); Manhart, Susanne; Demuth, Hans-Ulrich [Probiodrug AG, Biocenter, Halle (Saale) (Germany); Speck, Madeleine; Pederson, Raymond A. [University of British Columbia, Department of Cellular and Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC (Canada); McIntosh, Christopher H.S. [University of British Columbia, Department of Cellular and Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC (Canada)], E-mail:



Efficacy of hand-broadcast application of baits containing 0.005% diphacinone in reducing rat populations in Hawaiian forests  

USGS Publications Warehouse

Introduced black rats (Rattus rattus), Polynesian rats (R. exulans/i>), and Norway rats (R. norvegicus) impact insular bird, plant, and invertebrate populations worldwide. We investigated the efficacy of hand-broadcast application of Ramik® Green containing 0.005% diphacinone for rodent control in paired 4-ha treatment and non-treatment plots in both wet and mesic forest in Hawai?i. Radio telemetry of black rats, the predominant species, indicated 100% mortality in both treatment plots within about one week of bait application. Live trapping and non-toxic census bait block monitoring two to four weeks after each of 12 repeat bait applications in the wet forest, and three repeat bait applications in the mesic forest, indicated rat abundance was reduced on average by 84–88%. However, reinvasion could have occurred within this time. Rat populations in the treatment plots usually recovered to pre-poison levels within two to five months. House mice (Mus musculus), Indian mongooses (Herpestes auropunctatus), and feral cats (Felis catus) also ate bait or other animals that had eaten bait. This study demonstrates the efficacy of ground-based broadcast toxicant baits for the control of rats in Hawaiian montane wet forests.

Foote, David; Lindsey, Gerald D.; Perry, Charlotte F.; Spurr, Eric



Parenteral paradichlorobenzene exposure reduces sperm production, alters sperm morphology and exhibits an androgenic effect in rats and mice.  


Rats and mice (8 animals per species per group) were injected subcutaneously or intraperitoneally with paradichlorobenzene (PDCB) at doses of 0, 100, 200 and 400 mg/kg/day, 4-5 days a week, for 8 weeks (for rats) and either 2 or 6 weeks (for mice). Prostate and seminal vesicle weights were significantly increased in PDCB-treated rats but not in mice. Major histopathologic injuries were not found in testis and epididymis of both species. Daily sperm production was depressed in both species in a dose-response manner. Serum testosterone levels were not significantly changed in both species. Sperm morphology was evaluated in rats intraperitoneally administered PDCB at a dose of 800 mg/kg. Abnormal sperms with reduced hook, bent neck, coiled flagellum, bent flagellum and bent flagellum tip were significantly increased in treated rats. In Hershberger assay, PDCB administration increased weights of ventral prostate gland, seminal vesicle, levator ani/bulbocavernosus muscle and glans penis in castrated rats, and also weights of ventral prostate gland and glans penis in castrated mice. PDCB and 2,5-dichlorophenol (the major metabolite) did not bind androgen receptor (AR) up to 10 mM. In conclusion, PDCB affects sperm production and morphology but is somewhat androgenic independently from AR binding in rats and mice. PMID:20932873

Takahashi, Osamu; Ohashi, Norio; Nakae, Dai; Ogata, Akio



A Horseradish Peroxidase Study of Motorneuron Pools of the Forelimb and Hindlimb Musculature of the Axolotl  

Microsoft Academic Search

Motorneuron pools innervating axolotl limb muscles have been investigated by using the retrograde neuronal tracer horseradish peroxidase. Four muscles in the forelimb (biceps, anconeus, flexor digitorum and extensor digitorum) and four functionally equivalent muscles in the hindlimb (puboischiotibialis, iliotibialis, flexor digitorum and extensor digitorum) were studied. Motorneuron pools were characterized by using four criteria: position in the rostrocaudal axis; position

N. Stephens; N. Holder



INTRODUCTION The forelimb and hindlimb buds are derived from territories of  

E-print Network

of limb identity are linked by a requirement for Tbx5. Key words: Limb development, Limb-type identity plate tissue from limb forming regions from as early as stage 8 (four-somite stage) will develop the developing forelimb or hindlimb. The T-box transcription factor Tbx5 is first detected in the prospective

Tabin, Cliff


Identification of a Murine Locus Conveying Susceptibility to Cadmium-Induced Forelimb Malformations  

Microsoft Academic Search

The heavy metal cadmium (Cd), an environmentally ubiquitous contaminant, is a potent teratogen in mice. When administered parenterally, it induces an array of malformations that vary in scope and severity with the route, dose, time of administration, and the strain of the animal. When administered intraperitoneally on day 9.0 of gestation, 4 mg\\/kg cadmium chloride produces forelimb defects (predominantly ectrodactyly)

David N. Hovland; Rita M Cantor; Grace S Lee; Antonio F Machado; Michael D Collins



Forelimb regeneration in thyroidectomized adult newts following organ culture and autografting of the thyroid glands  

Microsoft Academic Search

Thyroidectomy and organ culture of adult newt thyroid glands three days prior to forelimb amputation was followed by autografting the glands subcutaneously into the animal's lower jaw region 9, 18 or 25 days postamputation (GC9, 18, 25 day series). This was an attempt, utilizing 515 animals, to elucidate further the role of the thyroids in regeneration. Amputated limbs of the

Richard A. Liversage; Pauline J. Brandes



Comparative Myology of the Forelimb of Squirrels (Sciuridae) RICHARD W. THORINGTON, JR.,* KAROLYN DARROW,  

E-print Network

Comparative Myology of the Forelimb of Squirrels (Sciuridae) RICHARD W. THORINGTON, JR.,* KAROLYN.C. 20004 ABSTRACT The musculature of the shoulder, arm, and forearm was stud- ied in 19 genera of squirrels, representing the Pteromyinae (flying squirrels) and all 7 tribes of the Sciurinae (tree and ground squirrels

Mathis, Wayne N.


Polyethylene glycol reduces inflammation and aberrant crypt foci in carcinogen-initiated rats  

Microsoft Academic Search

Polyethylene glycol 8000 inhibits the formation of tumors and of aberrant crypt foci (ACF) in carcinogen-initiated rats. We asked: is the inhibition associated with a reduction of colonic inflammation and an increase in colonic cell permeability? Twenty-eight, male F 344 rats were divided into two groups, 10 control animals and 18 animals initiated with azoxymethane. Nine of the rats in

Pernilla C. Karlsson; Roisin Hughes; Joseph J. Rafter; W. Robert Bruce



Yacon diet (Smallanthus sonchifolius, Asteraceae) improves hepatic insulin resistance via reducing Trb3 expression in Zucker fa/fa rats  

PubMed Central

Objective: Yacon is a perennial plant forming a clump of >20 big, edible underground tubers. Yacon, which originates from South America, has become increasingly popular in the Japanese diet for tubers have a lower caloric value and a high fiber content. Recent studies have suggested that yacon feeding ameliorates diabetes as indicated by reduced blood glucose. Methods: We fed male Zucker fa/fa rats for 5 weeks with isocaloric normal chow diet containing from 6.5% control aroid or 6.5% yacon. Insulin sensitivity was evaluated by euglycemic-hyperinsulinemic clamp study. Results: Body weight was comparable between yacon- and aroid-fed rats. In the basal state, yacon feeding had an effect to lower fasting glucose levels from 184.1±4.1 to 167.8±2.7?mg?dl?1 (P<0.01), as well as basal hepatic glucose output (HGO) from 9.9±0.4 to 7.4 ± 0.2?mg?kg?1 per min (P<0.01). During the clamp studies, the glucose infusion rate required to maintain euglycemia was increased by 12.3% in yacon-fed rat. The insulin suppression of HGO was also increased in yacon-fed rats compared with control rats (85.3±2.4% vs 77.0±3.0% P<0.05), whereas the glucose disposal rate was not different between the two groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt was significantly enhanced in liver but not in skeletal muscle. Furthermore, tribbles 3 (Trb3) expression, which is a negative regulator of Akt activity, was markedly reduced in the liver of yacon-fed rats compared with control rats. Conclusion: These results indicate that the effect of yacon feeding to reduce blood glucose is likely due to its beneficial effects on hepatic insulin sensitivity in the insulin resistant state. PMID:23712282

Satoh, H; Audrey Nguyen, M T; Kudoh, A; Watanabe, T



From fish to modern humans - comparative anatomy, homologies and evolution of the pectoral and forelimb musculature  

PubMed Central

In a recent study Diogo & Abdala [(2007) JMorphol268, 504–517] reported the results of the first part of a research project on the comparative anatomy, homologies and evolution of the pectoral muscles of osteichthyans (bony fish and tetrapods). That report mainly focused on actinopterygian fish but also compared these fish with certain non-mammalian sarcopterygians. This study, which reports the second part of the research project, focuses mainly on sarcopterygians and particularly on how the pectoral and forelimb muscles have evolved during the transitions from sarcopterygian fish and non-mammalian tetrapods to monotreme and therian mammals and humans. The data obtained by our own dissections of all the pectoral and forelimb muscles of representative members of groups as diverse as sarcopterygian fish, amphibians, reptiles, monotremes and therian mammals such as rodents, tree-shrews, colugos and primates, including humans, are compared with the information available in the literature. Our observations and comparisons clearly stress that, with regard to the number of pectoral and forelimb muscles, the most striking transition within sarcopterygian evolutionary history was that leading to the origin of tetrapods. Whereas extant sarcopterygian fish have an abductor and adductor of the fin and a largely undifferentiated hypaxial and epaxial musculature, extant salamanders such as Ambystoma have more than 40 pectoral and forelimb muscles. There is no clear increase in the number of pectoral and forelimb muscles within the evolutionary transition that led to the origin of mammals and surely not to that leading to the origin of primates and humans. PMID:19438764

Diogo, R; Abdala, V; Aziz, M A; Lonergan, N; Wood, B A



Postnatal Maturation of the Red Nucleus Motor Map Depends on Rubrospinal Connections with Forelimb Motor Pools  

PubMed Central

The red nucleus (RN) and rubrospinal tract (RST) are important for forelimb motor control. Although the RST is present postnatally in cats, nothing is known about when rubrospinal projections could support motor functions or the relation between the development of the motor functions of the rubrospinal system and the corticospinal system, the other major system for limb control. Our hypothesis is that the RN motor map is present earlier in development than the motor cortex (M1) map, to support early forelimb control. We investigated RN motor map maturation with microstimulation and RST cervical enlargement projections using anterograde tracers between postnatal week 3 (PW3) and PW16. Microstimulation and tracer injection sites were verified histologically to be located within the RN. Microstimulation at PW4 evoked contralateral wrist, elbow, and shoulder movements. The number of sites producing limb movement increased and response thresholds decreased progressively through PW16. From the outset, all forelimb joints were represented. At PW3, RST projections were present within the cervical intermediate zone, with a mature density of putative synapses. In contrast, beginning at PW5 there was delayed and age-dependent development of forelimb motor pool projections and putative rubromotoneuronal synapses. The RN has a more complete forelimb map early in development than previous studies showed for M1, supporting our hypothesis of preferential rubrospinal rather than corticospinal control for early movements. Remarkably, development of the motor pool, not intermediate zone, RST projections paralleled RN motor map development. The RST may be critical for establishing the rudiments of motor skills that subsequently become refined with further CST development. PMID:24647962

Williams, Preston T. J. A.; Kim, Sangsoo



Radiographs Reveal Exceptional Forelimb Strength in the Sabertooth Cat, Smilodon fatalis  

PubMed Central

Background The sabertooth cat, Smilodon fatalis, was an enigmatic predator without a true living analog. Their elongate canine teeth were more vulnerable to fracture than those of modern felids, making it imperative for them to immobilize prey with their forelimbs when making a kill. As a result, their need for heavily muscled forelimbs likely exceeded that of modern felids and thus should be reflected in their skeletons. Previous studies on forelimb bones of S. fatalis found them to be relatively robust but did not quantify their ability to withstand loading. Methodology/Principal Findings Using radiographs of the sabertooth cat, Smilodon fatalis, 28 extant felid species, and the larger, extinct American lion Panthera atrox, we measured cross-sectional properties of the humerus and femur to provide the first estimates of limb bone strength in bending and torsion. We found that the humeri of Smilodon were reinforced by cortical thickening to a greater degree than those observed in any living felid, or the much larger P. atrox. The femur of Smilodon also was thickened but not beyond the normal variation found in any other felid measured. Conclusions/Significance Based on the cross-sectional properties of its humerus, we interpret that Smilodon was a powerful predator that differed from extant felids in its greater ability to subdue prey using the forelimbs. This enhanced forelimb strength was part of an adaptive complex driven by the need to minimize the struggles of prey in order to protect the elongate canines from fracture and position the bite for a quick kill. PMID:20625398

Meachen-Samuels, Julie A.; Van Valkenburgh, Blaire



Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke.  


Neural plasticity is widely believed to support functional recovery following brain damage. Vagus nerve stimulation paired with different forelimb movements causes long-lasting map plasticity in rat primary motor cortex that is specific to the paired movement. We tested the hypothesis that repeatedly pairing vagus nerve stimulation with upper forelimb movements would improve recovery of motor function in a rat model of stroke. Rats were separated into 3 groups: vagus nerve stimulation during rehabilitation (rehab), vagus nerve stimulation after rehab, and rehab alone. Animals underwent 4 training stages: shaping (motor skill learning), prelesion training, postlesion training, and therapeutic training. Rats were given a unilateral ischemic lesion within motor cortex and implanted with a left vagus nerve cuff. Animals were allowed 1 week of recovery before postlesion baseline training. During the therapeutic training stage, rats received vagus nerve stimulation paired with each successful trial. All 17 trained rats demonstrated significant contralateral forelimb impairment when performing a bradykinesia assessment task. Forelimb function was recovered completely to prelesion levels when vagus nerve stimulation was delivered during rehab training. Alternatively, intensive rehab training alone (without stimulation) failed to restore function to prelesion levels. Delivering the same amount of stimulation after rehab training did not yield improvements compared with rehab alone. These results demonstrate that vagus nerve stimulation repeatedly paired with successful forelimb movements can improve recovery after motor cortex ischemia and may be a viable option for stroke rehabilitation. PMID:24553102

Khodaparast, Navid; Hays, Seth A; Sloan, Andrew M; Fayyaz, Tabbassum; Hulsey, Daniel R; Rennaker, Robert L; Kilgard, Michael P



Maternal exercise during pregnancy reduces risk of mammary tumorigenesis in rat offspring.  


Breast cancer is the most common cancer among women. Emerging research indicates that modifying lifestyle factors during pregnancy may convey long-term health benefits to offspring. This study was designed to determine whether maternal exercise during pregnancy leads to reduced mammary tumorigenesis in female offspring. Pregnant rats were randomly assigned to exercised and sedentary groups, with the exercised group having free access to a running wheel and the sedentary group housed with a locked wheel during pregnancy. Female pups from exercised or sedentary dams were weaned at 21 days of age and fed a high fat diet without access to a running wheel. At 6 weeks, all pups were injected with the carcinogen N-methyl-N-nitrosourea. Mammary tumor development in all pups was monitored for 15 weeks. Pups from exercised dams had a substantially lower tumor incidence (42.9%) compared with pups from sedentary dams (100%). Neither tumor latency nor histological grade differed between the two groups. These data are the first to demonstrate that exercise during pregnancy potentiates reduced tumorigenesis in offspring. This study provides an important foundation towards developing more effective modes of behavior modification for cancer prevention. PMID:24950432

Camarillo, Ignacio G; Clah, Leon; Zheng, Wei; Zhou, Xuanzhu; Larrick, Brienna; Blaize, Nicole; Breslin, Emily; Patel, Neal; Johnson, Diamond; Teegarden, Dorothy; Donkin, Shawn S; Gavin, Timothy P; Newcomer, Sean



Silybin reduces obliterated retinal capillaries in experimental diabetic retinopathy in rats.  


Silybin has been previously reported to possess anti-inflammatory properties, raising the possibility that it may reduce vascular damage in diabetic retinopathy. Present study was designed to investigate this potential effect of silybin and its underlying mechanisms in experimental diabetic retinopathy. Diabetes was induced with streptozotocin (STZ) plus high-fat diet in Sprague-Dawley rats, and silybin was administrated for 22 weeks after the induction of diabetes. Histochemical and immunofluorescence techniques were used to assess the obliterated retinal capillaries, leukostasis, and level of retinal intercellular adhesion molecule-1 (ICAM-1). Western blot was performed to quantitate the expression of retinal ICAM-1. Results showed that silybin treatment significantly prevented the development of obliterated retinal capillaries in diabetes, compared with vehicle treatment. In addition, leukostasis and level of the retinal ICAM-1 were found to decrease considerably in silybin-treated diabetic groups. In conclusion, these results indicate that silybin reduces obliterated retinal capillaries in experimental diabetes, and the recovered retinal vascular leukostasis and level of ICAM-1 at least partly contributes to the preventive effect of silybin. PMID:25066112

Zhang, Hong-Tao; Shi, Kai; Baskota, Attit; Zhou, Fang-Li; Chen, Ya-Xi; Tian, Hao-Ming



Intermittent anoxia reduces oxygen free radicals formation during reoxygenation in rat hepatocytes.  


The sensitivity of liver cells to anoxia is a major problem afflicting liver preservation and transplantation. Intermittent ischemia has been proposed to reduce reperfusion injury. The aim of the study was to assess oxygen free radical formation and cell injury during continuous or intermittent anoxia/reoxygenation in rat hepatocytes. Anion superoxide was measured by lucigenin-enhanced chemiluminescence and cell damage by LDH release and trypan blue uptake. During anoxia, superoxide generation dropped to background level in both groups; trypan blue uptake and LDH release, which increased progressively, were significantly greater in hepatocytes exposed to continuous compared to intermittent anoxia. During reoxygenation, a massive generation of superoxide anion formation, followed by a sharp increase in LDH release, was observed in both groups. However, both oxyradical generation and cell injury were significantly greater in cells exposed to continuous compared to intermittent anoxia. The data, showing that intermittent oxygen deprivation reduce liver cell injury and oxygen free radical formation determined by anoxia/reoxygenation, suggest a novel possible approach to the reduction of reperfusion injury. PMID:9358250

Gasbarrini, A; Colantoni, A; Di Campli, C; De Notariis, S; Masetti, M; Iovine, E; Mazziotti, A; Massari, I; Gasbarrini, G; Pola, P; Bernardi, M



Targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced sustained ventricular tachycardia in conscious rats  

PubMed Central

The Cardiac Arrhythmia Suppression Trial demonstrated that antiarrhythmic drugs not only fail to prevent sudden cardiac death, but actually increase overall mortality. These findings have been confirmed in additional trials. The “proarrhythmic” effects of most currently available antiarrhythmic drugs makes it essential that we investigate novel strategies for the prevention of sudden cardiac death. Targeted ablation of cardiac sympathetic neurons may become a therapeutic option by reducing sympathetic activity. Thus cholera toxin B subunit (CTB) conjugated to saporin (a ribosomal inactivating protein that binds to and inactivates ribosomes; CTB-SAP) was injected into both stellate ganglia to test the hypothesis that targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced, sustained ventricular tachycardia in conscious rats. Rats were randomly divided into three groups: 1) control (no injection); 2) bilateral stellate ganglia injection of CTB; and 3) bilateral stellate ganglia injection of CTB-SAP. CTB-SAP rats had a reduced susceptibility to ischemia-induced, sustained ventricular tachycardia. Associated with the reduced susceptibility to ventricular arrhythmias were a reduced number of stained neurons in the stellate ganglia and spinal cord (segments T1-T4), as well as a reduced left ventricular norepinephrine content and sympathetic innervation density. Thus CTB-SAP retrogradely transported from the stellate ganglia is effective at ablating cardiac sympathetic neurons and reducing the susceptibility to ventricular arrhythmias. PMID:20173045

Lujan, Heidi L.; Palani, Gurunanthan; Zhang, Lijie



Fructose-rich diet leads to reduced aerobic capacity and to liver injury in rats  

PubMed Central

The main purpose of this research was to investigate the alterations in the aerobic capacity and appearance of metabolic alterations in Wistar rats fed on fructose-rich diet. We separated twenty-eight rats into two groups according to diet: a control group (C) (balanced diet) and a fructose-rich diet group (F). The animals were fed these diets for 60 d (d 120 to 180). We performed insulin, glucose as well as a minimum lactate test, at d 120 and 180. At the end of the experiment, sixteen animals were euthanized, and the following main variables were analysed: aerobic capacity, the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, serum and liver triglyceride concentrations, serum and liver thiobarbituric acid reactive substance (TBARS) concentrations, serum and liver catalase and superoxide dismutase (SOD) activity and haematoxylin-eosin histology (HE) in hepatocytes. The remaining twelve animals were submitted to an analysis of their hepatic lipogenic rate. The animals fed a fructose-rich diet exhibited a reduction in aerobic capacity, glucose tolerance and insulin sensitivity and increased concentrations of triglycerides and TBARS in the liver. Catalase and SOD activities were reduced in the livers of the fructose-fed animals. In addition, the serum AST/ALT ratio was higher than that of the C group, which indicates hepatic damage, and the damage was confirmed by histology. In conclusion, the fructose-rich diet caused significant liver damage and a reduction in insulin sensitivity in the animals, which could lead to deleterious metabolic effects. PMID:22713601



Relaxation of rat aorta by farrerol correlates with potency to reduce intracellular calcium of VSMCs.  


Farrerol, isolated from Rhododendron dauricum L., has been proven to be an important multifunctional physiologically active component, but its vasoactive mechanism is not clear. The present study was performed to observe the vasoactive effects of farrerol on rat aorta and to investigate the possible underlying mechanisms. Isolated aortic rings of rat were mounted in an organ bath system and the myogenic effects stimulated by farrerol were studied. Intracellular Ca2+ ([Ca2+]in) was measured by molecular probe fluo-4-AM and the activities of L-type voltage-gated Ca2+ channels (LVGC) were studied with whole-cell patch clamp in cultured vascular smooth muscle cells (VSMCs). The results showed that farrerol significantly induced dose-dependent relaxation on aortic rings, while this vasorelaxation was not affected by NG-nitro-l-arginine methylester ester or endothelium denudation. In endothelium-denuded aortas, farrerol also reduced Ca2+-induced contraction on the basis of the stable contraction induced by KCl or phenylephrine (PE) in Ca2+-free solution. Moreover, after incubation with verapamil, farrerol can induce relaxation in endothelium-denuded aortas precontracted by PE, and this effect can be enhanced by ruthenium red, but not by heparin. With laser scanning confocal microscopy method, the farrerol-induced decline of [Ca2+]in in cultured VSMCs was observed. Furthermore, we found that farrerol could suppress Ca2+ influx via LVGC by patch clamp technology. These findings suggested that farrerol can regulate the vascular tension and could be developed as a practicable vasorelaxation drug. PMID:24747597

Qin, Xiaojiang; Hou, Xiaomin; Zhang, Mingsheng; Liang, Taigang; Zhi, Jianmin; Han, Lingge; Li, Qingshan



Chronic phencyclidine administration reduces the expression and editing of specific glutamate receptors in rat prefrontal cortex.  


Phencyclidine (PCP) induces a form of psychosis that mimics naturally occurring schizophrenia in the most relevant domains of the psychopathology. In this report, we investigated the effect of chronic treatment with PCP on expression and RNA editing of alpha-amino-propionic acid (AMPA) and kainate (KA) glutamate receptor (GluR), in the rat prefrontal cortex and the hippocampus. We found that chronic, but not acute, PCP treatment decreased GluRs expression in the rat prefrontal cortex but not in the hippocampus. In particular, the mRNA coding for GluR2 and GluR3 subunits were reduced by 50%, whereas those coding for KA GluR5 and GluR6 were decreased by 30%. In addition, we observed a decrease of the editing levels of the R/G site in the flop form of both GluR2 and GluR3 and a significant increase in the editing level of GluR6 Q/R site. The variation in the editing level of the R/G sites suggests that chronic PCP treatment induced the formation of glutamate receptor subunits with slower resensitization kinetics and, with respect to kainate receptors, an increase in the Q/R editing level might generate receptor channels with a lower permeability to cations. Combining all the data, it can be inferred that the PCP treatment induced a specific and site-selective reduction of glutamatergic neurotransmission in the prefrontal cortex but not in the hippocampus. PMID:17706642

Barbon, Alessandro; Fumagalli, Fabio; La Via, Luca; Caracciolo, Luca; Racagni, Giorgio; Riva, Marco Andrea; Barlati, Sergio



Exercise training combined with angiotensin II receptor blockade reduces oxidative stress after myocardial infarction in rats  

PubMed Central

Increased oxidative stress and decrease in antioxidant enzymes have been suggested to be involved in the pathophysiology of myocardial infarction (MI). In this study, treadmill exercise training and losartan treatment began 1 week post-MI and lasted 8 weeks. We evaluated the changes in the mRNA and protein expressions for the enzymatic antioxidants-superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase after exercise and losartan treatment in post-MI rats. Our results demonstrated that GPx and catalase mRNA levels were comparable among all the groups, while the mRNA level for manganese SOD (MnSOD) was significantly increased in exercise training with/without losartan treatment as compared to the sedentary MI group. Moreover, the mRNA level for gp91phox was dramatically decreased by a combination of exercise and losartan treatment. The protein levels for MnSOD were significantly elevated by exercise training in combination with losartan treatment. The protein levels for catalase were significantly increased in response to exercise, and it was further augmented by exercise together with losartan treatment. Thiobarbituric acid-reactive substances in plasma were significantly increased in the MI rats, but were decreased by exercise or losartan treatment, indicating that both exercise and losartan may reduce lipid oxidative damage. In addition, catalase and SOD enzymatic activities were significantly enhanced by exercise combined with losartan treatment. Our results suggest that exercise training improves catalase and MnSOD expression and attenuates oxidative stress. These effects are potentiated when combining exercise with angiotensin II receptor blockade. PMID:20660022

Xu, Xiaohua; Zhao, Weiyan; Wan, Wenhan; Ji, Lisa L.; Powers, Anthony S.; Erikson, John M.; Zhang, John Q.



Reduced Renshaw Recurrent Inhibition after Neonatal Sciatic Nerve Crush in Rats  

PubMed Central

Renshaw recurrent inhibition (RI) plays an important gated role in spinal motion circuit. Peripheral nerve injury is a common disease in clinic. Our current research was designed to investigate the change of the recurrent inhibitory function in the spinal cord after the peripheral nerve crush injury in neonatal rat. Sciatic nerve crush was performed on 5-day-old rat puppies and the recurrent inhibition between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSR) elicited from the sectioned dorsal roots and recorded either from the LG-S and MG nerves by antidromic stimulation of the synergist muscle nerve. Our results demonstrated that the MSR recorded from both LG-S or MG nerves had larger amplitude and longer latency after neonatal sciatic nerve crush. The RI in both LG-S and MG motoneuron pools was significantly reduced to virtual loss (15–20% of the normal RI size) even after a long recovery period upto 30 weeks after nerve crush. Further, the degree of the RI reduction after tibial nerve crush was much less than that after sciatic nerve crush indicatig that the neuron-muscle disconnection time is vital to the recovery of the spinal neuronal circuit function during reinnervation. In addition, sciatic nerve crush injury did not cause any spinal motor neuron loss but severally damaged peripheral muscle structure and function. In conclusion, our results suggest that peripheral nerve injury during neonatal early development period would cause a more sever spinal cord inhibitory circuit damage, particularly to the Renshaw recurrent inhibition pathway, which might be the target of neuroregeneration therapy. PMID:24778886

Shu, Liang; Su, Jingjing; Jing, Lingyan; Huang, Ying; Di, Yu; Peng, Lichao; Liu, Jianren



Relaxation of Rat Aorta by Farrerol Correlates with Potency to Reduce Intracellular Calcium of VSMCs  

PubMed Central

Farrerol, isolated from Rhododendron dauricum L., has been proven to be an important multifunctional physiologically active component, but its vasoactive mechanism is not clear. The present study was performed to observe the vasoactive effects of farrerol on rat aorta and to investigate the possible underlying mechanisms. Isolated aortic rings of rat were mounted in an organ bath system and the myogenic effects stimulated by farrerol were studied. Intracellular Ca2+ ([Ca2+]in) was measured by molecular probe fluo-4-AM and the activities of L-type voltage-gated Ca2+ channels (LVGC) were studied with whole-cell patch clamp in cultured vascular smooth muscle cells (VSMCs). The results showed that farrerol significantly induced dose-dependent relaxation on aortic rings, while this vasorelaxation was not affected by NG-nitro-l-arginine methylester ester or endothelium denudation. In endothelium-denuded aortas, farrerol also reduced Ca2+-induced contraction on the basis of the stable contraction induced by KCl or phenylephrine (PE) in Ca2+-free solution. Moreover, after incubation with verapamil, farrerol can induce relaxation in endothelium-denuded aortas precontracted by PE, and this effect can be enhanced by ruthenium red, but not by heparin. With laser scanning confocal microscopy method, the farrerol-induced decline of [Ca2+]in in cultured VSMCs was observed. Furthermore, we found that farrerol could suppress Ca2+ influx via LVGC by patch clamp technology. These findings suggested that farrerol can regulate the vascular tension and could be developed as a practicable vasorelaxation drug. PMID:24747597

Qin, Xiaojiang; Hou, Xiaomin; Zhang, Mingsheng; Liang, Taigang; Zhi, Jianmin; Han, Lingge; Li, Qingshan



Propagation of the cardiac impulse in the diabetic rat heart: reduced conduction reserve  

PubMed Central

Diabetes mellitus is a growing epidemic with severe cardiovascular complications. Although much is known about mechanical and electrical cardiac dysfunction in diabetes, few studies have investigated propagation of the electrical signal in the diabetic heart and the associated changes in intercellular gap junctions. This study was designed to investigate these issues, using hearts from control and diabetic rats. Diabetic conditions were induced by streptozotocin (STZ), given i.v. 7–14 days before experiments. Optical mapping with the voltage-sensitive dye di-4-ANEPPS, using hearts perfused on a Langendorff apparatus, showed little change in baseline conduction velocity in diabetic hearts, reflecting the large reserve of function. However, both the gap junction uncoupler heptanol (0.5–1 mm) and elevated potassium (9 mm, to reduce cell excitability) produced a significantly greater slowing of impulse propagation in diabetic hearts than in controls. The maximal action potential upstroke velocity (an index of the sodium current) and resting potential was similar in single ventricular myocytes from control and diabetic rats, suggesting similar electrical excitability. Immunoblotting of connexin 43 (Cx43), a major gap junction component, showed no change in total expression. However, immunofluorescence labelling of Cx43 showed a significant redistribution, apparent as enhanced Cx43 lateralization. This was quantified and found to be significantly larger than in control myocytes. Labelling of two other gap junction proteins, N-cadherin and ?-catenin, showed a (partial) loss of co-localization with Cx43, indicating that enhancement of lateralized Cx43 is associated with non-functional gap junctions. In conclusion, conduction reserve is smaller in the diabetic heart, priming it for impaired conduction upon further challenges. This can desynchronize contraction and contribute to arrhythmogenesis. PMID:17185336

Nygren, A; Olson, M L; Chen, K Y; Emmett, T; Kargacin, G; Shimoni, Y



Reduced Walker 256 carcinosarcoma growth in vasopressin-deficient Brattleboro rats.  


The growth pattern of carcinosarcoma Walker 256 was studied in rats with different levels of vasopressin in the blood. The Brattleboro rats are unable to synthesize vasopressin in a consequence of deletion in the coding gene. Hybrids from crossbreeding of the mutant Brattleboro and normal WAG rats inherit the one intact vasopressin gene and hold nearly normal hormone level. It was found that non-strain-specific carcinosarcoma Walker 256 intensively grows in WAG rats and their offsprings from crossbreeding with Brattleboro rats, and tumor development is equally terminated in them by death. Carcinosarcoma grows less intensely in Brattleboro rats; the tumor nodes increased only within the first 2 weeks, after which, the tumor began to decrease and eventually disappeared. Infusion of exogenous vasopressin to Brattleboro rats intensifies a tumor growth in the first 2 weeks after the inoculation of Walker 256 cells; however, it does not prevent a following regression and resorption of tumors. PMID:20559788

Khegay, Igor I; Popova, Nelli A; Ivanova, Ludmila N



Gene Transfer of Extracellular Superoxide Dismutase Reduces Arterial Pressure in Spontaneously Hypertensive Rats Role of Heparin-Binding Domain  

Microsoft Academic Search

Oxidative stress may contribute to hypertension. The goals of this study were to determine whether extracellular superoxide dismutase (ECSOD) reduces arterial pressure in spontaneously hypertensive rats (SHR) and whether its heparin-binding domain (HBD), which is responsible for cellular binding, is necessary for the function of ECSOD. Three days after intravenous injection of an adenoviral vector expressing human ECSOD (AdECSOD), mean

Yi Chu; Shinichiro Iida; Donald D. Lund; Robert M. Weiss; Gerald F. DiBona; Yoshimasa Watanabe; Frank M. Faraci; Donald D. Heistad


Spinal subarachnoid adrenal medullary transplants reduce hind paw swelling and peripheral nerve transport following formalin injection in rats  

Microsoft Academic Search

Previous studies have demonstrated that adrenal medullary chromaffin cells transplanted into the spinal subarachnoid space significantly reduced pain-related behavior following hind paw plantar formalin injection in rats. The data suggests a centrally mediated antinociceptive mechanism. The spinal transplants may have effects on sciatic nerve function as well. To address this, the current study examined the effects of spinal adrenal transplants

Uri Herzberg; Aldric Hama; Jacqueline Sagen



The chronic administration of docosahexaenoic acid reduces the spatial cognitive deficit following transient forebrain ischemia in rats  

Microsoft Academic Search

The purpose of this study was to investigate whether chronic administration of docosahexaenoic acid is able to reduce spatial cognitive deficit following transient ischemia in rats. In addition, we investigated whether the chronic treatment of docosahexaenoic acid is able to protect the hippocampal neuronal damage induced by either hypoxia in vitro or cerebral ischemia in vivo. A chronic administration of

M. Okada; T. Amamoto; M. Tomonaga; A. Kawachi; K. Yazawa; K. Mine; M. Fujiwara



Reactive oxygen species and lipid peroxidation inhibitors reduce mechanical sensitivity in a chronic neuropathic pain model of spinal cord injury in rats.  


Chronic neuropathic pain is a common consequence of spinal cord injury (SCI), develops over time and negatively impacts quality of life, often leading to substance abuse and suicide. Recent evidence has demonstrated that reactive oxygen species (ROS) play a role in contributing to neuropathic pain in SCI animal models. This investigation examines four compounds that reduce ROS and the downstream lipid peroxidation products, apocynin, 4-oxo-tempo, U-83836E, and tirilazad, and tests if these compounds can reduce nocioceptive behaviors in chronic SCI animals. Apocynin and 4-oxo-tempo significantly reduced abnormal mechanical hypersensitivity measured in forelimbs and hindlimbs in a model of chronic SCI-induced neuropathic pain. Thus, compounds that inhibit ROS or lipid peroxidation products can be used to ameliorate chronic neuropathic pain. We propose that the application of compounds that inhibit reactive oxygen species (ROS) and related downstream molecules will also reduce the behavioral measures of chronic neuropathic pain. Injury or trauma to nervous tissue leads to increased concentrations of ROS in the surviving tissue. Further damage from ROS molecules to dorsal lamina neurons leads to membrane excitability, the physiological correlate of chronic pain. Chronic pain is difficult to treat with current analgesics and this research will provide a novel therapy for this disease. PMID:25051888

Hassler, Shayne N; Johnson, Kathia M; Hulsebosch, Claire E



Hypothermia modulates cytokine responses after neonatal rat hypoxic-ischemic injury and reduces brain damage.  


While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24?hr after HII with HT (32?; n?=?18) or normothermia (NT, 35?; n?=?15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72?hr post-HII). Lesion volumes (24?hr) were reduced in HT pups (total 74%, p?reduced interleukin-1? (IL-1?) at all time points (p?reduces total and penumbral lesion volumes (at 24 and 48?hr), potentially by decreasing IL-1? without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72?hr post-HII when IL-1? levels remained low suggests that after rewarming, mechanisms unrelated to IL-1? expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury. PMID:25424430

Yuan, Xiangpeng; Ghosh, Nirmalya; McFadden, Brian; Tone, Beatriz; Bellinger, Denise L; Obenaus, Andre; Ashwal, Stephen



Reduced protein oxidation in Wistar rats supplemented with marine ?3 PUFAs.  


The potential effects of various dietary eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6) ratios (1:1, 2:1, and 1:2, respectively) on protein redox states from plasma, kidney, skeletal muscle, and liver were investigated in Wistar rats. Dietary fish oil groups were compared with animals fed soybean and linseed oils, vegetable oils enriched in ?6 linoleic acid (LA; 18:2) and ?3 ?-linolenic acid (ALA; 18:3), respectively. Fish oil treatments were effective at reducing the level of total fatty acids in plasma and enriching the plasmatic free fatty acid fraction and erythrocyte membranes in EPA and DHA. A proteomic approach consisting of fluorescein 5-thiosemicarbazide (FTSC) labeling of protein carbonyls, FTSC intensity visualization on 1-DE or 2-DE gels, and protein identification by MS/MS was used for the protein oxidation assessment. Albumin was found to be the most carbonylated protein in plasma for all dietary groups, and its oxidation level was significantly modulated by dietary interventions. Supplementation with an equal EPA:DHA ratio (1:1) showed the lowest oxidation score for plasma albumin, followed in increasing order of carbonylation by 1:2 <2:1 ? linseed < soybean. Oxidation patterns of myofibrillar skeletal muscle proteins and cytosolic proteins from kidney and liver also indicated a protective effect on proteins for the fish oil treatments, the 1:1 ratio exhibiting the lowest protein oxidation scores. The effect of fish oil treatments at reducing carbonylation on specific proteins from plasma (albumin), skeletal muscle (actin), and liver (albumin, argininosuccinate synthetase, 3-?-hydroxysteroid dehydrogenase) was remarkable. This investigation highlights the efficiency of dietary fish oil at reducing in vivo oxidative damage of proteins compared to oils enriched in the 18-carbon polyunsaturated fatty acids ?3 ALA and ?6 LA, and such antioxidant activity may differ among different fish oil sources because of variations in EPA/DHA content. PMID:23159545

Méndez, Lucía; Pazos, Manuel; Gallardo, José M; Torres, Josep L; Pérez-Jiménez, Jara; Nogués, Rosa; Romeu, Marta; Medina, Isabel



Angiotensin Converting Enzyme Inhibition Reduces Cardiovascular Responses to Acute Stress in Myocardially Infarcted and Chronically Stressed Rats  

PubMed Central

Previous studies showed that chronically stressed and myocardially infarcted rats respond with exaggerated cardiovascular responses to acute stress. The present experiments were designed to elucidate whether this effect can be abolished by treatment with the angiotensin converting enzyme (ACE) inhibitor captopril. Sprague Dawley rats were subjected either to sham surgery (Groups 1 and 2) or to myocardial infarction (Groups 3 and 4). The rats of Groups 2 and 4 were also exposed to mild chronic stressing. Four weeks after the operation, mean arterial blood pressure (MABP) and heart rate (HR) were measured under resting conditions and after application of acute stress. The cardiovascular responses to the acute stress were determined again 24?h after administration of captopril orally. Captopril significantly reduced resting MABP in each group. Before administration of captopril, the maximum increases in MABP evoked by the acute stressor in all (infarcted and sham-operated) chronically stressed rats and also in the infarcted nonchronically stressed rats were significantly greater than in the sham-operated rats not exposed to chronic stressing. These differences were abolished by captopril. The results suggest that ACE may improve tolerance of acute stress in heart failure and during chronic stressing. PMID:25045668

Cudnoch-Jedrzejewska, A.; Czarzasta, K.; Puchalska, L.; Dobruch, J.; Borowik, O.; Pachucki, J.; Szczepanska-Sadowska, E.



Fish oil supplementation reduces cachexia and tumor growth while improving renal function in tumor-bearing rats.  


The objective of the present work was to study the renal function of healthy and tumor-bearing rats chronically supplemented with fish oil (FO), a source of n-3 polyunsaturated fatty acids. Weanling male rats were divided in two groups, one control (C) and another orally supplemented for 70 days with FO (1 g/kg body weight). After this time, half the animals of each group were injected in the right flank with a suspension of Walker 256 tumor cells (W and WFO). The W group had less proteinemia reflecting cachectic proteolysis, FO reversed this fact. Tumor weight gain was also reduced in WFO. Glomerular filtration rate (GFR) was not different in FO or W compared to C, but was higher in WFO. Renal plasma flow (RPF) was higher in the FO supplemented groups. The W group had lower plasma osmolality than the C group, but FO supplementation resulted in normalization of this parameter. Fractional sodium excretion (FE(Na+)) of FO rats was similar to C. Proximal Na(+) reabsorption, evaluated by lithium clearance, was similar among the groups. Urinary thromboxane B(2) (TXB(2)) excretion was lower in the supplemented groups. The number of macrophages in renal tissue was higher in W compared to C rats, but was lower in WFO rats compared to W rats. In conclusion, FO supplementation resulted in less tumor growth and cachexia, and appeared to be renoprotective, as suggested by higher RPF and GFR. PMID:23015313

Coelho, Isabela; Casare, Fernando; Pequito, Danielle C T; Borghetti, Gina; Yamazaki, Ricardo K; Brito, Gleisson A P; Kryczyk, Marcelo; Fernandes, Luiz Claudio; Coimbra, Terezila M; Fernandez, Ricardo



Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor-bearing DA rats.  


Mucositis is a common side effect of cancer chemotherapy for which there is currently no treatment. Irinotecan is a commonly used effective chemotherapeutic agent, causing severe gastrointestinal mucositis and diarrhea. Previous research suggests that palifermin is potentially antimucotoxic. The primary aim of this study was to determine whether palifermin was effective in ameliorating irinotecan-induced gastrointestinal mucositis. We also determined the protective effects of single large and multiple small doses of palifermin. Tumor-bearing DA rats were treated with a single large (10 mg/kg) dose of palifermin 3 days prior to, or multiple small (3 mg/kg day for 3 days) doses of palifermin or vehicle control prior to, receiving 2 doses of 150 mg/kg irinotecan. Animals were killed at 6, 24, 48, 72, 96, 120, or 144 hr after treatment. The primary endpoints were diarrhea and mortality. Gastrointestinal morphometry, histopathology and apoptosis were assessed. Tumor weights and mitoses were measured to ensure palifermin did not promote tumor growth. Data were analyzed using Peritz' F-test, Student's t-test and Tukey-Kramer multiple comparison test. Animals pretreated with palifermin tolerated irinotecan treatment better than control animals with less severe diarrhea (5% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 x 3 mg/kg palifermin and 28% in animals receiving irinotecan only) and reduced mortality (2% in animals receiving 10 mg/kg palifermin, 11% in animals receiving 3 x 3 mg/kg palifermin and 28% in animals receiving irinotecan only). Small and large intestinal weights were maintained. Intestinal morphometry was not maintained in palifermin-pretreated rats despite being increased prior to irinotecan treatment. Palifermin pretreatment did not prevent apoptosis that peaked at 6 hr in the jejunum or colon, but prevented apoptosis at 96 hr in the small intestine. Palifermin pretreatment in both treatment regimens significantly reduces diarrhea and mortality following irinotecan administration without adversely affecting tumor growth. This positive response warrants further investigation, particularly in humans. PMID:15800945

Gibson, Rachel J; Bowen, Joanne M; Keefe, Dorothy M K



Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin.  


Recently, in rat abdominal aorta terminoterminal-anastomosis the stable gastric pentadecapeptide BPC 157 prevents obstructive thrombus formation and rapidly destroys already formed obstructive thrombus. Also, BPC 157 wound healing may signify the clot as conductive matrix or "scaffold" to speed up wound healing process, and decrease bleeding. Here, in rats, BPC 157 (10 ?g/kg, 10 ng/kg) improved always reduced bleeding time and amount of bleeding after (tail) amputation only, heparin (250 mg/kg, 25mg/kg, 10mg/kg i.v.), warfarin (1.5mg/kg i.g. once daily for 3 consecutive days), aspirin (0.1g/kg i.g. (once daily/3 consecutive days) or 1.0 g/kg i.p. once), and amputation associated with those agents application. BPC 157 counteracting regimens (i.v., i.p., i.g. (immediately after any challenge)) correspondingly follow the route of bleeding-agents application. All heparin-, warfarin-, and aspirin-rats and normal-rats that received BPC 157 exhibited lesser fall in platelets count. BPC 157 attenuated over-increased APTT-, TT-values in 10mg/kg heparin-rats, but did not influence heparin activity (anti-Xa test). Indicatively, unless counteracted in BPC 157 rats, excessive bleeding-acute thrombocytopenia (<20% of initial values in heparin-rats) approaches substantial fall in platelets count known in type II HIT. Also, BPC 157 markedly prolongs the survival time (heparin-rats, 25mg/kg, right foot amputation). PMID:21840572

Stupnisek, Mirjana; Franjic, Sandra; Drmic, Domagoj; Hrelec, Masa; Kolenc, Danijela; Radic, Bozo; Bojic, Davor; Vcev, Aleksandar; Seiwerth, Sven; Sikiric, Predrag



The distal forelimb musculature in aquatic and terrestrial turtles: phylogeny or environmental constraints?  

PubMed Central

We compared the muscular anatomy of the distal front limb in terrestrial and aquatic chelonians to test whether observed differences between the two groups are associated with their divergent lifestyles and locomotor modes. Given the different use of the forelimb in the two environments (body support and propulsion on land vs. mainly propulsion in water) we expected that: (1) aquatic and terrestrial turtles would show differences in their muscular anatomy, with aquatic species having more individualized muscle bundles to allow for the complex forearm movements observed during swimming, and (2) that terrestrial turtles would have more robust muscles to support their body weight against gravity. To address these questions, we examined the forelimb myology and associated tissues in six aquatic or semi-aquatic turtles (Phyrnops hilarii, Podocnemis unifilis, Trachemys scripta, Sacalia bealei, Cuora amboinensis and Mauremys caspica) and six terrestrial or semi-terrestrial turtles (Geochelone chilensis, Testudo graeca, Cuora galbinifrons, Glyptemys insculpta, Terrapene carolina and Rhinoclemmys pulcherrima). This paper describes the general structure of the forelimb musculature in all species, and quantifies muscle masses in those species with more than five specimens available (Ph. hilarii, Po. unifilis and Ge. chilensis). The general structure of the forelimb muscles in the strictly terrestrial species Ge. chilensis and Tes. graeca was found to be notably different from the pattern of the aquatic and semi-aquatic species examined, showing a distinct fusion of the different muscular bodies. Ter. carolina also show a distinctly terrestrial pattern, but a less extensive tendon development. R. pulcherrima and Gl. insculpta were found to be morphologically intermediate; in the geoemydids the strictly terrestrial bauplan never appears. Quantitative differences in the robustness or mass of the distal forelimb muscles were also observed for the species investigated, supporting our prediction that the extensor muscles are more robust in terrestrial turtles. However, in contrast to our expectations, not only the extensor muscles of the distal forelimb (which are crucial in providing both body support and propulsion), but all muscles acting around the wrist were found to be heavier in terrestrial turtles. PMID:19172731

Abdala, Virginia; Manzano, Adriana S; Herrel, Anthony



Dietary L-arginine supplementation reduces Methotrexate-induced intestinal mucosal injury in rat  

PubMed Central

Background Arginine (ARG) and nitric oxide maintain the mucosal integrity of the intestine in various intestinal disorders. In the present study, we evaluated the effects of oral ARG supplementation on intestinal structural changes, enterocyte proliferation and apoptosis following methotrexate (MTX)-induced intestinal damage in a rat. Methods Male rats were divided into four experimental groups: Control rats, CONTR-ARG rats, were treated with oral ARG given in drinking water 72 hours before and 72 hours following vehicle injection, MTX rats were treated with a single dose of methotrexate, and MTX-ARG rats were treated with oral ARG following injection of MTX. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. RT-PCR was used to determine bax and bcl-2 mRNA expression. Results MTX-ARG rats demonstrated greater jejunal and ileal bowel weight, greater ileal mucosal weight, greater ileal mucosal DNA and protein levels, greater villus height in jejunum and ileum and crypt depth in ileum, compared to MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-ARG rats (vs MTX) was accompanied by decreased bax mRNA and protein expression and increased bcl-2 protein levels. Conclusions Treatment with oral ARG prevents mucosal injury and improves intestinal recovery following MTX- injury in the rat. PMID:22545735



Sleep deprivation attenuates experimental stroke severity in rats.  


Indirect epidemiological and experimental evidence suggest that the severity of injury during stroke is influenced by prior sleep history. The aim of our study was to test the effect of acute sleep deprivation on early outcome following experimental stroke. Young male Sprague-Dawley rats (n=20) were subjected to focal cerebral ischemia by reversible right middle cerebral artery occlusion (MCAO) for 90 min. In 10 rats, MCAO was performed just after 6-h of total sleep deprivation (TSD) by "gentle handling", whereas the other rats served as controls. Neurological function during the first week after stroke was monitored using a battery of behavioral tests investigating the asymmetry of sensorimotor deficit (tape removal test and cylinder test), bilateral sensorimotor coordination (rotor-rod and Inclined plane) and memory (T-maze and radial maze). Following MCAO, control rats had impaired behavioral performance in all tests. The largest impairment was noted in the tape test where the tape removal time from the left forelimb (contralateral to MCAO) was increased by approximately 10 fold (p<0.01). In contrast, rats subjected to TSD had complete recovery of sensorimotor performance consistent with a 2.5 fold smaller infarct volume and reduced morphological signs of neuronal injury at day 7 after MCAO. Our data suggest that brief TSD induces a neuroprotective response that limits the severity of a subsequent stroke, similar to rapid ischemic preconditioning. PMID:20045410

Moldovan, Mihai; Constantinescu, Alexandra Oana; Balseanu, Adrian; Oprescu, Nicoleta; Zagrean, Leon; Popa-Wagner, Aurel



Hippocampal neuroligin-2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats.  


Disturbances of the excitation/inhibition (E/I) balance in the brain were recently suggested as potential factors underlying disorders like autism and schizophrenia resulting in associated behavioral alterations including changes in social and emotional behavior as well as abnormal aggression. Neuronal cell adhesion molecules (nCAMs) and mutations in these genes were found to be strongly implicated in the pathophysiology of these disorders. Neuroligin2 (nlgn2) is a postsynaptic cell adhesion molecule, which is predominantly expressed at inhibitory synapses and required for synapse specification and stabilization. Changes in the expression of nlgn2 were shown to result in alterations of social behavior as well as altered inhibitory synaptic transmission, hence modifying the E/I balance. In our study, we focused on the role of nlgn2 in the dorsal hippocampus in the regulation of emotional and social behaviors. To this purpose, we injected an AAV construct overexpressing nlgn2 in the hippocampus of rats and investigated the effects on behavior and on markers for the E/I ratio. We could show an increase in GAD65, a GABA-synthesizing protein in neuronal terminals, and furthermore, reduced exploration of novel stimuli and less offensive behavior. Our data suggest nlgn2 in the hippocampus to be strongly implicated in maintaining the E/I balance in the brain and thereby modulating social and emotional behavior. PMID:23451101

Kohl, Christine; Riccio, Orbicia; Grosse, Jocelyn; Zanoletti, Olivia; Fournier, Céline; Schmidt, Mathias V; Sandi, Carmen



Hippocampal Neuroligin-2 Overexpression Leads to Reduced Aggression and Inhibited Novelty Reactivity in Rats  

PubMed Central

Disturbances of the excitation/inhibition (E/I) balance in the brain were recently suggested as potential factors underlying disorders like autism and schizophrenia resulting in associated behavioral alterations including changes in social and emotional behavior as well as abnormal aggression. Neuronal cell adhesion molecules (nCAMs) and mutations in these genes were found to be strongly implicated in the pathophysiology of these disorders. Neuroligin2 (nlgn2) is a postsynaptic cell adhesion molecule, which is predominantly expressed at inhibitory synapses and required for synapse specification and stabilization. Changes in the expression of nlgn2 were shown to result in alterations of social behavior as well as altered inhibitory synaptic transmission, hence modifying the E/I balance. In our study, we focused on the role of nlgn2 in the dorsal hippocampus in the regulation of emotional and social behaviors. To this purpose, we injected an AAV construct overexpressing nlgn2 in the hippocampus of rats and investigated the effects on behavior and on markers for the E/I ratio. We could show an increase in GAD65, a GABA-synthesizing protein in neuronal terminals, and furthermore, reduced exploration of novel stimuli and less offensive behavior. Our data suggest nlgn2 in the hippocampus to be strongly implicated in maintaining the E/I balance in the brain and thereby modulating social and emotional behavior. PMID:23451101

Kohl, Christine; Riccio, Orbicia; Grosse, Jocelyn; Zanoletti, Olivia; Fournier, Celine



Lycium barbarum polysaccharides reduce intestinal ischemia/reperfusion injuries in rats.  


Inflammation and oxidative stress exert important roles in intestinal ischemia-reperfusion injury (IRI). Lycium barbarum polysaccharides (LBPs) have shown effective antioxidative and immunomodulatory functions in different models. The purpose of the present study was to assess the effects and potential mechanisms of LBPs in intestinal IRI. Several free radical-generating and lipid peroxidation models were used to assess the antioxidant activities of LBPs in vitro. A common IRI model was used to induce intestinal injury by clamping and unclamping the superior mesenteric artery in rats. Changes in the malondialdehyde (MDA), tumor necrosis factor (TNF)-?, activated nuclear factor (NF)-?B, intracellular adhesion molecule (ICAM)-1, E-selectin, and related antioxidant enzyme levels, polymorphonuclear neutrophil (PMN) accumulation, intestinal permeability, and intestinal histology were examined. We found that LBPs exhibited marked inhibitory action against free radicals and lipid peroxidation in vitro. LBPs increased the levels of antioxidant enzymes and reduced intestinal oxidative injury in animal models of intestinal IRI. In addition, LBPs inhibited PMN accumulation and ICAM-1 expression and ameliorated changes in the TNF-? level, NF-?B activation, intestinal permeability, and histology. Our results indicate that LBPs treatment may protect against IRI-induced intestinal damage, possibly by inhibiting IRI-induced oxidative stress and inflammation. PMID:23743330

Yang, Xuekang; Bai, Hua; Cai, Weixia; Li, Jun; Zhou, Qin; Wang, Yunchuan; Han, Juntao; Zhu, Xiongxiang; Dong, Maolong; Hu, Dahai



Preconditioning reduces hypoxia-evoked alterations in glutamatergic Ca2+ signaling in rat cortex.  


The aims of this study were (1) to characterize calcium signaling in rat cortex induced by repeated in vitro application of the glutamatergic agonists L-glutamate, NMDA, AMPA and DHPG, (2) to analyze the influence of transient severe hypobaric hypoxia (180 Torr) administered in vivo on calcium responses to stimulation of glutamate receptors by their agonists, and (3) to evaluate the effects of preconditioning with intermittent mild hypobaric hypoxia (360 Torr) 24 h before the severe hypoxia, on these Ca2+ responses. Intracellular Ca2+ dynamics was studied using the fluorescent probes fura-2 and chlortetracycline to monitor free and bound calcium (Cai and Cab) respectively. In control cortical slices, application of L-glutamate, NMDA and AMPA induced concomitant increases in Cai and Cab, reflecting Ca2+ influx and its intracellular accumulation in neurons. DHPG, an agonist of group I mGlu receptors induced a decrease in Cab accompanied by a rise in Cai levels, indicating Ca2+ mobilization. In cortical slices collected 24 h after severe hypoxia, the responses of Cab to glutamate administration were increased, DHPG-induced shifts were reversed, the increase in Cab after the first application of AMPA was reduced, while after the second, Cab rises were potentiated, and the increases in Cab evoked by NMDA application were slightly suppressed. The alterations of responses in Cab to the selective agonists were completely prevented by preconditioning with mild hypoxia. Our results suggest that protection of normal glutamatergic calcium signaling contributes to tolerance to hypoxia induced by preconditioning. PMID:18511953

Semenov, Dmitry G; Samoilov, Mikhail O; Lazarewicz, Jerzy W



Oral administration of Eucalyptus globulus extract reduces the alloxan-induced oxidative stress in rats.  


In light of evidence that some complications of diabetes mellitus may be caused or exacerbated by an oxidative stress, the putative protective effect of Eucalyptus globulus, a medicinal plant, was investigated in alloxan-diabetic rats. E. globulus extract was given in drinking water for 15 days at a daily dose equivalent to 130 mg dry leaves/kg of body weight. Lipids peroxidation level and activities of catalase, superoxide-dismutase and glutathione peroxidase were then measured in liver and kidney. Under our experimental conditions, eucalyptus extract was found to significantly reduce the blood glucose level in diabetic animals but failed to restore the liver glycogen level, whereas insulin lowered blood glucose and restored liver glycogen to high concentration. Our results suggest that the antihyperglycemic action of eucalyptus extract is not exerted via the stimulation of insulin secretion but rather unveil a proper effect of the extract involving the enhancement of peripheral glucose uptake. In addition, eucalyptus extract appears to exert an antioxidative activity demonstrated (1) by the increase of catalase, superoxide-dismutase and gluthatione-peroxidase activities in liver and kidney, and (2) a lowering of lipids peroxidation level in these organs. In conclusion, the present study indicates that extract of E. globulus, administered per os, could be used with some profit in diabetic patients. PMID:19540215

Ahlem, Soussi; Khaled, Hamden; Wafa, Marouane; Sofiane, Bezzine; Mohamed, Damak; Jean-Claude, Murat; Abdelfattah, El Feki



Losartan reduces trinitrobenzene sulphonic acid-induced colorectal fibrosis in rats  

PubMed Central

BACKGROUND: Intestinal fibrosis is a challenging clinical condition in several fibrostenosing enteropathies, particularly Crohn’s disease. Currently, no effective preventive measures or medical therapies are available for intestinal fibrosis. Fibrosis, due to an abnormal accumulation of extracellular matrix proteins, is a chronic and progressive process mediated by cell/matrix/cytokine and growth factor interactions, but may be a reversible phenomenon. Of the several molecules regulating fibrogenesis, transforming growth factor-beta 1 (TGF-?1) appears to play a pivotal role; it is strongly induced by the local activation of angiotensin II. The levels of both TGF-?1 and angiotensin II are elevated in fibrostenosing Crohn’s disease. AIMS: To evaluate the in vivo effect of losartan – an angiotensin II receptor antagonist – on the course of chronic colitis-associated fibrosis and on TGF-?1 expression. METHODS: Colitis was induced by intrarectal instillation of trinitrobenzene sulphonic acid (TNBS) (15 mg/mL) while losartan was administered orally daily by gavage (7 mg/kg/day) for 21 days. Three groups of rats were evaluated: control (n=10); TNBS treated (n=10); and TNBS + losartan treated (n=10). Inflammation and fibrosis of the colon were evaluated by macro- and microscopic score analysis. Colonic TGF-?1 levels was measured using ELISA. RESULTS: Twenty-one days after induction, losartan significantly improved the macro- and microscopic scores of fibrosis in the colonic wall and reduced TGF-?1 concentration. CONCLUSIONS: Prophylactic oral administration of losartan reduces the colorectal fibrosis complicating the TNBS-induced chronic colitis, an effect that appears to be mediated by a downregulation of TGF-?1 expression. PMID:22288068

Wengrower, Dov; Zanninelli, Giuliana; Latella, Giovanni; Necozione, Stefano; Metanes, Issa; Israeli, Eran; Lysy, Joseph; Pines, Mark; Papo, Orit; Goldin, Eran



Acetylcholine-induced arteriolar dilation is reduced in streptozotocin-induced diabetic rats with motor nerve dysfunction  

PubMed Central

Diabetes mellitus produces marked abnormalities in motor nerve conduction, but the mechanism is not clear. In the present study we hypothesized that in the streptozotocin (STZ)-induced diabetic rat impaired vasodilator function is associated with reduced endoneural blood flow (EBF) which may contribute to nerve dysfunction.We examined whether diabetes-induced reductions in sciatic nerve conduction velocity and EBF were associated with impaired endothelium-dependent dilation in adjacent arterioles. We measured motor nerve conduction velocity (MNCV) in the sciatic nerve using a non-invasive procedure, and sciatic nerve nutritive blood flow using microelectrode polarography and hydrogen clearance. In vitro videomicroscopy was used to quantify arteriolar diameter responses to dilator agonists in arterioles overlying the sciatic nerve.MNCV and EBF in 4-week-STZ-induced diabetic rats were decreased by 22% and 49% respectively. Arterioles were constricted with U46619 and dilation to acetylcholine (ACh), aprikalim, or sodium nitroprusside (SNP) examined. All agonists elicited dose-dependent dilation in control and diabetic rats, although ACh-induced dilation was significantly reduced in diabetic rats. Treating vessels from normal or diabetic rats with indomethacin (INDO) alone did not significantly affect ACh-induced relaxation. However, ACh-induced vasodilation was significantly reduced by treatment with KCl or N?-nitro-L-arginine (LNNA) alone. Combining LNNA and KCl further reduced ACh-induced dilation in these vessels.Diabetes causes vasodilator dysfunction in a microvascular bed that provides circulation to the sciatic nerve. These studies imply that ACh-induced dilation in these vessels is mediated by multiple mechanisms that may include the endothelial-dependent production of nitric oxide and endothelial-derived hyperpolarizing factor. This impaired vascular response is associated with neural dysfunction. PMID:10516670

Terata, K; Coppey, L J; Davidson, E P; Dunlap, J A; Gutterman, D D; Yorek, M A



Acetylcholine-induced arteriolar dilation is reduced in streptozotocin-induced diabetic rats with motor nerve dysfunction.  


1. Diabetes mellitus produces marked abnormalities in motor nerve conduction, but the mechanism is not clear. In the present study we hypothesized that in the streptozotocin (STZ)-induced diabetic rat impaired vasodilator function is associated with reduced endoneural blood flow (EBF) which may contribute to nerve dysfunction. 2. We examined whether diabetes-induced reductions in sciatic nerve conduction velocity and EBF were associated with impaired endothelium-dependent dilation in adjacent arterioles. We measured motor nerve conduction velocity (MNCV) in the sciatic nerve using a non-invasive procedure, and sciatic nerve nutritive blood flow using microelectrode polarography and hydrogen clearance. In vitro videomicroscopy was used to quantify arteriolar diameter responses to dilator agonists in arterioles overlying the sciatic nerve. 3. MNCV and EBF in 4-week-STZ-induced diabetic rats were decreased by 22% and 49% respectively. Arterioles were constricted with U46619 and dilation to acetylcholine (ACh), aprikalim, or sodium nitroprusside (SNP) examined. All agonists elicited dose-dependent dilation in control and diabetic rats, although ACh-induced dilation was significantly reduced in diabetic rats. Treating vessels from normal or diabetic rats with indomethacin (INDO) alone did not significantly affect ACh-induced relaxation. However, ACh-induced vasodilation was significantly reduced by treatment with KCl or Nomega-nitro-L-arginine (LNNA) alone. Combining LNNA and KCl further reduced ACh-induced dilation in these vessels. 4. Diabetes causes vasodilator dysfunction in a microvascular bed that provides circulation to the sciatic nerve. These studies imply that ACh-induced dilation in these vessels is mediated by multiple mechanisms that may include the endothelial-dependent production of nitric oxide and endothelial-derived hyperpolarizing factor. This impaired vascular response is associated with neural dysfunction. PMID:10516670

Terata, K; Coppey, L J; Davidson, E P; Dunlap, J A; Gutterman, D D; Yorek, M A



Noopept reduces the postischemic functional and metabolic disorders in the brain of rats with different sensitivity to hypoxia.  


Chronic cerebral ischemia was induced by ligation of both common carotid arteries in Wistar rats, divided by sensitivity to hypoxia into highly sensitive and low-sensitive. Noopept (peptide preparation), injected (0.5 mg/kg) during 7 days after occlusion of the carotid arteries, reduced the neurological disorders in rats with high and low sensitivity to hypoxia and improved their survival during the postischemic period. Noopept normalized behavior disordered by cerebral ischemia (according to the open field and elevated plus maze tests), prevented accumulation of LPO products and inhibition of antioxidant systems in the brain of rats with high and low sensitivity to hypoxia. Hence, noopept exhibited a neuroprotective effect in cerebral ischemia. PMID:19529857

Zarubina, I V; Shabanov, P D



Dietary resistant starch dose-dependently reduces adiposity in obesity-prone and obesity-resistant male rats  

PubMed Central

Background Animal studies show that diets containing resistant starch (RS) at levels not achievable in the human diet result in lower body weight and/or adiposity in rodents. We aimed to determine whether RS dose-dependently reduces adiposity in obesity-prone (OP) and obesity-resistant (OR) rats. Methods Male Sprague–Dawley rats (n=120) were fed a moderate-fat, high-energy diet for 4 wk. Rats that gained the most weight (40%) were classified as obesity-prone (OP) and obesity-resistant (OR) rats were the 40% that gained the least weight. OP and OR rats were randomly allocated to one of six groups (n=8 for each phenotype). One group was killed for baseline measurements, the other five groups were allocated to AIN-93 based diets that contained 0, 4, 8, 12 and 16% RS (as high amylose maize starch) for 4 wk. These diets were matched for total carbohydrate content. At 0, 4 and 7 wk from the start of the study insulin sensitivity was calculated by homeostasis model assessment of insulin resistance (HOMA-IR) and adiposity was determined by dual-energy X-ray absorptiometry (DXA). At 8 wk, rats were euthanized and fat pad weights, intestinal digesta short chain fatty acid (SCFA) pools and plasma gut hormone levels were determined. Results Obesity prone rats gained less weight with 4, 12 and 16% RS compared to 0% RS, but the effect in OR animals was significant only at 16% RS. Irrespective of phenotype, diets containing ?8% RS reduced adiposity compared to 0% RS. Energy intake decreased by 9.8 kJ/d for every 4% increase in RS. All diets containing RS increased total SCFA pools in the caecum and lowered plasma GIP concentrations compared to the 0% RS, whereas plasma GLP-1 and PYY were increased when the diet contained at least 8% RS. Insulin sensitivity was not affected by RS. Conclusion RS in amounts that could be potentially consumed by humans were effective in reducing adiposity and weight gain in OP and OR rats, due in part to a reduction in energy intake, and changes in gut hormones and large bowel carbohydrate fermentation. PMID:23098187



Ghrelin promotes antioxidant enzyme activity and reduces lipid peroxidation in the rat ovary  

Microsoft Academic Search

Antioxidant properties of ghrelin have been recently reported on various oxidative stresses in limited tissues. This study was set to examine the possible antioxidative effects of ghrelin in rat ovarian tissue. Twenty eight female adult Wistar rats were randomly allocated into control and treatment groups. Treatment group (n=14) received 2nmol of ghrelin as subcutaneous injection for 14 consecutive days or

Arash Kheradmand; Masoud Alirezaei; Mahdi Birjandi



Morphometry of Macaca mulatta forelimb. I. Shoulder and elbow muscles and segment inertial parameters.  


The present study examined the morphometric properties of the forelimb, including the inertial properties of the body segments and the morphometric parameters of 21 muscles spanning the shoulder and/or elbow joints of six Macaca mulatta and three M. fascicularis. Five muscle parameters are presented: optimal fascicle length (L(0)(M)), tendon slack length (L(S)(T)), physiological cross-sectional area (PCSA), pennation angle (alpha(0)), and muscle mass (m). Linear regressions indicate that muscle mass, and to a lesser extent PCSA, correlated with total body weight. Segment mass, center-of-mass, and the moment of inertia of the upper arm, forearm, and hand are also presented. Our data indicate that for some segments, radius of gyration (rho) predicts segment moment of inertia better than linear regressions based on total body weight. Key differences between the monkey and human forelimb are highlighted. PMID:10972970

Cheng, E J; Scott, S H



Extract of Ginkgo biloba (EGb 761) improves behavioral performance and reduces histopathology after cortical contusion in the rat.  


Male rats received bilateral frontal cortex contusions and were injected with 100 mg/kg of EGb 761 or an equal volume of vehicle beginning 5 min after injury and then with 1 injection/day for 7 days. The rats were tested for spontaneous motor behavior on days 1, 5, 10, and 15 postinjury and then for 10 days of spatial navigation performance in the Morris Water Maze (MWM), beginning on the day 8 after the contusion. Brain tissue was removed for examination on the 18th day after injury. Contused rats given EGb 761 performed more like intact rats on measures of spontaneous motor activity while vehicle-treated counterparts remained more active than either shams or EGb 761-treated animals by the conclusion of testing. Contusion-only rats were worse than shams on spatial performance, while those given EGb 761 were less impaired. Histological analyses indicated that EGb 761 failed to prevent loss of tissue at the primary site of impact. However, the extract reduced retrograde degeneration of neurons, gliosis in the thalamus, and ex vacuo hydrocephalus. EGb 761 treatment also decreased the loss of ChAT-positive neurons in the dorsomedial caudate-putamen and in the nucleus basalis magnocellularis (NBM). The results of this study indicate that EGb 761 could be a possible treatment for traumatic brain injury. PMID:21551523

Hoffman, S W; Stein, D G



Dexmedetomidine reduces response tendency, but not accuracy of rats in attention and short-term memory tasks.  


The present study investigated the role of alpha 2-adrenergic mechanisms in the performance of motor responses, attention and short-term memory in rats. A low dose (3.0 micrograms/kg, s.c.) of dexmedetomidine, an alpha 2-adrenoceptor agonist, reduced response tendency in an attentional task and a working memory task, but it did not affect the choice accuracy of rats. Atipamezole (300 micrograms/kg), an alpha 2-adrenoceptor antagonist, increased anticipatory responding. Although atipamezole did not affect the number of omissions, it reversed the effects of dexmedetomidine on that parameter. We also investigated the effects of dexmedetomidine in rats with partial destruction of noradrenergic nerves induced by the neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride). On its own, DSP-4 treatment did not affect choice accuracy or behavioural activity of rats in the attentional task. The effects of dexmedetomidine (0.3-3.0 micrograms/kg) on anticipatory responses did not differ between controls and DSP-4 group. Furthermore, the effect on omissions was not consistently diminished in DSP-4 treated rats. These results suggest that the activation of postsynaptic alpha 2-adrenoreceptors may be responsible for dexmedetomidine-induced reduction of response tendency while attention and short-term memory are not markedly affected. PMID:8981606

Ruotsalainen, S; Haapalinna, A; Riekkinen, P J; Sirviö, J



Activity of cAMP-dependent protein kinase is reduced in protein-energy malnourished rats.  


Glucagon decreases glutathione synthesis in hepatocytes from well-nourished rats. However, in hepatocytes from malnourished rats, glucagon does not inhibit glutathione synthesis, suggesting a desensitization of cAMP-mediated signal transduction. We investigated the mechanism for this desensitization of cAMP-mediated responsiveness in malnourished rats by comparing the signal transduction pathways in rats fed very low protein diets (0.5 g protein/100 g diet) with those of rats fed diets adequate in protein (15 g protein/100 g diet) for 2 wk. Glucagon receptor and forskolin-stimulated cAMP production were greater in hepatocytes from malnourished rats. Stimulation of adenylyl cyclase with forskolin, guanine nucleotides or manganese in hepatic membranes was also enhanced after malnutrition. Moreover, quantity of the stimulatory guanine nucleotide regulatory protein was 70-80% greater in hepatocytes from malnourished rats but the inhibitory guanine nucleotide regulatory protein was not different. These results suggested that desensitization of cAMP-mediated signal transduction after malnutrition occurred at a site distal to cAMP production. Maximal activity of cAMP-dependent protein kinase was 60% lower in liver homogenates from malnourished rats compared with controls. This difference in activity was confined to the cytosolic compartment, with no difference in activity observed in the particulate fraction. Lower activity of cAMP-dependent protein kinase in the cytosol of malnourished rats was associated with a 43% reduction in the quantity of regulatory subunit type I, with no difference in the regulatory subunit type II. These data indicate that desensitization of cAMP signal transduction in rat liver after malnutrition is due to a decrease in the quantity and activity of cAMP-dependent protein kinase. PMID:7876914

Rozwadowski, M; Stephen, L L; Goss, P M; Bray, T M; Nagy, L E



Reduced contraction strength with increased intracellular [Ca2+] in left ventricular trabeculae from failing rat hearts  

PubMed Central

Intracellular calcium ([Ca2+]i) and isometric force were measured in left ventricular (LV) trabeculae from spontaneously hypertensive rats (SHR) with failing hearts and normotensive Wistar-Kyoto (WKY) controls. At a physiological stimulation frequency (5 Hz), and at 37 °C, the peak stress of SHR trabeculae was significantly (P ?; 0.05) reduced compared to WKY (8 ± 1 mN mm?2(n = 8)vs. 21 ± 5 mN mm?2(n = 8), respectively). No differences between strains in either the time-to-peak stress, or the time from peak to 50 % relaxation were detected. Measurements using fura-2 showed that in the SHR both the peak of the Ca2+ transient and the resting [Ca2+]i were increased compared to WKY (peak: 0.69 ± 0.08 vs. 0.51 ± 0.08 ?m (P ? 0.1) and resting: 0.19 ± 0.02 vs. 0.09 ± 0.02 ?m (P ? 0.05), SHR vs. WKY, respectively). The decay of the Ca2+ transient was prolonged in SHR, with time constants of: 0.063 ± 0.002 vs. 0.052 ± 0.003 s (SHR vs. WKY, respectively). Similar results were obtained at 1 Hz stimulation, and for[Ca2+]o between 0.5 and 5 mm. The decay of the caffeine-evoked Ca2+ transient was slower in SHR (9.8 ± 0.7 s (n = 8)vs. 7.7 ± 0.2 s (n = 8) in WKY), but this difference was removed by use of the SL Ca2+-ATPase inhibitor carboxyeosin. Histological examination of transverse sections showed that the fractional content of perimysial collagen was increased in SHR compared to WKY (18.0 ± 4.6 % (n = 10)vs. 2.9 ± 0.9 % (n = 11) SHR vs. WKY, respectively). Our results show that differences in the amplitude and the time course of the Ca2+ transient between SHR and WKY do not explain the reduced contractile performance of SHR myocardium per se. Rather, we suggest that, in this animal model of heart failure, contractile function is compromised by increased collagen, and its three-dimensional organisation, and not by reduced availability of intracellular Ca2+. PMID:12527740

Ward, Marie-Louise; Pope, Adele J; Loiselle, Denis S; Cannell, Mark B



Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats  

PubMed Central

Background Intracerebral hemorrhage (ICH) remains a serious clinical problem lacking effective treatment. Urocortin (UCN), a novel anti-inflammatory neuropeptide, protects injured cardiomyocytes and dopaminergic neurons. Our preliminary studies indicate UCN alleviates ICH-induced brain injury when administered intracerebroventricularly (ICV). The present study examines the therapeutic effect of UCN on ICH-induced neurological deficits and neuroinflammation when administered by the more convenient intraperitoneal (i.p.) route. Methods ICH was induced in male Sprague-Dawley rats by intrastriatal infusion of bacterial collagenase VII-S or autologous blood. UCN (2.5 or 25 ?g/kg) was administered i.p. at 60 minutes post-ICH. Penetration of i.p. administered fluorescently labeled UCN into the striatum was examined by fluorescence microscopy. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/wet method. Blood-brain barrier (BBB) disruption was assessed using the Evans blue assay. Hemorrhagic volume and lesion volume were assessed by Drabkin's method and morphometric assay, respectively. Pro-inflammatory cytokine (TNF-?, IL-1?, and IL-6) expression was evaluated by enzyme-linked immunosorbent assay (ELISA). Microglial activation and neuronal loss were evaluated by immunohistochemistry. Results Administration of UCN reduced neurological deficits from 1 to 7 days post-ICH. Surprisingly, although a higher dose (25 ?g/kg, i.p.) also reduced the functional deficits associated with ICH, it is significantly less effective than the lower dose (2.5 ?g/kg, i.p.). Beneficial results with the low dose of UCN included a reduction in neurological deficits from 1 to 7 days post-ICH, as well as a reduction in brain edema, BBB disruption, lesion volume, microglial activation and neuronal loss 3 days post-ICH, and suppression of TNF-?, IL-1?, and IL-6 production 1, 3 and 7 days post-ICH. Conclusion Systemic post-ICH treatment with UCN reduces striatal injury and neurological deficits, likely via suppression of microglial activation and inflammatory cytokine production. The low dose of UCN necessary and the clinically amenable peripheral route make UCN a potential candidate for development into a clinical treatment regimen. PMID:22257737



Force- and moment-generating capacities of muscles in the distal forelimb of the horse  

PubMed Central

A detailed musculoskeletal model of the distal equine forelimb was developed to study the influence of musculoskeletal geometry (i.e. muscle paths) and muscle physiology (i.e. force–length properties) on the force- and moment-generating capacities of muscles crossing the carpal and metacarpophalangeal joints. The distal forelimb skeleton was represented as a five degree-of-freedom kinematic linkage comprised of eight bones (humerus, radius and ulna combined, proximal carpus, distal carpus, metacarpus, proximal phalanx, intermediate phalanx and distal phalanx) and seven joints (elbow, radiocarpal, intercarpal, carpometacarpal, metacarpophalangeal (MCP), proximal interphalangeal (pastern) and distal interphalangeal (coffin)). Bone surfaces were reconstructed from computed tomography scans obtained from the left forelimb of a Thoroughbred horse. The model was actuated by nine muscle–tendon units. Each unit was represented as a three-element Hill-type muscle in series with an elastic tendon. Architectural parameters specifying the force-producing properties of each muscle–tendon unit were found by dissecting seven forelimbs from five Thoroughbred horses. Maximum isometric moments were calculated for a wide range of joint angles by fully activating the extensor and flexor muscles crossing the carpus and MCP joint. Peak isometric moments generated by the flexor muscles were an order of magnitude greater than those generated by the extensor muscles at both the carpus and the MCP joint. For each flexor muscle in the model, the shape of the maximum isometric joint moment–angle curve was dominated by the variation in muscle force. By contrast, the moment–angle curves for the muscles that extend the MCP joint were determined mainly by the variation in muscle moment arms. The suspensory and check ligaments contributed more than half of the total support moment developed about the MCP joint in the model. When combined with appropriate in vivo measurements of joint kinematics and ground-reaction forces, the model may be used to determine muscle–tendon and joint–reaction forces generated during gait. PMID:12892409

Brown, Nicholas AT; Pandy, Marcus G; Kawcak, Christopher E; Mcllwraith, C Wayne



Hox C6 expression during development and regeneration of forelimbs in larval Notophthalmus viridescens  

Microsoft Academic Search

A central theme concerning the epimorphic regenerative potential of urodele amphibian appendages is that limb regeneration\\u000a in the adult parallels larval limb development. Results of previous research have led to the suggestion that homeobox containing\\u000a genes are ”re-expressed” during the epimorphic regeneration of forelimbs of adult Notophthalmus viridescens in patterns which retrace larval limb development. However, to date no literature

Paul A. Khan; Catherine Tsilfidis; Richard A. Liversage



N-Acetylcysteine and deferoxamine reduce pulmonary oxidative stress and inflammation in rats after coal dust exposure  

SciTech Connect

Coal dust inhalation induces oxidative damage and inflammatory infiltration on lung parenchyma. Thus, the aim of this study was to determine whether N-acetylcysteine (NAC) administered alone or in combination with deferoxamine (DFX), significantly reduced the inflammatory infiltration and oxidative damage in the lungs of rats exposed to coal dust. Forty-two male Wistar rats (200-250 g) were exposed to the coal dust (3 mg/0.5 mL saline, 3 days/week, for 3 weeks) by intratracheal instillation. The animals were randomly divided into three groups: saline 0.9% (n = 8), supplemented with NAC (20 mg/kg of body weight/day, intraperitoneal injection (i.p.)) (n = 8), and supplemented with NAC (20 mg/kg of body weight/day, i.p.) plus DFX (20 mg/kg of body weight/week) (n = 8). Control animals received only saline solution (0.5 mL). Lactate dehydrogenase activity and total cell number were determined in the bronchoalveolar lavage fluid. We determined lipid peroxidation and oxidative protein damage parameters and catalase and superoxide dismutase activities in the lungs of animals. Intratracheal instillation of coal dust in the lungs of rats led to an inflammatory response and induced significant oxidative damage. The administration of NAC alone or in association with DFX reduced the inflammatory response and the oxidative stress parameters in rats exposed to coal dust.

Pinho, R.A.; Silveira, P.C.L.; Silva, L.A.; Streck, E.L.; Dal-Pizzol, F.; Moreira, J.C.F.



Achyranthes bidentata Polypeptides Reduces Oxidative Stress and Exerts Protective Effects against Myocardial Ischemic/Reperfusion Injury in Rats  

PubMed Central

Achyranthes bidentata, a Chinese medicinal herb, is reported to be neuroprotective. However, its role in cardioprotection remains largely unknown. Our present study aimed to investigate the effects of Achyranthes bidentata polypeptides (ABPP) preconditioning on myocardial ischemia/reperfusion (MI/R) injury and to test the possible mechanisms. Rats were treated with ABPP (10 mg/kg/d, i.p.) or saline once daily for one week. Afterward, all the animals were subjected to 30 min of myocardial ischemia followed by 4 h of reperfusion. ABPP preconditioning for one week significantly improved cardiac function following MI/R. Meanwhile, ABPP reduced infarct size, plasma creatine kinase (CK)/lactate dehydrogenase (LDH) activities and myocardial apoptosis at the end of reperfusion in rat hearts. Moreover, ABPP preconditioning significantly inhibited superoxide generation, gp91phox expression, malonaldialdehyde formation and enhanced superoxide dismutase activity in I/R hearts. Furthermore, ABPP treatment inhibited PTEN expression and increased Akt phosphorylation in I/R rat heart. PI3K inhibitor wortmannin blocked Akt activation, and abolished ABPP-stimulated anti-oxidant effect and cardioprotection. Our study demonstrated for the first time that ABPP reduces oxidative stress and exerts cardioprotection against MI/R injury in rats. Inhibition of PTEN and activation of Akt may contribute to the anti-oxidant capacity and cardioprotection of ABPP. PMID:24084726

Tie, Ru; Ji, Lele; Nan, Ying; Wang, Wenqing; Liang, Xiangyan; Tian, Fei; Xing, Wenjuan; Zhu, Miaozhang; Li, Rong; Zhang, Haifeng



The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats.  


This report compares the effects of progesterone and its metabolite, allopregnanolone, on the early injury cascade (apoptosis) and long-term functional deficits after TBI. Progesterone (16 mg/kg) or allopregnanolone (4, 8, or 16 mg/kg) were injected at 1 h, 6 h, and then for 5 consecutive days after bilateral contusions of the frontal cortex in adult male rats. Within one day after injury, progesterone and allopregnanolone reduced both the expression of pro-apoptotic proteins caspase-3 and Bax, and apoptotic DNA fragmentation. Progesterone and allopregnanolone also reduced the size of glial fibrillary acid protein (GFAP)-positive astrocytes at the lesion site 24 h after injury. Compared to sham-operated controls at 19 days after injury, injured rats given either progesterone or any of three doses of allopregnanolone had equivalent numbers of ChAT-positive cells in the nucleus basalis magnocellularis. At 19 days post-injury, rats given progesterone or allopregnanolone (8 mg/kg) showed improved performance in a spatial learning task compared to injured rats given only the vehicle. These results provide evidence of the anti-apoptotic and anti-astrogliotic effects of progesterone and allopregnanolone and help to explain why better cognitive performance is observed after injury when animals are given either neurosteroid. PMID:15665606

Djebaili, Myriam; Guo, Qingmin; Pettus, Edward H; Hoffman, Stuart W; Stein, Donald G



The phylogeny of the red panda (Ailurus fulgens): evidence from the forelimb.  


Within the order Carnivora, the phylogeny of the red panda (Ailurus fulgens) is contentious, with morphological and molecular studies supporting a wide range of possible relationships, including close ties to procyonids, ursids, mustelids and mephitids. This study provides additional morphological data, including muscle maps, for the forelimb of Ailurus, based on the dissection of four cadavers from the National Zoological Park, Washington, DC, USA. The red panda forelimb is characterized by a number of primitive features, including the lack of m. rhomboideus profundus, a humeral insertion for m. cleidobrachialis, the presence of mm. brachioradialis, articularis humeri and coracobrachialis, a single muscle belly for m. extensor digitorum lateralis with tendons to digits III-V, four mm. lumbricales, and the presence of mm. flexor digitorum brevis manus, adductores digiti I, II and V, and abductor digiti I and V. Red pandas resemble Ailuropoda, mustelids and some procyonids in possessing a soft tissue origin of m. flexor digitorum superficialis. In addition, red pandas are similar to ursids and procyonids in having a variable presence of m. biceps brachii caput breve. Furthermore, Ailurus and some ursids lack m. rhomboideus capitis. The forelimb muscle maps from this study represent a valuable resource for analyzing the functional anatomy of fossil ailurids and some notes on the Miocene ailurid, Simocyon batalleri, are presented. PMID:19930516

Fisher, Rebecca E; Adrian, Brent; Barton, Michael; Holmgren, Jennifer; Tang, Samuel Y



The phylogeny of the red panda (Ailurus fulgens): evidence from the forelimb  

PubMed Central

Within the order Carnivora, the phylogeny of the red panda (Ailurus fulgens) is contentious, with morphological and molecular studies supporting a wide range of possible relationships, including close ties to procyonids, ursids, mustelids and mephitids. This study provides additional morphological data, including muscle maps, for the forelimb of Ailurus, based on the dissection of four cadavers from the National Zoological Park, Washington, DC, USA. The red panda forelimb is characterized by a number of primitive features, including the lack of m. rhomboideus profundus, a humeral insertion for m. cleidobrachialis, the presence of mm. brachioradialis, articularis humeri and coracobrachialis, a single muscle belly for m. extensor digitorum lateralis with tendons to digits III–V, four mm. lumbricales, and the presence of mm. flexor digitorum brevis manus, adductores digiti I, II and V, and abductor digiti I and V. Red pandas resemble Ailuropoda, mustelids and some procyonids in possessing a soft tissue origin of m. flexor digitorum superficialis. In addition, red pandas are similar to ursids and procyonids in having a variable presence of m. biceps brachii caput breve. Furthermore, Ailurus and some ursids lack m. rhomboideus capitis. The forelimb muscle maps from this study represent a valuable resource for analyzing the functional anatomy of fossil ailurids and some notes on the Miocene ailurid, Simocyon batalleri, are presented. PMID:19930516

Fisher, Rebecca E; Adrian, Brent; Barton, Michael; Holmgren, Jennifer; Tang, Samuel Y



Hox5 interacts with Plzf to restrict Shh expression in the developing forelimb  

PubMed Central

To date, only the five most posterior groups of Hox genes, Hox9–Hox13, have demonstrated loss-of-function roles in limb patterning. Individual paralog groups control proximodistal patterning of the limb skeletal elements. Hox9 genes also initiate the onset of Hand2 expression in the posterior forelimb compartment, and collectively, the posterior HoxA/D genes maintain posterior Sonic Hedgehog (Shh) expression. Here we show that an anterior Hox paralog group, Hox5, is required for forelimb anterior patterning. Deletion of all three Hox5 genes (Hoxa5, Hoxb5, and Hoxc5) leads to anterior forelimb defects resulting from derepression of Shh expression. The phenotype requires the loss of all three Hox5 genes, demonstrating the high level of redundancy in this Hox paralogous group. Further analyses reveal that Hox5 interacts with promyelocytic leukemia zinc finger biochemically and genetically to restrict Shh expression. These findings, along with previous reports showing that point mutations in the Shh limb enhancer lead to similar anterior limb defects, highlight the importance of Shh repression for proper patterning of the vertebrate limb. PMID:24218595

Xu, Ben; Hrycaj, Steven M.; McIntyre, Daniel C.; Baker, Nicholas C.; Takeuchi, Jun K.; Jeannotte, Lucie; Gaber, Zachary B.; Novitch, Bennett G.; Wellik, Deneen M.



Enzymatically synthesized glycogen reduces lipid accumulation in diet-induced obese rats.  


Based on a recent study indicating that enzymatically synthesized glycogen (ESG) possesses a dietary, fiber-like action, we hypothesized that ESG can reduce the risk of obesity. In this study, the antiobesity effects of ESG were investigated in a model of diet-induced obesity. Male Sprague-Dawley rats were divided into 4 groups and fed a normal or high-fat diet, with or without 20% ESG, for 4 weeks. Body weight, food intake, lipid deposition in the white adipose tissues and liver, fecal lipid excretion, and plasma lipid profiles were measured. At week 3, the body fat mass was measured using an x-ray computed tomography system, which showed that ESG significantly suppressed the high-fat diet-induced lipid accumulation. Similar results were observed in the weight of the adipose tissue after the experiment. Moreover, ESG significantly suppressed the lipid accumulation in the liver but increased fecal lipid excretion. The plasma concentrations of triacylglycerol and nonesterified fatty acid were lowered after a high-fat diet, whereas the total bile acid concentration was increased by ESG. However, the hepatic messenger RNA (mRNA) levels of enzymes related to lipid metabolism were not affected by ESG. Conversely, the mRNA levels of long-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase were up-regulated by ESG in the muscle. These results suggest that the combined effects of increased fecal lipid excretion, increased mRNA levels of enzymes that oxidize fatty acids in the muscle, and increased total bile acid concentration in the plasma mediate the inhibitory effect of ESG on lipid accumulation. PMID:24034574

Furuyashiki, Takashi; Ogawa, Rui; Nakayama, Yoko; Honda, Kazuhisa; Kamisoyama, Hiroshi; Takata, Hiroki; Yasuda, Michiko; Kuriki, Takashi; Ashida, Hitoshi



Docosahexaenoic acid reduces cellular inflammatory response following permanent focal cerebral ischemia in rats.  


Cellular inflammatory response plays an important role in ischemic brain injury and anti-inflammatory treatments in stroke are beneficial. Dietary supplementation with docosahexaenoic acid (DHA) shows anti-inflammatory and neuroprotective effects against ischemic stroke. However, its effectiveness and its precise modes of neuroprotective action remain incompletely understood. This study provides evidence of an alternative target for DHA and sheds light on the mechanism of its physiological benefits. We report a global inhibitory effect of 3 consecutive days of DHA preadministration on circulating and intracerebral cellular inflammatory responses in a rat model of permanent cerebral ischemia. DHA exhibited a neuroprotective effect against ischemic deficits by reduction of behavioral disturbance, brain infarction, edema and blood-brain barrier disruption. The results of enzymatic assay, Western blot, real-time reverse transcriptase polymerase chain reaction and flow cytometric analysis revealed that DHA reduced central macrophages/microglia activation, leukocyte infiltration and pro-inflammatory cytokine expression and peripheral leukocyte activation after cerebral ischemia. In parallel with these immunosuppressive phenomena, DHA attenuated post-stroke oxidative stress, c-Jun N-terminal kinase (JNK) phosphorylation, c-Jun phosphorylation and activating protein-1 (AP-1) activation but further elevated ischemia-induced NF-E2-related factor-2 (Nrf2) and heme oxygenase-1 (HO-1) expression. DHA treatment also had an immunosuppressive effect in lipopolysaccharide/interferon-?-stimulated glial cultures by attenuating JNK phosphorylation, c-Jun phosphorylation and AP-1 activation and augmenting Nrf2 and HO-1 expression. In summary, we have shown that DHA exhibited neuroprotective and anti-inflammatory effects against ischemic brain injury and these effects were accompanied by decreased oxidative stress and JNK/AP-1 signaling as well as enhanced Nrf2/HO-1 expression. PMID:24139673

Chang, Cheng-Yi; Kuan, Yu-Hsiang; Li, Jian-Ri; Chen, Wen-Ying; Ou, Yen-Chuan; Pan, Hung-Chuan; Liao, Su-Lan; Raung, Shue-Ling; Chang, Chen-Jung; Chen, Chun-Jung



Fenugreek seeds reduce aluminum toxicity associated with renal failure in rats  

PubMed Central

Despite the reports on safety concerns regarding the relationship between aluminum salts and neurological and bone disease, many countries continue to use aluminum as phosphate binders among patients with renal failure. In search for a diet supplement that could reduce aluminum toxicity related to renal failure, we carried out this prospective animal study in which the fenugreek seeds were assessed for their effects on rats nephrotoxicity induced by aluminum chloride (AlCl3). Oral AlCl3 administration during 5 months (500 mg/kg bw i.g for one month then 1600 ppm via drinking water) led to plasma biochemical changes, an inhibition of alkaline phosphatase (ALP), a decrease of total antioxidant status (TAS), and an induction of lipid peroxidation (LPO) in the blood and brain, in addition to kidney atrophy and morphological alterations at the level of Bowman's capsule, the glomerulus and different sorts of tubules, reminiscent of some known kidney disease. The treatment with the whole fenugreek seed powder (FSP) (5% in the diet) during the last 2 months showed its effectiveness in restoring normal plasma values of urea, creatinine, ALP and glucose, as well as re-increasing the TAS, inhibiting LPO and alleviating histopathological changes in the injured kidneys. This study highlights the induced nephrotoxicicity, as well as the related toxicity in the brain and bone, by chronic oral ingestion of the aluminum salts. However, the maintenance of a diet supplemented with fenugreek seeds could offer protection for the kidney, bone and brain, at the same time. PMID:24353832

Bakhta, Hayfa; Haouas, Zohra; Flehi-Slim, Imen; Ben Cheikh, Hassen



Glucose-6-phosphate reduces calcium accumulation in rat brain endoplasmic reticulum.  


Brain cells expend large amounts of energy sequestering calcium (Ca(2+)), while loss of Ca(2+) compartmentalization leads to cell damage or death. Upon cell entry, glucose is converted to glucose-6-phosphate (G6P), a parent substrate to several metabolic major pathways, including glycolysis. In several tissues, G6P alters the ability of the endoplasmic reticulum (ER) to sequester Ca(2+). This led to the hypothesis that G6P regulates Ca(2+) accumulation by acting as an endogenous ligand for sarco-endoplasmic reticulum calcium ATPase (SERCA). Whole brain ER microsomes were pooled from adult male Sprague-Dawley rats. Using radio-isotopic assays, (45)Ca(2+) accumulation was quantified following incubation with increasing amounts of G6P, in the presence or absence of thapsigargin, a potent SERCA inhibitor. To qualitatively assess SERCA activity, the simultaneous release of inorganic phosphate (Pi) coupled with Ca(2+) accumulation was quantified. Addition of G6P significantly and decreased Ca(2+) accumulation in a dose-dependent fashion (1-10 mM). The reduction in Ca(2+) accumulation was not significantly different that seen with addition of thapsigargin. Addition of glucose-1-phosphate or fructose-6-phosphate, or other glucose metabolic pathway intermediates, had no effect on Ca(2+) accumulation. Further, the release of Pi was markedly decreased, indicating G6P-mediated SERCA inhibition as the responsible mechanism for reduced Ca(2+) uptake. Simultaneous addition of thapsigargin and G6P did decrease inorganic phosphate in comparison to either treatment alone, which suggests that the two treatments have different mechanisms of action. Therefore, G6P may be a novel, endogenous regulator of SERCA activity. Additionally, pathological conditions observed during disease states that disrupt glucose homeostasis, may be attributable to Ca(2+) dystasis caused by altered G6P regulation of SERCA activity. PMID:22529775

Cole, Jeffrey T; Kean, William S; Pollard, Harvey B; Verma, Ajay; Watson, William D



Memantine reduces consumption of highly palatable food in a rat model of binge eating  

PubMed Central

Excessive consumption of highly palatable food has been linked to the development of eating disorders and obesity, and can be modeled in non-food-deprived rats by offering them a limited (2-h daily) access to an optional dietary fat. Since the glutamatergic system has recently emerged as a viable target for binge-eating medication development, we compared the effects of subchronic treatment with glutamatergic receptor antagonists to the effects of a reference appetite-suppressing agent sibutramine on highly palatable food (lard) and normal chow intake. In three separate experiments, the consumption of a standard laboratory chow and lard were measured during 12 days of medication treatment and for 6 days afterwards. Generalized estimating equations analysis demonstrated that sibutramine (7.5 mg/kg, PO) significantly decreased lard consumption, with a concurrent increase in chow consumption. Sibutramine effects disappeared after treatment discontinuation. The NMDA receptor antagonist memantine (5 mg/kg, IP) significantly decreased lard consumption and increased chow consumption, comparable to effects of sibutramine; however, memantine’s effects persisted after treatment discontinuation. The effects of the mGluR5 antagonist MTEP (7.5 mg/kg, IP) on food consumption were in the same direction as seen with memantine, but the observed differences were not significant. In an additional control experiment, sibutramine and memantine reduced unlimited (24 h) chow intake during the treatment phase. Present results provide evidence that glutamatergic neurotransmission might be involved in the regulation of excessive consumption of highly palatable foods, and suggest that NMDA receptor may be an attractive target for developing obesity and disordered eating pharmacotherapies. PMID:20571841

Kos, Tomasz; Zhang, Yulei; Bisaga, Adam



Acute and chronic estradiol treatments reduce memory deficits induced by transient global ischemia in female rats  

PubMed Central

Transient global ischemia induces selective, delayed neuronal death in the hippocampal CA1 and delayed cognitive deficits. Estrogen treatment ameliorates hippocampal injury associated with global ischemia. Although much is known about the impact of estrogen on neuronal survival, relatively little is known about its impact on functional outcome assessed behaviorally. We investigated whether long-term estradiol (21-day pellets implanted 14 days prior to ischemia) or acute estradiol (50 ?g infused into the lateral ventricles immediately after ischemia) attenuates ischemia-induced cell loss and improves visual and spatial working memory in ovariectomized female rats. Global ischemia significantly impaired visual and spatial memory, assessed by object recognition and object placement tests at 6–9 days. Global ischemia did not affect locomotion, exploration, or anxiety-related behaviors, assessed by an open-field test at 6 days. Long-term estradiol prevented the ischemia-induced deficit in visual working memory, maintaining normal performance in tests with retention intervals of up to 1 h. Long-term estradiol also prevented ischemia-induced deficits in spatial memory tests with short (1 and 7 min), but not longer (15 min), retention intervals. Acute estradiol significantly improved visual memory assessed with short retention intervals, but did not prevent deficits in spatial memory. Acute estradiol significantly increased the number of surviving CA1 neurons, assessed either at 7 days after ischemia or after the completion of behavioral testing 9 days after ischemia. In contrast, chronic estradiol did not reduce CA1 cell death 9 days after ischemia. Thus, long-term estradiol at near physiological levels and acute estradiol administered after ischemic insult improve functional recovery after global ischemia. These findings have important implications for intervention in the neurological sequellae associated with global ischemia. PMID:16125703

Gulinello, Maria; Lebesgue, Diane; Jover-Mengual, Teresa; Zukin, R. Suzanne; Etgen, Anne M.



Motor-Evoked Potential Confirmation of Functional Improvement by Transplanted Bone Marrow Mesenchymal Stem Cell in the Ischemic Rat Brain  

PubMed Central

This study investigated the effect of bone marrow mesenchymal stem cells (BMSCs) on the motor pathway in the transient ischemic rat brain that were transplanted through the carotid artery, measuring motor-evoked potential (MEP) in the four limbs muscle and the atlantooccipital membrane, which was elicited after monopolar and bipolar transcortical stimulation. After monopolar stimulation, the latency of MEP was significantly prolonged, and the amplitude was less reduced in the BMSC group in comparison with the control group (P < .05). MEPs induced by bipolar stimulation in the left forelimb could be measured in 40% of the BMSC group and the I wave that was not detected in the control group was also detected in 40% of the BMSC group. Our preliminary results imply that BMSCs transplanted to the ischemic rat brain mediate effects on the functional recovery of the cerebral motor cortex and the motor pathway. PMID:21772790

Jang, Dong-Kyu; Park, Sang-In; Han, Young-Min; Jang, Kyung-Sool; Park, Moon-Seo; Chung, Young-An; Kim, Min-Wook; Maeng, Lee-So; Huh, Pil-Woo; Yoo, Do-Sung; Jung, Seong-Whan



S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke  

Microsoft Academic Search

Preservation of endothelial functions with low-dose nitric oxide (NO) and inhibition of excessive production of NO from inducible NO synthase (iNOS) is a potential therapeutic approach for acute stroke. Based on this hypothesis, an NO modulator, S-nitrosoglutathione (GSNO) was used, which provided neuroprotection in a rat model of focal cerebral ischemia. Administration of GSNO after the onset of ischemia reduced

Mushfiquddin Khan; Bipanjeet Sekhon; Shailendra Giri; Manu Jatana; Anne G Gilg; Kamesh Ayasolla; Chinnasamy Elango; Avtar K Singh; Inderjit Singh



17?-estradiol reduces the effect of metabolic inhibition on gap junction intercellular communication in rat cardiomyocytes via the estrogen receptor  

Microsoft Academic Search

The effects of 17?-estradiol (E2) on gap junction intercellular communication (GJIC) were assessed by Lucifer yellow dye coupling in cultured neonatal rat cardiomyocytes after metabolic inhibition (MI) using potassium cyanide and sodium iodoacetate. MI significantly reduced dye coupling of cardiomyocytes to 8.5% ± 0.6% of control levels, and pretreatment with E2, but not its inactive isomer 17?-estradiol, dose-dependently (EC50 =

Tun-Hui Chung; Seu-Mei Wang; Jiahn-Chun Wu



A single pretreatment with 8-OH-DPAT reduces behavioral indices of serotonin 1A receptor activation in ovariectomized rats  

Microsoft Academic Search

The effects of prior treatment with 8-OH-DPAT on 8-OH-DPAT-induced eating behavior, hypothermia, flat body posture and forepaw treading were examined in ovariectomized rats. Twenty-four hours after a single pretreatment with 0.25 mg\\/kg of the drug, the eating behavior and flat body posture induced by 8-OH-DPAT were reduced relative to that seen following the first treatment with the drug. In contrast,

N. Maswood; L. Uphouse



Dietary Conjugated Linoleic Acid Reduces Rat Adipose Tissue Cell Size Rather than Cell Number1  

Microsoft Academic Search

We investigated the basis for the reduction in fat pad size in rats fed conjugated linoleic acid (CLA). In the first study, growing female Sprague-Dawley rats (initial weight150 g) were fed diets containing 0, 0.25 and 0.5 g\\/100 g diet of a purified (97% CLA) and 0.5% of a feed-grade (55% CLA) source of CLA for 5 wk to determine

Michael J. Azain; Dorothy B. Hausman; Matthew B. Sisk; William P. Flatt; Dennis E. Jewell


Folic acid reduces adhesion molecules VCAM-1 expession in aortic of rats with hyperhomocysteinemia  

Microsoft Academic Search

To investigate effects of supplementation of folic acid on the expression of adhesion molecules VCAM-1 in the aortas of rats with hyperhomocysteinemia. Thirty male SD rats (200±20 g) were invided into 3 groups (n=10 for each group): control group(Control), high Met group(Met) and Met plus Folate group(Met+Folate), fed. for 45 days.Plasma Hcy levels were higher with the high-methionine diet (140.68±36.87

Ming Li; Jian Chen; Yu-Shu Li; Yi-Bai Feng; Xiang Gu; Chun-Zhi Shi



Reduced Expression of GABA Transporter GAT3 in Helpless Rats, an Animal Model of Depression  

Microsoft Academic Search

Mood disorders have been linked to glial and synaptic pathology such as disturbed neurotransmission of ?-aminobutyric acid\\u000a (GABA). We evaluated the expression of GABAergic marker genes in rats with helpless behaviour, an animal model of depression.\\u000a Male Sprague-Dawley rats from inbred lines were tested for helpless behaviour and grouped according to failures in terminating\\u000a foot shock currents. Expression levels of

M. Zink; B. Vollmayr; P. J. Gebicke-Haerter; F. A. Henn



Prostatic Relaxation Induced by Loperamide Is Reduced in Spontaneously Hypertensive Rats  

PubMed Central

This paper shows a new finding about the decrease of relaxative response to loperamide in prostate of spontaneously hypertensive rats (SHR) as compare to normal rats (WKY). Authors demonstrated the reduction of ATP-sensitive potassium channels is resposible for this change using immunoblotting analysis and the decrease of action induced by diazoxide. This view is not mentioned before and is the first one reporting this result. PMID:22645476

Lee, Liang-Ming; Lu, Chih-Cheng; Chung, Hsien-Hui; Cheng, Juei-Tang



Intermittent hypoxia reduces upper airway stability in lean but not obese Zucker rats.  


Obstructive sleep apnea involves intermittent periods of airway occlusions that lead to repetitive oxygen desaturations. Exposure to chronic intermittent hypoxia (IH) in rats increases diurnal blood pressure and alters skeletal muscle physiology. The impact of IH on upper airway muscle function is unknown. We hypothesize that IH exposure increases upper airway collapsibility in rats due to alterations of the muscles surrounding the upper airway. Lean and obese rats were exposed to cyclic alterations in O(2) levels (20.6%-5%) every 90 s, 8 h/day for 6 days/wk for 12 wk. Following the exposure period, arterial pressure was recorded via the tail artery in conscious unrestrained rats. Mean arterial pressure was increased in lean IH but not in obese IH-exposed Zucker rats (P < 0.05). The pharyngeal pressure associated with airway collapse (P(crit)) was measured under anesthesia during baseline conditions and then during supramaximal stimulation of the hypoglossal nerve (cnXII). Baseline P(crit) was more positive (more collapsible) in lean but not obese rats following 12 wk of IH (P < 0.05), while supramaximal stimulation of cnXII increased airway stability (decreased P(crit)) in both lean and obese Zucker rats following IH to levels that were similar to their respective room air controls. The in vitro peak tension and the expression of the individual myosin heavy chain isoforms from the upper airway muscles were unaltered following IH. We conclude that IH leads to increases in baseline collapsibility in lean Zucker rats exposed to IH by nonmyogenic mechanisms. PMID:17459910

Ray, Andrew D; Magalang, Ulysses J; Michlin, Charles P; Ogasa, Toshiyuki; Krasney, John A; Gosselin, Luc E; Farkas, Gaspar A



Low-Power 2MHz Pulsed-Wave Transcranial Ultrasound Reduces Ischemic Brain Damage in Rats  

Microsoft Academic Search

It is largely unknown whether prolonged insonation with ultrasound impacts the ischemic brain tissue by itself. Our goal was\\u000a to evaluate safety and the effect of high-frequency ultrasound on infarct volume in rats. Thirty-two Long–Evans rats with\\u000a permanent middle cerebral and carotid artery occlusions received either 2-MHz ultrasound at two levels of insonation power\\u000a (128 or 10 mW) or no ultrasound

Andrei V. Alexandrov; Kristian Barlinn; Roger Strong; Anne W. Alexandrov; Jaroslaw Aronowski


Palmatine from Coptidis rhizoma reduces ischemia–reperfusion-mediated acute myocardial injury in the rat  

Microsoft Academic Search

The aim of the present study was to evaluate the protective effect of palmatine, one of active ingredients of Coptidis rhizoma, against myocardial ischemia–reperfusion (I\\/R) injury is due to its antioxidant and anti-inflammatory action. Adult male rats were subjected to 30min of ischemia and 6 or 24h of reperfusion. Rats were randomized to receive vehicle or palmatine 1h before reperfusion.

Young Min Kim; Yu Mi Ha; Yong Chun Jin; Lian Yu Shi; Yong Soo Lee; Hye Jung Kim; Han Geuk Seo; Jae Soo Choi; Yeong Shik Kim; Sam Sik Kang; Jae Heun Lee; Ki Churl Chang



Involvement of aberrant DNA methylation on reduced expression of lysophosphatidic acid receptor-1 gene in rat tumor cell lines  

SciTech Connect

Lysophosphatidic acid (LPA) is a bioactive phospholipid that stimulates cell proliferation, migration, and protects cells from apoptosis. It interacts with specific G protein-coupled transmembrane receptors. Recently, it has been reported that alterations of LPA receptor expression might be important in the malignant transformation of tumor cells. Therefore, to assess an involvement of DNA methylation in reduced expression of the LPA receptor-1 (lpa1) gene, we investigated the expression of the lpa1 gene and its DNA methylation patterns in rat tumor cell lines. Both rat brain-derived neuroblastoma B103 and liver-derived hepatoma RH7777 cells used in this study indicated no expression of lpa1. For the analysis of methylation status, bisulfite sequencing was performed with B103 and RH7777 cells, comparing with other lpa1 expressed cells and normal tissues of brain and liver. The lpa1 expressed cells and tissues were all unmethylated in this region of lpa1. In contrast, both B103 and RH7777 cells were highly methylated, correlating with reduced expression of the lpa1. Treatment with 5-aza 2'-deoxycytidine induced expression of lpa1 gene in B103 and RH7777 cells after 24 h. In RH7777 cells treated with 5-aza 2'-deoxycytidine, stress fiber formation was also observed in response to LPA in RH7777 cells, but not in untreated RH7777 cells. These results suggest that aberrant DNA methylation of the lpa1 gene may be involved in its reduced expression in rat tumor cells.

Tsujiuchi, Toshifumi [Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan)]. E-mail:; Shimizu, Kyoko [Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Onishi, Mariko [Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Sugata, Eriko [Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Fujii, Hiromasa [Department of Orthopedic Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Mori, Toshio [RI Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Honoki, Kanya [Department of Orthopedic Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Fukushima, Nobuyuki [Laboratory of Molecular Neurobiology, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan)



Microencapsulated Bifidobacterium longum subsp. infantis ATCC 15697 Favorably Modulates Gut Microbiota and Reduces Circulating Endotoxins in F344 Rats  

PubMed Central

The gut microbiota is a bacterial bioreactor whose composition is an asset for human health. However, circulating gut microbiota derived endotoxins cause metabolic endotoxemia, promoting metabolic and liver diseases. This study investigates the potential of orally delivered microencapsulated Bifidobacterium infantis ATCC 15697 to modulate the gut microbiota and reduce endotoxemia in F344 rats. The rats were gavaged daily with saline or microencapsulated B. infantis ATCC 15697. Following 38 days of supplementation, the treated rats showed a significant (P < 0.05) increase in fecal Bifidobacteria (4.34 ± 0.46 versus 2.45 ± 0.25% of total) and B. infantis (0.28 ± 0.21 versus 0.52 ± 0.12 % of total) and a significant (P < 0.05) decrease in fecal Enterobacteriaceae (0.80 ± 0.45 versus 2.83 ± 0.63% of total) compared to the saline control. In addition, supplementation with the probiotic formulation reduced fecal (10.52 ± 0.18 versus 11.29 ± 0.16?EU/mg; P = 0.01) and serum (0.33 ± 0.015 versus 0.30 ± 0.015?EU/mL; P = 0.25) endotoxins. Thus, microencapsulated B. infantis ATCC 15697 modulates the gut microbiota and reduces colonic and serum endotoxins. Future preclinical studies should investigate the potential of the novel probiotic formulation in metabolic and liver diseases. PMID:24967382

Saha, Shyamali; Prakash, Satya



Diphenyl diselenide reduces mechanical and thermal nociceptive behavioral responses after unilateral intrastriatal administration of 6-hydroxydopamine in rats.  


Parkinson's disease (PD) patients, in addition to motor dysfunction, also present alterations in pain sensation. The present study characterized the antinociceptive effects of diphenyl diselenide ((PhSe)2) in a model of nociception induced by unilateral, intrastriatal 6-hydroxydopamine (6-OHDA) injection in rats. Male adult Wistar rats received 20 ?g/3 ?l of 6-OHDA (in saline solution containing 0.02 % of ascorbic acid) or 3 ?l of vehicle into the right striatum (1.0 mm anterior, 3.0 mm lateral, and 5.0 mm ventral-with respect to the bregma). Thirty days after injection, rats received (PhSe)2 intragastrically at a dose of 10 mg/kg 1 h before behavioral tests (von Frey hairs, hot plate, tail immersion, formalin, and open field). Our results demonstrated that 6-OHDA injection to rats augmented the response frequency of von Frey hairs (VHF) stimulation, besides reducing the thermal withdrawal latency in the hot plate test. Importantly, the (PhSe)2 treatment decreased the mechanical allodynia measured by the response frequency of VHF stimulation and diminished the thermal nociception in the hot plate test in 6-OHDA-injected rats. In conclusion, these results revealed that a single oral administration of (PhSe)2 1 h prior to the accomplishment of the behavioral tests was effective to attenuate the increased mechanical and thermal nociception caused by a single intrastriatal 6-OHDA injection to rats. Furthermore, other clarifying studies are warranted to improve the evidence bases for future clinical use of (PhSe)2 as a new alternative therapy for the treatment of painful symptoms associated to PD. PMID:23821314

da Rocha, Juliana Trevisan; Pinton, Simone; Gai, Bibiana Mozzaquatro; Nogueira, Cristina Wayne



Dietary L-glutamine supplementation reduces the growth of the Morris Hepatoma 7777 in exercise-trained and sedentary rats.  


Dietary glutamine supplementation and exercise have been reported independently to enhance immune function and reduce tumor growth. We study the effect of both of these interventions on the growth of the Morris Hepatoma 7777, implanted in 59 female Sprague-Dawley Buffalo rats. Rats were fed a nutritionally complete, purified diet with or without L-glutamine 20 g/kg diet and randomized to swim 3 h/d or to remain sedentary. After 14 d, the mean tumor weight of glutamine-supplemented rats was lower (P < 0.0001) than that of unsupplemented rats (5.8 +/- 0.4 vs. 8.7 +/- 0.5 g, respectively). Exercise did not alter tumor growth. Glutamine supplementation increased [3H] thymidine incorporation by splenocytes incubated with Concanavalin A and the proportion of natural killer cells in spleen, but not cytotoxic activity against YAC-1 cells. Glutamine supplementation did not alter glutamine concentrations in plasma (691 +/- 12 mumol/L) or soleus muscle (5328 +/- 102 pmol/mg) but resulted in higher (P < 0.004) plasma concentrations of leucine, isoleucine and valine, precursors of glutamine. Splenocytes from exercised rats had a higher (P < 0.001) mitogen response than those from sedentary rats. Isolated tumor cells demonstrated high rates of non-oxidative glucose and glutamine metabolism and consumption of glutamine, tryptophan and methionine. However, neither diet nor exercise significantly affected glucose or glutamine metabolism by tumor cells. The precise mechanism of tumor growth suppression by oral glutamine supplementation is not clear but may be related to changes in substrate availability, improved tumor-directed natural killer cytotoxic activity or a faster response to an immune challenge. PMID:9040560

Shewchuk, L D; Baracos, V E; Field, C J



Lactobacillus plantarum NDC 75017 alleviates the learning and memory ability in aging rats by reducing mitochondrial dysfunction  

PubMed Central

The aim of the present study was to investigate the protective effect of Lactobacillus plantarum NDC 75017 on D-galactose (D-gal)-induced mitochondrial dysfunction in the rat cerebral cortex. Fifty rats were randomly divided into five groups (n=10 in each group). The rats in the aging model group were subcutaneously injected with 100 mg/kg D-gal and those in the protective groups were additionally orally administered L. plantarum NDC 75017 at doses of 1×108, 1×109 or 1×1010 CFU/100 mg body weight/day, respectively. The control rats were administrated an equal volume of the vehicle. Following continuous treatment for seven weeks, the learning and memory abilities and mitochondrial ultrastructure, function and adenosine triphosphate (ATP) levels were examined. The results showed that the learning and memory abilities and mitochondrial levels of ATP were significantly decreased in the D-gal-induced aging model group compared with those in the control group (P<0.01). In addition, marked changes in the mitochondrial functions and ultrastructure were observed between the groups. Seven weeks of L. plantarum NDC 75017 and D-gal coadministration significantly improved the learning and memory abilities of the rats compared with the D-gal-induced aging model group. Furthermore, the combination regime significantly improved the mitochondrial ultrastructure and functions, including the mitochondrial respiratory chain, mitochondrial membrane potential and mitochondrial permeability transition. The results revealed that the L. plantarum NDC 75017 was able to alleviate learning and memory injuries in aging rats by reducing the mitochondrial dysfunction induced by D-gal. PMID:25371742




Repeated rat-forced swim test: reducing the number of animals to evaluate gradual effects of antidepressants.  


The forced swim test (FST) is a pre-clinical test to short and long term treatment with antidepressant drugs (ADT), which requires between-subject designs. Herein a modified protocol of the FST using within-subject design (repeated rat-FST) was evaluated. Male Wistar rats were submitted to 15 min of swimming (Day 1: pretest) followed by three subsequent 5 min-swimming tests one week apart (Day 2: test, Day 7: retest 1, Day 14: retest 2). To determine the temporal and factorial characteristics of the variables scored in the repeated rat-FST, the protocol was carried out in untreated animals (E1). To validate the method, daily injections of Fluoxetine (FLX, 2.5mg/kg, i.p.) or saline were given over a 2-week period (E2). Tests and retests have been videotaped for further register of the latency, frequency and duration of behaviors. Over retesting the latency to immobility decreased whereas duration of immobility tended to increase. Factorial analysis revealed that the test, the retest 1 as well as the retest 2 have variables suitable to detection of antidepressant-like effects of ADT. Compared to saline, FLX chronically administrated reduced duration of immobility whereas increased duration of swimming in retest 2. The data suggest that repeated rat-FST detected the gradual increase in the efficacy of low doses of FLX over time. Therefore, repeated rat-FST seemed suitable to detect short and long term effects of selective serotonin reuptake inhibitors, or other ADT, thus reducing the number of animals used in the screenings of this type of compounds. PMID:21167866

Mezadri, T J; Batista, G M; Portes, A C; Marino-Neto, J; Lino-de-Oliveira, C



D-serine treatment reduces cocaine-primed reinstatement in rats following extended access to cocaine self-administration  

PubMed Central

The most intractable feature of drug addiction is the high rate of relapse, even following extended periods of abstinence from drug-taking. Evidence suggests that allowing rats extended access to cocaine self-administration leads to behavioral characteristics in these animals that are consistent with the development of addiction in humans. In the current study, rats were allowed to self-administer cocaine over a total of 22 daily sessions, the final 7 of which were long-access (LgA) sessions of 6 hours duration. Assessments of reinstatement of drug-seeking behavior were made following reintroduction to the drug-taking environment and noncontingent priming with either CS or cocaine in both extinguished and abstinent subject groups. Three separate groups of rats were treated with either saline or D-serine (100mg/kg i.p.) administered 2 hrs prior to, or immediately following, each extinction training session. Saline-treated LgA rats were resistant to the effects of extinction training to reduce noncontingent priming of reinstatement of drug-seeking behavior with either CS or cocaine. In contrast, treatment with D-serine either before or immediately following the sessions resulted in a significant enhancement in the ability of extinction training to reduce cocaine-primed reinstatement of drug-seeking behavior. These results suggest that D-serine can act to enhance the consolidation of extinction learning in LgA rats, and is therefore a promising adjunctive agent along with behavioral therapy for the treatment of cocaine addiction. PMID:20541592

Kelamangalath, Lakshmi; Wagner, John J.



Effect of two lipid emulsions on reversing high-dose levobupivacaine-induced reduced vasoconstriction in the rat aortas.  


The goals of this study were to determine which lipid emulsion (Intralipid(®) and Lipofundin MCT/LCT(®)) is more effective in reversing high-dose levobupivacaine-induced reduced vasoconstriction in isolated rat aortas and to examine the associated cellular mechanisms with a particular focus on the endothelium. Two lipid emulsion concentration-response curves were generated using high-dose levobupivacaine-induced reduced vasoconstriction and vasodilation of isolated aortas pretreated with or without 60 mM KCl. Endothelial nitric oxide synthase (eNOS) and caveolin-1 phosphorylation were measured in rat aortic tissue treated with levobupivacaine in the presence or absence of lipid emulsion. Dichlorofluorescein oxidation, a measure of reactive oxygen species production, was measured in lipid emulsion-treated human umbilical vein endothelial cells. In levobupivacaine (0.3 mM)-induced reduced vasoconstriction of isolated aorta, the magnitude of the Intralipid(®)- and Lipofundin MCT/LCT(®)-mediated reversal was not significantly different. Lipid emulsion reversal of levobupivacaine-induced reduced vasoconstriction was greater in endothelium-intact aortas than in endothelium-denuded aortas. The two lipid emulsions similarly inhibited levobupivacaine-induced eNOS phosphorylation in aortic tissue. Pretreatment with both lipid emulsions increased dichlorofluorescein oxidation. Both Intralipid(®) and Lipofundin MCT/LCT(®) are equally effective for vascular tone recovery from high-dose levobupivacaine-induced reduced vasoconstriction. This reversal is mediated partially by decreasing nitric oxide bioavailability. PMID:23877627

Ok, Seong-Ho; Park, Chang-Shin; Kim, Hye Jung; Lee, Soo Hee; Choi, Bo-Hwa; Eun, So Young; Kim, Kyung-Nam; Yang, Seong Min; Shin, Il-Woo; Choi, Mun-Jeoung; Sohn, Ju-Tae



Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats[S  

PubMed Central

Acyl CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final step in triacylglycerol (TAG) synthesis and is highly expressed in the small intestine. Because DGAT-1 knockout mice are resistant to diet-induced obesity, we investigated the acute effects of intragastric (IG) infusion of a small molecule diacylglycerol acyltransferase-1 inhibitor (DGAT-1i) on eating, circulating fat metabolites, indirect calorimetry, and hepatic and intestinal expression of key fat catabolism enzymes in male rats adapted to an 8 h feeding-16 h deprivation schedule. Also, the DGAT-1i effect on fatty acid oxidation (FAO) was investigated in enterocyte cell culture models. IG DGAT-1i infusions reduced energy intake compared with vehicle in high-fat diet (HFD)-fed rats, but scarcely in chow-fed rats. IG DGAT-1i also blunted the postprandial increase in serum TAG and increased ?-hydroxybutyrate levels only in HFD-fed rats, in which it lowered the respiratory quotient and increased intestinal, but not hepatic, protein levels of Complex III of the mitochondrial respiratory chain and of mitochondrial hydroxymethylglutaryl-CoA synthase. Finally, the DGAT-1i enhanced FAO in CaCo2 (EC50 = 0.3494) and HuTu80 (EC50 = 0.00762) cells. Thus, pharmacological DGAT-1 inhibition leads to an increase in intestinal FAO and ketogenesis when dietary fat is available. This may contribute to the observed eating-inhibitory effect. PMID:23449193

Schober, Gudrun; Arnold, Myrtha; Birtles, Susan; Buckett, Linda K.; Pacheco-Lopez, Gustavo; Turnbull, Andrew V.; Langhans, Wolfgang; Mansouri, Abdelhak



The nitroderivative of aspirin, NCX 4016, reduces infarct size caused by myocardial ischemia-reperfusion in the anesthetized rat.  


NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic ventricular dysfunction and to reduce myocardial infarct size in the rabbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) and aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Drugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachycardia and fibrillation; they were reduced dose dependently and correlated with survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardiac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arrhythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by L-NAME. The beneficial effects of NCX 4016 appear to derive in large part from the NO moiety, which modulates a number of cellular events leading to inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis. PMID:11259566

Rossoni, G; Manfredi, B; Colonna, V D; Bernareggi, M; Berti, F



Downregulation of fibronectin overexpression reduces basement membrane thickening and vascular lesions in retinas of galactose-fed rats.  


Overexpression of extracellular matrix (ECM) components is closely associated with the development of vascular basement membrane (BM) thickening, a histological hallmark of diabetic microangiopathy. To determine whether BM thickening of retinal capillaries could be prevented by down regulating synthesis of fibronectin, an ECM component, we used antisense oligos targeted against translation initiation site of the fibronectin transcript in galactose-fed rat, an animal model of diabetic retinopathy. After 2 months of galactose-feeding, intravitreal administration of 3 micro mol/l antisense fibronectin oligos was initiated at monthly intervals for 3 months. The antisense strategy significantly reduced fibronectin mRNA and protein level in the retinas of treated eyes compared with untreated eyes of galactose-fed rats (130 +/- 16 vs. 179 +/- 18% of control, P < 0.01, and 144 +/- 28 vs. 204 +/- 22% of control, respectively, r = 0.9) and resulted in partial reduction of retinal capillary BM width (123 +/- 16 vs. 201 +/- 12 nm, P < 0.03). In eyes treated with antisense fibronectin oligos, approximately 35% reduction in both pericyte loss and acellular retinal capillaries was observed (P < 0.04 and P < 0.03, respectively). Glycohemoglobin level was consistently elevated in the treated (6.9 +/- 0.6%) and untreated (6.5 +/- 0.7%) galactose-fed rats compared with control rats (4.5 +/- 0.8%). Overall, these results indicate that downregulation of fibronectin synthesis reduces BM thickening in retinal capillaries with beneficial effect to retinal lesions. The antisense fibronectin oligos may provide a useful approach for reducing vascular lesions in diabetic retinopathy. The thickened vascular BM may be a potential therapeutic target for preventing retinal lesions in diabetic retinopathy. PMID:12716757

Roy, Sayon; Sato, Tsuyoshi; Paryani, Gulabray; Kao, Richard



Green tea decoction improves glucose tolerance and reduces weight gain of rats fed normal and high-fat diet.  


Green tea containing polyphenols exerts antidiabetic and antiobesity effects, but the mechanisms involved are not fully understood. In this study, we first analyzed and compared polyphenol compounds [epigallocatechin gallate (EGCG), epigallocatechin (EGC)] in decoction of green tea leaves versus usual green tea extracts. Second, the effects of acute (30 min) or chronic (6 weeks) oral administration of green tea decoction (GTD) on intestinal glucose absorption were studied in vitro in Ussing chamber, ex vivo using isolated jejunal loops and in vivo through glucose tolerance tests. Finally, we explore in rat model fed normal or high-fat diet the effects of GTD on body weight, blood parameters and on the relative expression of glucose transporters SGLT-1, GLUT2 and GLUT4. GTD cooked for 15 min contained the highest amounts of phenolic compounds. In fasted rats, acute administration of GTD inhibited SGLT-1 activity, increased GLUT2 activity and improved glucose tolerance. Similarly to GTD, acute administration of synthetic phenolic compounds (2/3 EGCG+1/3 EGC) inhibited SGLT-1 activity. Chronic administration of GTD in rat fed high-fat diet reduced body weight gain, circulating triglycerides and cholesterol and improved glucose tolerance. GTD-treated rats for 6 weeks display significantly reduced SGLT-1 and increased GLUT2 mRNA levels in the jejunum mucosa. Moreover, adipose tissue GLUT4 mRNA levels were increased. These results indicate that GTD, a traditional beverage rich in EGCG and EGC reduces intestinal SGLT-1/GLUT2 ratio, a hallmark of regulation of glucose absorption in enterocyte, and enhances adipose GLUT4 providing new insights in its possible role in the control of glucose homeostasis. PMID:24656388

Snoussi, Chahira; Ducroc, Robert; Hamdaoui, Mohamed Hédi; Dhaouadi, Karima; Abaidi, Houda; Cluzeaud, Francoise; Nazaret, Corinne; Le Gall, Maude; Bado, André



Preclinical efficacy of sodium narcistatin to reduce inflammation and joint destruction in rats with adjuvant-induced arthritis.  


Current therapies for the treatment of rheumatoid arthritis (RA) do not work for all patients, can lose efficacy over time, and can have significant side effects. The discovery of new, effective therapies for RA remains an unmet medical need. The Amaryllidaceae isocarbostyril narciclasine was previously shown to prophylactically reduce paw swelling in rats with adjuvant-induced arthritis (AA). In this study, the efficacy of sodium narcistatin (SNS), a water-soluble cyclic phosphate pro-drug of narciclasine, was assessed in AA rats for anti-inflammatory and bone-sparing properties after disease onset. AA rats were given daily intraperitoneal injections of SNS (1.75, 3.5, or 5 mg/kg/day, in 500 ?l sterile endotoxin-free saline) or saline from disease onset through severe disease stages. Footpad widths and radiographic scoring were used as indicators of inflammation and joint destruction, respectively. Ex vivo cytokine production by peripheral blood mononuclear cells (PMBC), splenocytes, and draining lymph node (DLN) cells were determined using ELISAs. SNS treatment dose-dependently reduced joint inflammation (~70%) and bone loss (~50%) compared with AA controls. SNS treatment also reduced spleen weight (without affecting body weight), pro-inflammatory cytokine production by PMBC, splenocytes, and DLN cells, and site-dependently altered T-helper (Th)1-/Th2-type and anti-inflammatory cytokine profiles. SNS dramatically reduces inflammation and has bone-sparing properties, possibly by reducing immune cell pro-inflammatory cytokine production. Our findings support the development of SNS as a therapeutic for RA. PMID:22159913

Lubahn, Cheri; Schaller, Jill A; Shewmacker, Eric; Wood, Carlo; Bellinger, Denise L; Byron, Donna; Melody, Noeleen; Pettit, George R; Lorton, Dianne



Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines.  


Exercise raises brain serotonin release and is postulated to cause fatigue in athletes; ingestion of branched-chain amino acids (BCAA), by competitively inhibiting tryptophan transport into brain, lowers brain tryptophan uptake and serotonin synthesis and release in rats, and reputedly in humans prevents exercise-induced increases in serotonin and fatigue. This latter effect in humans is disputed. But BCAA also competitively inhibit tyrosine uptake into brain, and thus catecholamine synthesis and release. Since increasing brain catecholamines enhances physical performance, BCAA ingestion could lower catecholamines, reduce performance and thus negate any serotonin-linked benefit. We therefore examined in rats whether BCAA would reduce both brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Sedentary and exercising rats received BCAA or vehicle orally; tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis rates were measured 1 h later in brain. BCAA reduced brain tryptophan and tyrosine concentrations, and serotonin and catecholamine synthesis. These reductions in tyrosine concentrations and catecholamine synthesis, but not tryptophan or serotonin synthesis, could be prevented by co-administering tyrosine with BCAA. Complete essential amino acid mixtures, used to maintain or build muscle mass, were also studied, and produced different effects on brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Since pharmacologically increasing brain catecholamine function improves physical performance, the finding that BCAA reduce catecholamine synthesis may explain why this treatment does not enhance physical performance in humans, despite reducing serotonin synthesis. If so, adding tyrosine to BCAA supplements might allow a positive action on performance to emerge. PMID:23904096

Choi, Sujean; Disilvio, Briana; Fernstrom, Madelyn H; Fernstrom, John D



Steroidogenesis in fetal male rats is reduced by DEHP and DINP, but endocrine effects of DEHP are not modulated by DEHA in fetal, prepubertal and adult male rats.  


The plasticizer di(2-ethylhexyl)phthalate (DEHP) exhibits antiandrogenic effects in perinatally exposed male rats. Di(2-ethylhexyl) adipate (DEHA) and diisononyl phthalate (DINP) are currently being evaluated as potential substitutes for DEHP, but similarities in structure and metabolism of DEHP with DEHA and DINP have led to the hypothesis that similarities in action may also exist. Pregnant Wistar rats were gavaged during gestation and lactation with vehicle, DEHP (300 or 750 mg/kg bodyweight per day), DINP (750 mg/kg bodyweight per day), DEHP (750 mg/kg bodyweight per day) in combination with DEHA (400 mg/kg bodyweight per day), or DEHP (300 mg/kg bodyweight per day) in combination with DINP (750 mg/kg bodyweight per day). DINP and DEHP were both shown to reduce testicular testosterone production ex vivo and testosterone levels in testes and plasma of male fetuses at gestation day 21, indicating a similar mechanism of action for DINP and DEHP. Additionally, plasma LH levels in male fetuses were elevated. Neonatal anogenital distance was reduced and the number of nipples at postnatal day 13 increased in DEHP-exposed male offspring. Serum inhibin B levels were significantly reduced in DEHP-exposed prepubertal male offspring, and in a few adult males. No modulating effects of DEHA on the endocrine effects of DEHP were detected, but a tendency towards an accumulating effect of DEHP and DINP in combination on suppression of testosterone synthesis was seen. PMID:15013064

Borch, Julie; Ladefoged, Ole; Hass, Ulla; Vinggaard, Anne Marie



The utility of the phosphate binder, ferric citrate hydrate (JTT-751), about phosphorus absorption-reducing effect in normal rats.  


Hyperphosphatemia is a risk factor for arterial calcification contributing to the high-cardiovascular mortality in patients with chronic kidney disease (CKD). Ferric citrate hydrate (JTT-751) is being developed as a treatment for hyperphosphatemia with chronic renal failure and has shown a serum phosphorus-lowering effect in CKD patients. In this study, we evaluated the combination effect of JTT-751 with the phosphorus absorption-reducing effect of calcium carbonate and compared phosphorus absorption-reducing efficacy between three phosphate binders including JTT-751. Normal rats were fed a diet containing either 1% calcium carbonate, 1% JTT-751 or 1% JTT-751 with 1% calcium carbonate, for 7 days. Both 1% calcium carbonate and 1% JTT-751 alone reduced urinary phosphorus excretion, and the combined treatment reduced it more than each single-treatment, without clearly influencing calcium or iron-metabolism. Next, normal rats were fed a diet containing either 0.3, 1 and 3% lanthanum carbonate or 2.3% JTT-751, for 7 days. Either 3% lanthanum carbonate or 2.3% JTT-751 reduced urinary phosphorus excretion. Finally, we compared the reduced amount of urinary phosphorus excretion per dose of compound, of which JTT-751 is comparable to that of calcium carbonate and is greater than that of the lanthanum carbonate. In conclusion, JTT-751 showed an additive effect on the phosphorus absorption-reducing effect of calcium carbonate without influencing calcium- and iron-metabolism, and had a phosphorus absorption-reducing efficacy comparable to or greater than other existing phosphate binders. PMID:24975675

Matsuo, Akira; Iida, Akio; Tanimoto, Minako; Matsushita, Mutsuyoshi; Miyamoto, Ken-ichi



Mild hypothermia reduces expression of Fas/FasL and MMP-3 after cerebral ischemia-reperfusion in rats  

PubMed Central

Objective(s): To investigate the effects of local mild hypothermia on the expression of Fas, FasL and MMP-3 after cerebral ischemia-reperfusion in rats. Materials and Methods: Male Wistar rats were divided into sham-operated group (Sham), normothermia group (NT), and hypothermia group (HT). MCAO/R model was established by Longa’s method, and reperfusion was allowed after 2 hr occlusion. Mild hypothermia (33±0.5°C) for 6 hr was initiated at the start of reperfusion. Immunohistochemistry was performed to determine expression Fas, FasL, and MMP-3. Results: Infarct volume was reduced in the hypothermia group (18.43±4.23%) compared with the normothermia group (24.76±5.76%) (P<0.05). In mild hypothermia group, numbers of Fas-positive and MMP-3 positive cells were significantly less than those of normothermia group (P<0.05). Neurological functional scores of mild hypothermia were significantly improved (P<0.05). Conclusion: Mild hypothermia decreases infarct volume after cerebral ischemia-reperfusion, reduces Fas and MMP-3 expression, but increases FasL in cerebral ischemia-reperfusion rats. PMID:25140208

Zhao, Jingkun; Duan, Shurong; Zhou, Jinxia; Sun, Ruihong; Zhang, Liming; Wang, Desheng



Kefir administration reduced progression of renal injury in STZ-diabetic rats by lowering oxidative stress.  


This study aimed at assessing the effects of Kefir, a probiotic fermented milk, on oxidative stress in diabetic animals. The induction of diabetes was achieved in adult male Wistar rats using streptozotocin (STZ). The animals were distributed into four groups as follows: control (CTL); control Kefir (CTLK); diabetic (DM) and diabetic Kefir (DMK). Starting on the 5th day of diabetes, Kefir was administered by daily gavage at a dose of 1.8 mL/day for 8 weeks. Before and after Kefir treatment, the rats were placed in individual metabolic cages to obtain blood and urine samples to evaluate urea, creatinine, proteinuria, nitric oxide (NO), thiobarbituric acid reactive substances (TBARS) and C-reactive protein (CRP). After sacrificing the animals, the renal cortex was removed for histology, oxidative stress and NOS evaluation. When compared to CTL rats, DM rats showed increased levels of glycemia, plasmatic urea, proteinuria, renal NO, superoxide anion, TBARS, and plasmatic CRP; also demonstrated a reduction in urinary urea, creatinine, and NO. However, DMK rats showed a significant improvement in most of these parameters. Despite the lack of differences observed in the expression of endothelial NO synthase (eNOS), the expression of inducible NO synthase (iNOS) was significantly lower in the DMK group when compared to DM rats, as assessed by Western blot analysis. Moreover, the DMK group presented a significant reduction of glycogen accumulation within the renal tubules when compared to the DM group. These results indicate that Kefir treatment may contribute to better control of glycemia and oxidative stress, which is associated with the amelioration of renal function, suggesting its use as a non-pharmacological adjuvant to delay the progression of diabetic complications. PMID:24406684

Punaro, Giovana R; Maciel, Fabiane R; Rodrigues, Adelson M; Rogero, Marcelo M; Bogsan, Cristina S B; Oliveira, Marice N; Ihara, Silvia S M; Araujo, Sergio R R; Sanches, Talita R C; Andrade, Lucia C; Higa, Elisa M S



Blooming reduces the antioxidant capacity of dark chocolate in rats without lowering its capacity to improve lipid profiles.  


Dark chocolate contains high levels of antioxidants which are linked to a reduced risk of cardiovascular disease. Chocolate blooming occurs after exposure to high temperatures. Although bloomed chocolate is safe for human consumption, it is not known whether or not the biological function of bloomed chocolate is affected. We hypothesized that bloomed chocolate would reduce the antioxidant potential and lipid-lowering properties of chocolate through altered expression of related genes. Thirty Sprague-Dawley rats were divided into 3 groups and fed either the control (CON), regular dark chocolate (RDC), or bloomed dark chocolate (BDC) diet. After 3 weeks, serum lipid levels and antioxidant capacity were measured. Hepatic expression of key genes was determined by real time polymerase chain reaction (PCR). Sensory characteristics of bloomed versus regular chocolate were assessed in 28 semi-trained panelists. Rats fed RDC exhibited greater serum antioxidant capacities compared to the CON (P < .05). Antioxidant levels of BDC were not different from RDC or CON. Both RDC and BDC lowered TG compared to CON (P < .05). The rats fed RDC had higher high-density lipoprotein levels compared to the CON (P < .05). In rats given RDC, fatty acid synthase gene expression was down-regulated and low-density lipoprotein receptor transcription was up-regulated (P < .05). Sensory panelists preferred the appearance and surface smoothness of the regular chocolate compared to bloomed chocolate (P < .001). Although blooming blunted the robust antioxidant response produced by regular dark chocolate, these results suggest that bloomed dark chocolate yields similarly beneficial effects on most blood lipid parameters or biomarkers. However, regular dark chocolate may be more beneficial for the improvement of antioxidant status and modulation of gene expression involved in lipid metabolism and promoted greater sensory ratings. PMID:23684443

Shadwell, Naomi; Villalobos, Fatima; Kern, Mark; Hong, Mee Young



Human umbilical cord mesenchymal stem cells reduce systemic inflammation and attenuate LPS-induced acute lung injury in rats  

PubMed Central

Background Mesenchymal stem cells (MSCs) possess potent immunomodulatory properties and simultaneously lack the ability to illicit immune responses. Hence, MSCs have emerged as a promising candidate for cellular therapeutics for inflammatory diseases. Within the context of this study, we investigated whether human umbilical cord-derived mesenchymal stem cells (UC-MSCs) could ameliorate lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in a rat model. Methods ALI was induced via injection of LPS. Rats were divided into three groups: (1) saline group(control), (2) LPS group, and (3) MSC + LPS group. The rats were sacrificed at 6, 24, and 48 hours after injection. Serum, bronchoalveolar lavage fluid (BALF), and lungs were collected for cytokine concentration measurements, assessment of lung injury, and histology. Results UC-MSCs increased survival rate and suppressed LPS-induced increase of serum concentrations of pro-inflammatory mediators TNF-?, IL-1?, and IL-6 without decreasing the level of anti-inflammatory cytokine IL-10. The MSC + LPS group exhibited significant improvements in lung inflammation, injury, edema, lung wet/dry ratio, protein concentration, and neutrophil counts in the BALF, as well as improved myeloperoxidase (MPO) activity in the lung tissue. Furthermore, UC-MSCs decreased malondialdehyde (MDA) production and increased Heme Oxygenase-1 (HO-1) protein production and activity in the lung tissue. Conclusion UC-MSCs noticeably increased the survival rate of rats suffering from LPS-induced lung injury and significantly reduced systemic and pulmonary inflammation. Promoting anti-inflammatory homeostasis and reducing oxidative stress might be the therapeutic basis of UC-MSCs. PMID:22974286



Ketamine reduces the induced spinal p38 MAPK and pro-inflammatory cytokines in a neuropathic rats  

PubMed Central

Background Neuropathic rats created by spinal nerve ligation are known to show higher levels of p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase p44/42 (ERK 1/2) of the mitogen-activated protein kinases (MAPKs). The authors of this study aimed to understand the effect of ketamine on p38 MAPK and inflammatory responses, as well as its effect on the development of neuropathic pain. Methods The neuropathic rats were prepared by Chung's method with Sprague-Dawley rats. The research was carried out on three groups, a sham-operated group, a neuropathic pain and normal saline (NP + NS) group, and a neuropathic pain and ketamine (NP + Keta) group. The normal saline or ketamine was infused into the neuropathic rats through a mini-osmotic pump implanted in the subcutaneous space. After a week, the quantities of phospho-p38, p38 MAPK and pro-inflammatory cytokines were measured and compared through western blots and reverse transcriptase-polymerase chain reaction. Results In comparison to the control group, the NP + NS group showed a significant increase of phospho-p38 and p38 MAPK, as well as of the proinflammatory cytokines, tumor necrosis factor ? (TNF?), and intercellular adhesion molecule 1 (ICAM1). However, in the NP + Keta group, phospho-p38, p38 MAPK and TNF? and, ICAM1 were reduced in comparison to the NP + NS group. The paw withdrawal threshold test also showed the trend of recovery from the mechanical allodynia in the NP + Keta group. Conclusions In the development of neuropathic pain, p38 MAPK and inflammatory responses are significantly related, and the use of ketamine reduces p38 MAPK and proinflammatory cytokines. Thus, the adequate use of ketamine could be effective for the prevention and treatment of neuropathic pain following peripheral injury. PMID:24567814

Kwon, So-Young; Yeom, Jae Hwa



Immuno-Modulator Metallo-Peptide Reduces Inflammatory State in Obese Zucker Fa/Fa Rats  

PubMed Central

Metabolic syndrome is a prothrombotic and proinflammatory chronic state. In obesity, the adipose tissue secretes various adipokines that take part in a variety of physiological and pathophysiological processes, including immunity and inflammation. Previous studies using a liver damage model treated with the immune-modulator metallo-peptide (IMMP) showed lessening in the degree of inflammation. Therefore, this study was set up to evaluate the anti-inflammatory effect of IMMP in obese Zucker fa/fa rats. We used Zucker-Lepr fa/fa and Zucker-Lean in this protocol. The groups received IMMP 50 ng/kg by i.p., three times per week for 8 weeks. Blood samples were collected by cardiac puncture and the serum was preserved at -80°C until analysis; the liver was excised and preserved in formaldehyde 4%. Analyses were performed to determine cytokine, insulin, glucose, triglyceride and cholesterol levels in serum, and histological analysis was also performed. IMMP treatment of obese rats resulted in decreased levels of proinflammatory cytokines (leptin, lL-6, IL-1betha, INF-gamma) and a chemokine (MCP-1), and increased levels of anti-inflammatory adipokine (adiponectin). In addition, treatment decreased the damage and hepatic steatosis generated in the tissue of obese rats. The IMMP exerted an anti-inflammatory effect in obese rats and therefore may be an effective and safe therapeutic alternative in the treatment of metabolic syndrome.

Gomez-Solis, Antonieta; Reyes-Esparza, Jorge; Garcia-Vazquez, Francisco; Alvarez-Ayala, Elizabeth; Rodriguez-Fragoso, Lourdes



Nefopam reduces thermal hypersensitivity in acute and postoperative pain models in the rat  

Microsoft Academic Search

The activity of nefopam, a centrally acting compound, not structurally related to other analgesics, was examined in acute and postoperative thermal pain models in the rat. Its antinociceptive potency was evaluated using heat noxious stimuli either in intact or in injured animals after skin and muscular incisions. In the hot plate and in the plantar tests, nefopam after acute administration

Philippe Girard; Yannick Pansart; Marie-Claude Coppe; Jean-Marie Gillardin



Endotoxin-stimulated nitric oxide production increases injury and reduces rat liver chemiluminescence during reperfusion  

Microsoft Academic Search

Background\\/Aims: Nitric oxide has many physiological functions and may play an important role in modulating tissue injury. However, the mechanism of NO action in ischemia\\/reperfusion injury is completely unknown. This report investigates the role of NO in hepatic reperfusion injury. Methods: Rat liver was oxygenated for 30 minutes, followed by 30 minutes of ischemia, and then reperfused for 30 minutes.

Tong T. Ma; Harry Ischiropoulos; Clifford A. Brass



Research Article Consumption of Hydrogen Water Reduces Paraquat-Induced Acute Lung Injury in Rats  

E-print Network

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Exposure to paraquat leads to acute lung injury and oxidative stress is widely accepted as a contributor to paraquat-induced acute lung injury. Recent studies have reported that consumption of water with dissolved molecular hydrogen to a saturated level (hydrogen water) prevents oxidative stress-induced diseases. Here, we investigated whether consumption of saturated hydrogen saline protects rats against paraquat-induced acute lung injury. Adult male Sprague-Dawley (SD) rats were randomly divided into four groups: Control group; hydrogen water-only group (HW group); paraquat-only group (PQ group); paraquat and hydrogen water group (PQ + HW group). The rats in control group and HW group drank pure water or hydrogen water; the rats in PQ group and PQ + HW group were intraperitonealy injected with paraquat (35 mg/kg) and then provided pure water or hydrogen water. Both biochemical and histological lung alterations were measured. The results showed that hydrogen water ameliorated these alterations, demonstrating that hydrogen water alleviated paraquat-induced acute lung injury possibly by inhibition of oxidative damage. 1.

Shulin Liu; Kan Liu; Qiang Sun; Wenwu Liu; Weigang Xu; Petar Denoble; Hengyi Tao; Xuejun Sun



Exercise Training Reduces Sympathetic Modulation on Cardiovascular System and Cardiac Oxidative Stress in Spontaneously Hypertensive Rats  

Microsoft Academic Search

BackgroundSpontaneously hypertensive rats (SHRs) show increased cardiac sympathetic activity, which could stimulate cardiomyocyte hypertrophy, cardiac damage, and apoptosis. Norepinephrine (NE)-induced cardiac oxidative stress seems to be involved in SHR cardiac hypertrophy development. Because exercise training (ET) decreases sympathetic activation and oxidative stress, it may alter cardiac hypertrophy in SHR. The aim of this study was to determine, in vivo, whether

Mariane Bertagnolli; Paulo C. Schenkel; Cristina Campos; Cristiano T. Mostarda; Dulce E. Casarini; Adriane Belló-Klein; Maria C. Irigoyen; Katya Rigatto




EPA Science Inventory

Iprodione (IPRO) is a dichlorophenyl dicarboximide fungicide similar to the androgen receptor (AR) antagonist vinclozolin. The current studies were designed to determine if IPRO would delay male rat pubertal development like vinclozolin and to identify the mechanism(s) of action...


The secreted integrin ligand nephronectin is necessary for forelimb formation in Xenopus tropicalis  

PubMed Central

While limb regeneration has been extensively studied in amphibians, little is known about the initial events in limb formation in metamorphosing anurans. The small secreted integrin ligand nephronectin (npnt) is necessary for development of the metanephros in mouse. Although expressed in many tissues, its role in other developmental processes is not well-studied. Here we show that a transgene insertion that disrupts this gene ablates forelimb formation in Xenopus tropicalis. Our results suggest a novel role for integrin signalling in limb development, and represent the first insertional phenotype to be cloned in amphibians. PMID:20977901

Abu-Daya, Anita; Nishimoto, Satoko; Fairclough, Lynn; Mohun, Timothy J.; Logan, Malcolm P.O.; Zimmerman, Lyle B.



Withania coagulans fruit extract reduces oxidative stress and inflammation in kidneys of streptozotocin-induced diabetic rats.  


The present study was carried out to investigate the changes in oxidative and inflammatory status in streptozotocin-induced diabetic rat's kidneys and serum following treatment with Withania coagulans, a popular herb of ethnomedicinal significance. The key markers of oxidative stress and inflammation such as inflammatory cytokines (IL-1?, IL-6, and TNF-?) and immunoregulatory cytokines (IL-4 and IFN-?) were increased in kidneys along with significant hyperglycemia. However, treatment of four-month diabetic rats with Withania coagulans (10?mg/kg) for 3 weeks significantly attenuated hyperglycemia and reduced the levels of proinflammatory cytokines in kidneys. In addition, Withania coagulans treatment restored the glutathione levels and inhibited lipid peroxidation along with marked reduction in kidney hypertrophy. The present study demonstrates that Withania coagulans corrects hyperglycemia and maintained antioxidant status and reduced the proinflammatory markers in kidneys, which may subsequently reduce the development and progression of renal injury in diabetes. The results of the present study are encouraging for its potential use to delay the onset and progression of diabetic renal complications. However, the translation of therapeutic efficacy in humans requires further studies. PMID:25295146

Ojha, Shreesh; Alkaabi, Juma; Amir, Naheed; Sheikh, Azimullah; Agil, Ahmad; Fahim, Mohamed Abdelmonem; Adem, Abdu



MEK inhibition reduces glial scar formation and promotes the recovery of sensorimotor function in rats following spinal cord injury  

PubMed Central

The aim of this study was to investigate the effect of U0126 on the formation of glial scars following spinal cord injury (SCI) in a rat model. Ninety adult female Sprague-Dawley rats were divided randomly into sham injury (group I), SCI (group II) and U0126 treatment (group III) groups, and functional outcome was observed during the 4 weeks following the injury. The P1 and N1 latencies and P1-N1 amplitudes of somatosensory-evoked potentials (SEPs) were collected one day prior to surgery, on the day of surgery and 14 and 28 days postoperatively. The expression levels of glial fibrillary acidic protein (GFAP) and vimentin (Vim) were assessed 14 and 28 days post-injury. Treatment with U0126 significantly increased locomotor function from the second week until 4 weeks post-SCI. At 14 and 28 days subsequent to the injury, the number of cells that were positive for GFAP expression in the U0126-treated group was significantly reduced and the GFAP-positive cells were observed to be smaller, with a reduced prominence and pale staining. Moreover, the area of glial scarring was smaller compared with that of the SCI controls. Inhibitors of MEK may reduce glial scar formation by suppressing the proliferation of astrocytes, and may improve hindlimb motor function. PMID:24348766




Withania coagulans Fruit Extract Reduces Oxidative Stress and Inflammation in Kidneys of Streptozotocin-Induced Diabetic Rats  

PubMed Central

The present study was carried out to investigate the changes in oxidative and inflammatory status in streptozotocin-induced diabetic rat's kidneys and serum following treatment with Withania coagulans, a popular herb of ethnomedicinal significance. The key markers of oxidative stress and inflammation such as inflammatory cytokines (IL-1?, IL-6, and TNF-?) and immunoregulatory cytokines (IL-4 and IFN-?) were increased in kidneys along with significant hyperglycemia. However, treatment of four-month diabetic rats with Withania coagulans (10?mg/kg) for 3 weeks significantly attenuated hyperglycemia and reduced the levels of proinflammatory cytokines in kidneys. In addition, Withania coagulans treatment restored the glutathione levels and inhibited lipid peroxidation along with marked reduction in kidney hypertrophy. The present study demonstrates that Withania coagulans corrects hyperglycemia and maintained antioxidant status and reduced the proinflammatory markers in kidneys, which may subsequently reduce the development and progression of renal injury in diabetes. The results of the present study are encouraging for its potential use to delay the onset and progression of diabetic renal complications. However, the translation of therapeutic efficacy in humans requires further studies. PMID:25295146

Ojha, Shreesh; Alkaabi, Juma; Amir, Naheed; Sheikh, Azimullah; Agil, Ahmad; Fahim, Mohamed Abdelmonem; Adem, Abdu



Lactobacillus fermentum BR11 and fructo-oligosaccharide partially reduce jejunal inflammation in a model of intestinal mucositis in rats.  


Although probiotics are beginning to enter mainstream medicine for disorders of the colon, their effects on the small bowel remain largely unexplored. We investigated the recently identified probiotic, Lactobacillus fermentum (L. fermentum) BR11 (BR11) and the prebiotic, fructo-oligosaccharide (FOS), both individually and in synbiotic combination, for their potential to alleviate intestinal mucositis. From Days 0-9, rats consumed skim milk (SM; saline + SM), low dose (LD-BR11; 1 x 10(6)cfu/ml), high dose (HD-BR11; 1 x 10(9)cfu/ml), LD-FOS (3%), HD-FOS (6%), or synbiotic (HD-BR11/FOS). On Day 7, rats were injected with 5-fluorouracil (5-FU; 150 mg/kg). All rats were sacrificed on Day 10. Intestinal tissues were collected for quantitative histology, sucrase, and myeloperoxidase (MPO) determinations. 5-FU decreased sucrase activity, villus height, crypt depth, and crypt cell proliferation compared to controls. Compared to 5-FU + SM, histological damage severity scores were increased for all treatments, although all were effective at reducing jejunal inflammation, indicated by reduced MPO activity (P < 0.05). The combination of BR11 and FOS did not provide additional protection. Moreover, HD-FOS and the synbiotic actually increased clinical mucositis severity (P < 0.05). We conclude that L. fermentum BR11 has the potential to reduce inflammation of the upper small intestine. However, its combination with FOS does not appear to confer any further therapeutic benefit for the alleviation of mucositis. PMID:19005975

Smith, Cassie L; Geier, Mark S; Yazbeck, Roger; Torres, Diana M; Butler, Ross N; Howarth, Gordon S



Stress-dose hydrocortisone reduces critical illness-related corticosteroid insufficiency associated with severe traumatic brain injury in rats  

PubMed Central

Introduction The spectrum of critical illness-related corticosteroid insufficiency (CIRCI) in severe traumatic brain injury (TBI) is not fully defined and no effective treatments for TBI-induced CIRCI are available to date. Despite growing interest in the use of stress-dose hydrocortisone as a potential therapy for CIRCI, there remains a paucity of data regarding its benefits following severe TBI. This study was designed to investigate the effects of stress-dose hydrocortisone on CIRCI development and neurological outcomes in a rat model of severe traumatic brain injury. Methods Rats were subjected to lateral fluid percussion injury of 3.2-3.5 atmosphere. These rats were then treated with either a stress-dose hydrocortisone (HC, 3 mg/kg/d for 5 days, 1.5 mg/kg on day 6, and 0.75 mg on day 7), a low-dose methylprednisolone (MP, 1 mg/kg/d for 5 days, 0.5 mg/kg on day 6, and 0.25 mg on day 7) or control saline solution intraperitoneally daily for 7 days after injury. Results We investigated the effects of stress-dose HC on the mortality, CIRCI occurrence, and neurological deficits using an electrical stimulation test to assess corticosteroid response and modified neurological severity score (mNSS). We also studied pathological changes in the hypothalamus, especially in the paraventricular nuclei (PVN), after stress-dose HC or a low dose of MP was administered, including apoptosis detected by a TUNEL assay, blood–brain barrier (BBB) permeability assessed by brain water content and Evans Blue extravasation into the cerebral parenchyma, and BBB integrity evaluated by CD31 and claudin-5 expression. We made the following observations. First, 70% injured rats developed CIRCI, with a peak incidence on post-injury day 7. The TBI-associated CIRCI was closely correlated with an increased mortality and delayed neurological recovery. Second, post-injury administration of stress-dose HC, but not MP or saline increased corticosteroid response, prevented CIRCI, reduced mortality, and improved neurological function during the first 14 days post injury dosing. Thirdly, these beneficial effects were closely related to improved vascular function by the preservation of tight junctions in surviving endothelial cells, and reduced neural apoptosis in the PVN of hypothalamus. Conclusions Our findings indicate that post-injury administration of stress-dose HC, but not MP reduces CIRCI and improves neurological recovery. These improvements are associated with reducing the damage to the tight junction of vascular endothelial cells and blocking neuronal apoptosis in the PVN of the hypothalamus. PMID:24131855



The phenomenon of reduced convulsive readiness in Krushinskii-Molodkina rats after multiple audiogenic convulsive seizures.  


Spectral analysis of activity in a number of brain structures (sensorimotor, visual and auditory cortex, hippocampus, caudate nucleus, medial central nucleus of the thalamus) was performed during the sleep-waking cycle in Krushinskii-Molodkina rats, which have an inherited predisposition to audiogenic convulsions; studies were performed on the background of the long-lasting, stable decrease in the level of convulsive readiness seen in these animals after multiple generalized audiogenic tonic-clonic convulsive seizures. The results showed that the decrease in the sensitivity of the rats to the convulsive action of sound correlates with a decrease in the intensity of the theta rhythm and an increase in alpha waves on the electroencephalogram in the state of calm waking. Possible rearrangements of the functioning of ascending brain systems in conditions of stable reductions in reactivity to sound after multiple convulsive seizures are discussed. PMID:17955382

Vataev, S I



Retinal horizontal cells reduced in a rat model of congenital stationary night blindness.  


This work was conducted to determine whether congenital stationary night blindness (CSNB), which is caused by a Cacna1f mutation, could affect development of second-order neurons in the retina, such as horizontal cells (HCs). The CSNB rats and age-matched wild type rats were sacrificed at postnatal days (PND) 15, 30 and 60. Morphometric analyses of HCs, which were labeled by a primary antibody to calbindin D-28K, were performed at the light microscopic level on retinal cross sections and whole mount retinas. Calbindin D-28K was measured by western blotting in retinal samples. We found that the average number and density of HCs, Calbindin level and thickness of OPL were all decreased significantly in CSNB group compared to control group. These results indicated that second-order retinal neurons, such as horizontal cells, are affected by retinal degeneration. The relationship between the absence of HCs and the gene defect of CSNB requires further research. PMID:22634626

Zheng, Lijuan; Yan, Yili; An, Jing; Zhang, Lei; Liu, Wei; Xia, Feng; Zhang, Zuoming



Nebivolol Reduces Proteinuria and Renal NADPH Oxidase-Generated Reactive Oxygen Species in the Transgenic Ren2 Rat  

PubMed Central

Background/Aims Renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation are crucial in the pathogenesis of hypertension, cardiovascular and renal disease. NADPH oxidase-mediated increases in reactive oxygen species (ROS) are an important mediator for RAAS-induced cardiovascular and renal injury. Increased levels of ROS can diminish the bioactivity of nitric oxide (NO), a critical modulator of RAAS effects on the kidney. Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO. Methods We utilized the transgenic Ren2 rat which displays heightened tissue RAAS, hypertension, and proteinuria. Ren2 rats (6–9 weeks of age) and age-matched Sprague-Dawley littermates were treated with nebivolol 10 mg/kg/day (osmotic mini-pump) for 21 days. Results Ren2 rats exhibited increases in systolic blood pressure, proteinuria, kidney cortical tissue total NADPH oxidase activity and subunits (Rac1, p67phox, and p47phox), ROS and 3-nitrotyrosine, as well as reductions in podocyte protein markers; each of these parameters improved with nebivolol treatment along with increases in renal endothelial NO synthase expression. Conclusions Our data suggest that nebivolol improves proteinuria through reductions in renal RAAS-mediated increases in NADPH oxidase/ROS and increases in bioavailable NO. PMID:19609077

Whaley-Connell, Adam; Habibi, Javad; Johnson, Megan; Tilmon, Roger; Rehmer, Nathan; Rehmer, Jenna; Wiedmeyer, Charles; Ferrario, Carlos M.; Sowers, James R.



Environmental enrichment reduces the function of D1 dopamine receptors in the prefrontal cortex of the rat.  


Environmental enrichment produces changes in spontaneous and psychostimulant-induced motor activity. Dopamine in the prefrontal cortex (PFC), through the activation of D1 receptors, has been suggested to play a role in modulating motor activity. The present study investigated the effects of environmental enrichment on spontaneous motor activity, prefrontal acetylcholine release following local D1 receptor stimulation and D1 receptor expression in the PFC. Male wistar rats (3 months of age) were housed in enriched or isolated conditions during 90 days. Animals were then implanted with guide cannulae to perform microdialysis experiments in the PFC. Spontaneous motor activity and acetylcholine extracellular concentrations were monitored simultaneously. Also spontaneous motor activity was measured in an open field. On completion of the experiments, the density of D1 receptors in the PFC was studied by immunocytochemistry. Rats housed in an enriched environment showed significantly lower spontaneous motor activity in the open field compared to isolated animals. Perfusion of the D1 agonist SKF38393 (50 microM; 40 min) in the PFC produced long lasting increases of spontaneous motor activity and of local dialysate concentrations of acetylcholine in both groups of rats. However, increases of both motor activity and acetylcholine concentrations were significantly lower in enriched compared to isolated animals. Moreover, the density of D1 receptors in the PFC was significantly reduced in animals housed in an enriched environment. These results are the first evidence suggesting that environmental enrichment during adult life changes the function of D1 dopamine receptors in the PFC. PMID:16955373

Del Arco, A; Segovia, G; Canales, J J; Garrido, P; de Blas, M; García-Verdugo, J M; Mora, F




PubMed Central

Cannabinoids have emerged as brain protective agents under neurodegenerative conditions. Many neuroprotective actions of cannabinoids depend on the activation of specific receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R). The aim of the present study was to determine whether the CB2R and CB1R agonist WIN 55,212-2 (WIN) protects neonatal brain against focal cerebral ischemia-reperfusion and whether anti-inflammatory mechanisms play a role in protection. 7-day-old rats were subjected to 90 minutes middle cerebral artery occlusion (MCAO) and injured rats identified by diffusion-weighted MRI during the occlusion. After reperfusion rats were subcutaneously administered 1mg/kg of WIN or vehicle twice daily until sacrifice. MCAO led to increased mRNA expression of CB2R (but not CB1R), chemokine receptors (CCR2 and CX3CR1) and cytokines (IL-1? and TNF?), as well as increased protein expression of chemokines MCP-1 and MIP-1? and microglial activation 24 hours after MCAO. WIN administration significantly reduced microglial activation at this point and attenuated infarct volume and microglial accumulation and proliferation in the injured cortex 72 hours after MCAO. Cumulatively, our results show that the cannabinoid agonist WIN protects against neonatal focal stroke in part due to inhibitory effects on microglia. PMID:22285309

Fernandez-Lopez, David; Faustino, Joel; Derugin, Nikita; Wendland, Michael; Lizasoain, Ignacio; Moro, Maria A.; Vexler, Zinaida S.



Chronic supplementation with shark liver oil for reducing tumor growth and cachexia in walker 256 tumor-bearing rats.  


We investigated the effect of chronic supplementation with shark liver oil (SLO), an antitumor supplement source of n-3 fatty acids and 1-O-alkylglycerols, alone and combined with coconut fat (CF), a source of saturated fatty acids, on Walker 256 tumor growth and cachexia. Male rats were supplemented daily and orally with SLO and/or CF (1 g per kg body weight) for 7 wk. After 7 wk, 50% of animals were subcutaneously inoculated with 3 × 10(7) Walker 256 tumor cells. After 14 days, the rats were killed, the tumors were removed for lipid peroxidation measurement, and blood was collected for glycemia, triacylglycerolemia, and lacticidemia evaluation. Liver samples were obtained for glycogen measurement. Unlike CF, supplementation with SLO promoted gain in body weight, reduction of tumor weight, and maintained glycemia, triacylglycerolemia, lacticidemia, and liver glycogen content to values similar to non-tumor-bearing rats. Combined supplementation of SLO with CF also showed a reversion of cachexia with gain in body mass, reduction of lacticidemia, maintaining the liver glycogen store, and reduction in tumor weight. SLO, alone or combined with CF, promoted increase of tumor lipid peroxidation. In conclusion, SLO supplemented chronically, alone or associated with CF, was able to reduce tumor growth and cachexia. PMID:21981555

Iagher, Fabíola; de Brito Belo, Sérgio Ricardo; Naliwaiko, Katya; Franzói, Andressa Machado; de Brito, Gleisson Alisson Pereira; Yamazaki, Ricardo Key; Muritiba, Ana Lúcia; Muehlmann, Luis Alexandre; Steffani, Jovani Antonio; Fernandes, Luiz Cláudio



Forelimb anatomy and the discrimination of the predatory behavior of carnivorous mammals: The thylacine as a case study.  


Carnivorous mammals use their forelimbs in different ways to capture their prey. Most terrestrial carnivores have some cursorial (running) adaptations, but ambush predators retain considerable flexibility in their forelimb movement, important for grappling with their prey. In contrast, predators that rely on pursuit to run down their prey have sacrificed some of this flexibility for locomotor efficiency, in the greater restriction of the forelimb motion to the parasagittal plane. In this article, we measured aspects of the forelimb anatomy (44 linear measurements) in 36 species of carnivorous mammals of known predatory behavior, and used multivariate analyses to investigate how well the forelimb anatomy reflects the predatory mode (ambush, pursuit, or pounce-pursuit). A prime intention of this study was to establish morphological correlates of behavior that could then be applied to fossil mammals: for this purpose, five individuals of the recently extinct thylacine (Thylacinus cynocephalus) were also included as unknowns. We show that the three different types of predators can be distinguished by their morphology, both in analyses where all the forelimb bones are included together, and in the separate analyses of each bone individually. Of particular interest is the ability to distinguish between the two types of more cursorial predators, pursuit and pounce-pursuit, which have previously been considered as primarily size-based categories. Despite a prior consideration of the thylacine as a "pounce-pursuit" or an "ambush" type of predator, the thylacines did not consistently cluster with any type of predatory carnivores in our analyses. Rather, the thylacines appeared to be more generalized in their morphology than any of the extant carnivores. The absence of a large diversity of large carnivorous mammals in Australia, past and present, may explain the thylacine's generalized morphology. J. Morphol. 275:1321-1338, 2014. © 2014 Wiley Periodicals, Inc. PMID:24934132

Janis, Christine M; Figueirido, Borja



Low Dietary Calcium Reduces 25-Hydroxycholecalciferol in Plasma of Rats1  

Microsoft Academic Search

We investigated whether dietary factors that are known to increase 1,25-(OH)2-cholecalciferol production can deplete plasma 25-OH-cholecalciferol. Plasma concentration of 25-OH-cholecalciferol, its metabolism in vivo and activities of renal mitochondria! 25-OH-cholecalciferol 1-hydroxylase ( 1-OHase) and 25-OH-cholecalciferol 24-hydroxylase (24-OHase) were measured in rats fed various amounts of calcium (Ca) and phosphorus (P). All diets contained 5 jig (200 lu) cholecalciferol per 100



Manganese Porphyrin Reduces Retinal Injury Induced by Ocular Hypertension in Rats  

PubMed Central

This study aimed to clarify the possible therapeutic benefit of preferential nitric oxide synthase (NOS) inhibition and catalytic antioxidant Mn (III) meso-tetrakis (N-n-hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP5+) treatment in a rat model of elevated intraocular pressure (EIOP). Rats were randomly divided into different experimental groups which received either intraperitoneal MnTnHex-2-PyP5+ (0.1 mg/kg/day), intragastric NOS inhibitor (S-methylthiourea: SMT; 5 mg/kg/day) or both agents for a period of 6 weeks. Ocular hypertension was induced by unilaterally cauterizing three episcleral vessels and the unoperated eye served as control. Neuroprotective effects of given treatments were determined via electrophysiological measurements of visual evoked potentials (VEP) while retina and vitreous levels of MnTnHex-2-PyP5+ were measured via LC-MS/MS. Latencies of all VEP components (P1, N1, P2, N2, P3) were significantly prolonged (p<0.05) in EIOP and returned to control levels following all three treatment protocols. Ocular hypertension significantly increased retinal protein nitration (p<0.001) which returned to baseline levels in all treated groups. NOS-2 expression and nitrate/nitrite levels were significantly greater in non-treated rats with EIOP. Retinal TUNEL staining showed apoptosis in all ocular hypertensive rats. The presented data confirm the role of oxidative injury in EIOP and highlight the protective effect of MnTnHex-2-PyP5+ treatment and NOS inhibition in ocular hypertension. PMID:21669199

Dogan, Serdar; Unal, Mustafa; Ozturk, Nihal; Yargicoglu, Piraye; Cort, Aysegul; Spasojevic, Ivan; Batinic-Haberle, Ines; Aslan, Mutay



Montelukast reduces sepsis-induced lung and renal injury in rats.  


This study was undertaken to examine the effects of montelukast (MNT) on lung and kidney injury in lipopolysaccharide (LPS) induced systemic inflammatory response. Rats were randomized into 5 groups (n = 8 rats/group): (i) Control; (ii) LPS treated (10 mg/kg body mass, by intraperitoneal (i.p.) injection); (iii) LPS + MNT (10 mg/kg, per oral (p.o.)); (iv) LPS + MNT (20 mg/kg, p.o); (v) LPS + dexamethasone (DEX; 1 mg/kg, i.p.). Twenty-four hours after sepsis was induced, the lung or kidney:body mass ratio and percent survival of rats were determined. Creatinine, blood urea nitrogen (BUN), albumin, total protein, and LDH activity were measured. Lung and kidney samples were taken for histological assessment and for determination of their malondialdehyde (MDA) and glutathione (GSH) contents. The expression of tumour necrosis factor ? (TNF-?) in tissue was evaluated immunohistochemically. LPS significantly increased the organ:body mass ratio, serum creatinine, BUN, and LDH, and decreased serum albumin and total protein levels. MDA levels increased in lung and kidney tissues after treatment with LPS, and there was a concomitant reduction in GSH levels. Immunohistochemical staining of lung and kidney specimens from LPS-treated rats revealed high expression levels of TNF-?. MNT suppresses the release of inflammatory and oxidative stress markers. Additionally, MNT effectively preserved tissue morphology as evidenced by histological evaluation. These results demonstrate that MNT could have lung and renoprotective effects against the inflammatory process during endotoxemia. This effect can be attributed to its antioxidant and (or) anti-inflammatory properties. PMID:25243774

Khodir, Ahmed E; Ghoneim, Hamdy A; Rahim, Mona Abdel; Suddek, Ghada M



Rolipram reduces the inotropic tachyphylaxis of glucagon in rat ventricular myocardium  

Microsoft Academic Search

Glucagon increases cardiac contractility through G s protein-coupled glucagon receptors, but the inotropic responses fade. The fade could be due to receptor desensitisation or to the action of phosphodiesterases (PDE), or to both mechanisms. We investigated the effects of the PDE4 inhibitor rolipram (1 ?M) on the inotropic and cAMP-responses to glucagon in paced right ventricular strips of the rat heart.

Maria Jesús Juan-Fita; Maria Luisa Vargas; Alberto J. Kaumann; Jesus Hernández Cascales



Creatine supplementation reduces increased homocysteine concentration induced by acute exercise in rats  

Microsoft Academic Search

The aim of this study was to evaluate the effect of creatine supplementation on homocysteine (Hcy) metabolism after acute\\u000a aerobic and anaerobic exercise. A total of 112 Wistar rats were divided into four groups: aerobic exercise (A), aerobic exercise\\u000a plus creatine supplementation (ACr), anaerobic exercise (An), and anaerobic exercise plus creatine-supplemented (AnCr). Creatine\\u000a supplementation consisted of the addition of 2%

Rafael Deminice; Helio Vannucchi; Lívia Maria Simões-Ambrosio; Alceu Afonso Jordao


Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets  

Microsoft Academic Search

Summary   Susceptibility of pancreatic islets to oxidant stress may affect islet viability and contribute to primary non function of\\u000a allo- or xenogenic grafts. We investigated the influence of overexpression of catalase (CAT) on the viability of human, porcine\\u000a and rat islets, as well as INS-1 beta-cell line. Islets were transfected with a replication-deficient adenovirus vector containing\\u000a human CAT cDNA under

P. Y. Benhamou; C. Moriscot; M. J. Richard; O. Beatrix; L. Badet; F. Pattou; J. Kerr-Conte; J. Chroboczek; P. Lemarchand; S. Halimi



Chemotherapy-induced pica and anorexia are reduced by common hepatic branch vagotomy in the rat.  


Anticancer agents, such as cisplatin, induce vomiting, nausea, and anorexia. Cisplatin primarily acts on vagal afferents to produce emesis, but little is known about how this drug generates nausea and anorexia. Electrophysiology indicates that cisplatin activates vagal afferents of the common hepatic branch (CHB). Rats lack an emetic response but do ingest kaolin clay (a pica response) when made sick by toxins, and this behavior can be inhibited by antiemetic drugs. It has been postulated that pica may serve as a proxy for emesis in the rat. The goal of this study was to assess the effect of CHB or ventral gastric (Gas) or celiac (Cel) branch vagotomies on pica and anorexia produced by cisplatin in the rat. The effects of apomorphine, a dopamine receptor agonist, which induces emesis via a central mechanism, were also assessed. Cisplatin-induced pica was suppressed by CHB vagotomy (a 61% reduction) but not by Gas and Cel vagotomy. Suppression of daily food intake and body weight following cisplatin treatment was also blunted by CHB ablation but not by Gas or Cel vagotomy. No vagotomy condition exhibited altered apomorphine-induced pica. The results indicate that the CHB, which innervates primarily the duodenum, plays an important role in cisplatin-induced malaise. These data suggest that pica has sensory pathways similar to emetic systems, since a vagotomy condition inhibited cisplatin-induced pica but had no effect on apomorphine-induced pica. This investigation contributes to the delineation of the physiology of pica and neural systems involved in malaise in the nonvomiting rat. PMID:18184757

De Jonghe, Bart C; Horn, Charles C



Lipid Nanocapsules Loaded with Rhenium-188 Reduce Tumor Progression in a Rat Hepatocellular Carcinoma Model  

PubMed Central

Background Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC188Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC188Re-SSS in a chemically induced hepatocellular carcinoma rat model. Methodology/Principal Findings Animals were treated with an injection of LNC188Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n?=?12; 120 MBq, n?=?11) were compared with sham (n?=?12), blank LNC (n?=?7) and 188Re-perrhenate (n?=?4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC188Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC188Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. Conclusions/Significance Overall, these results demonstrate that internal radiation with LNC188Re-SSS is a promising new strategy for hepatocellular carcinoma treatment. PMID:21408224

Vanpouille-Box, Claire; Lacoeuille, Franck; Roux, Jerome; Aube, Christophe; Garcion, Emmanuel; Lepareur, Nicolas; Oberti, Frederic; Bouchet, Francis; Noiret, Nicolas; Garin, Etienne; Benoit, Jean-Pierre; Couturier, Olivier; Hindre, Francois



A note on asymmetric use of the forelimbs during feeding in the European green toad (Bufo viridis).  


European green toads (Bufo viridis) were tested for one-sided forelimb lateralisation during prey ingestion, i.e., when pushing food into the mouth. Results showed that toads preferentially used their left forelimb to help themselves in the ingestion of living larvae. It is argued that previous failure to reveal lateralisation in tests in which B. viridis toads wiped a foreign object off their snout was due to prevalent activation of grooming behaviour; in contrast, lateralisation seems clear when specifically associated with feeding behaviour. PMID:17712715

Sovrano, Valeria Anna



Celecoxib reduces brain dopaminergic neuronaldysfunction, and improves sensorimotor behavioral performance in neonatal rats exposed to systemic lipopolysaccharide  

PubMed Central

Background Cyclooxygenase-2 (COX-2) is induced in inflammatory cells in response to cytokines and pro-inflammatory molecules, suggesting that COX-2 has a role in the inflammatory process. The objective of the current study was to examine whether celecoxib, a selective COX-2 inhibitor, could ameliorate lipopolysaccharide (LPS)-induced brain inflammation, dopaminergic neuronal dysfunction and sensorimotor behavioral impairments. Methods Intraperitoneal (i.p.) injection of LPS (2 mg/kg) was performed in rat pups on postnatal Day 5 (P5), and celecoxib (20 mg/kg) or vehicle was administered (i.p.) five minutes after LPS injection. Sensorimotor behavioral tests were carried out 24 h after LPS exposure, and brain injury was examined on P6. Results Our results showed that LPS exposure resulted in impairment in sensorimotor behavioral performance and injury to brain dopaminergic neurons, as indicated by loss of tyrosine hydroxylase (TH) immunoreactivity, as well as decreases in mitochondria activity in the rat brain. LPS exposure also led to increases in the expression of ?-synuclein and dopamine transporter proteins and enhanced [3H]dopamine uptake. Treatment with celecoxib significantly reduced LPS-induced sensorimotor behavioral disturbances and dopaminergic neuronal dysfunction. Celecoxib administration significantly attenuated LPS-induced increases in the numbers of activated microglia and astrocytes and in the concentration of IL-1? in the neonatal rat brain. The protective effect of celecoxib was also associated with an attenuation of LPS-induced COX-2+ cells, which were double labeled with TH + (dopaminergic neuron) or glial fibrillary acidic protein (GFAP) + (astrocyte) cells. Conclusion Systemic LPS administration induced brain inflammatory responses in neonatal rats; these inflammatory responses included induction of COX-2 expression in TH neurons and astrocytes. Application of the COX-2 inhibitor celecoxib after LPS treatment attenuated the inflammatory response and improved LPS-induced impairment, both biochemically and behaviorally. PMID:23561827



Filtrate of Phellinus linteus Broth Culture Reduces Infarct Size Significantly in a Rat Model of Permanent Focal Cerebral Ischemia.  


Phellinus linteus, a natural growing mushroom, has been known to exhibit anti-tumor, anti-inflammatory, anti-allergic and anti-oxidant effects. Aiming to exploit the neuroprotective effects of P. linteus, we evaluated its effects on infarct volume reduction in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion. Filtrate of P. linteus broth culture (various doses), fractionated filtrate (based on molecular weight) or control medium was administered intraperitoneally to rats before or after ischemia induction. Rats were killed at 24?h after the stroke surgery. Cortical and caudoputaminal infarct volumes were determined separately using an image analysis program following staining with 2,3,5-triphenyltetrazolium chloride. Significant cortical infarct volume reductions were found in the pre-treatment groups (30 and 60?minutes before onset of cerebral ischemia) compared with the control group, showing dose dependence. Posttreatment (30?minutes after ischemic onset) also significantly reduced cortical infarct volume. Furthermore, the higher molecular weight (?12?000) fraction of the culture filtrate was more effective compared with the lower molecular weight fraction. The present findings suggest that P. linteus may be a new promising approach for the treatment of focal cerebral ischemia, with the additional benefit of a wide therapeutic time window since significant infarct volume reduction is obtained by administration even after the ischemic event. Our finding that the higher molecular weight fraction of the P. linteus culture filtrate demonstrated more prominent effect may provide a clue to identify the neuroprotective substances and mechanisms. PMID:19155273

Suzuki, Sakiko; Kawamata, Takakazu; Okada, Yoshikazu; Kobayashi, Tomonori; Nakamura, Tomoyuki; Hori, Tomokatsu



The prevalence and risk factors associated with forelimb skin abrasions and sole bruising in preweaning piglets.  


The presence of skin abrasions and sole bruising in 264 preweaning piglets (1-30 days old) from 13 breeding units in south west England was investigated in 1995. The mean prevalence of forelimb skin abrasions among the pigs on the study farms was 36% (range 0-59%) and sole bruising was 50% (range 0-95%). Skin abrasions were located on three aspects on the front limbs: the carpus, the metacarpus and the digit. Lesions occurred early in a piglet's life; the modal ages for sole bruising was 4 days and for skin abrasions were 5 and 10 days. The presence of skin abrasions on the front limbs was significantly associated with the presence of sole bruising on the front feet. Logistic regression indicated that part-concrete, part-round-mesh (OR 56.4) and part-concrete, part-metal-rods floors (OR 15.9) and exposed aggregate (OR 4.6) were associated with an increased odds of sole bruising while the presence of sparse straw (OR 0.12) or deep straw (OR 0.12) in the pen was associated with lower odds of sole bruising. The same floor type (part-concrete, part-round-mesh) was associated with increased odds of forelimb skin abrasions (OR 2.2). A worn floor surface where the solid adjoined the perforated area (OR 4.6) and the presence of sparse shavings (OR 1.7) were also associated with an increased risk of skin abrasions. PMID:10327440

Mouttotou, N; Hatchell, F M; Green, L E



Inhibition of Src phosphorylation reduces damage to the blood-brain barrier following transient focal cerebral ischemia in rats  

PubMed Central

The disruption of the blood-brain barrier (BBB) caused by cerebral ischemia determines the extent of injury and patient prognosis. Inhibitors of Src can markedly minimize the infarct size and preserve neurological function. The Src protein tyrosine kinase (PTK) inhibitor, PP2, protects the rat brain against ischemic injury, possibly through the reduction of vascular endothelial growth factor A (VEGFA) expression and the upregulation of claudin-5 expression, which preserves the integrity of the BBB. In this study, the expression levels of phosphorylated (p)-Src, VEGFA and claudin-5 were determined to investigate the changes occurring in the levels of these proteins and to determine the benefits of PP2 treatment following cerebral ischemia/reperfusion (I/R). Our study included a sham-operated group, an I/R group, a vehicle-treated group (V) and a PP2-treated group (PP2). We found that the rats in the PP2 group exhibited greater preservation of neurological function and reduced VEGFA and p-Src protein expression compared with the rats in the I/R and V groups. Moreover, the mRNA and protein levels of claudin-5 were markedly higher in the PP2 group than in the I/R group or the V group after 3 days of reperfusion. Immunofluorescence staining revealed that the co-localized immunostaining of fibrinogen and claudin-5 was reduced in the PP2 group, which suggests that the exudation of fibrinogen in this group was less than that in the I/R and V groups. Furthermore, the reduced co-localization of immunostaining of glial fibrillary acidic protein (GFAP) and claudin-5 indicated that the rats in the PP2 group had only a slight disruption of the BBB. These findings suggested that PP2 treatment attenuated the disruption of the BBB following ischemia and minimized the neurological deficit; these effects were associated with a decreased VEGFA expression and an increased claudin-5 expression. Members of the Src PTK family may be critical targets for the protection of the BBB following cerebral ischemia. PMID:25269821




Inhibition of Src phosphorylation reduces damage to the blood-brain barrier following transient focal cerebral ischemia in rats.  


The disruption of the blood-brain barrier (BBB) caused by cerebral ischemia determines the extent of injury and patient prognosis. Inhibitors of Src can markedly minimize the infarct size and preserve neurological function. The Src protein tyrosine kinase (PTK) inhibitor, PP2, protects the rat brain against ischemic injury, possibly through the reduction of vascular endothelial growth factor A (VEGFA) expression and the upregulation of claudin-5 expression, which preserves the integrity of the BBB. In this study, the expression levels of phosphorylated (p)-Src, VEGFA and claudin-5 were determined to investigate the changes occurring in the levels of these proteins and to determine the benefits of PP2 treatment following cerebral ischemia/reperfusion (I/R). Our study included a sham-operated group, an I/R group, a vehicle-treated group (V) and a PP2-treated group (PP2). We found that the rats in the PP2 group exhibited greater preservation of neurological function and reduced VEGFA and p-Src protein expression compared with the rats in the I/R and V groups. Moreover, the mRNA and protein levels of claudin-5 were markedly higher in the PP2 group than in the I/R group or the V group after 3 days of reperfusion. Immunofluorescence staining revealed that the co-localized immunostaining of fibrinogen and claudin-5 was reduced in the PP2 group, which suggests that the exudation of fibrinogen in this group was less than that in the I/R and V groups. Furthermore, the reduced co-localization of immunostaining of glial fibrillary acidic protein (GFAP) and claudin-5 indicated that the rats in the PP2 group had only a slight disruption of the BBB. These findings suggested that PP2 treatment attenuated the disruption of the BBB following ischemia and minimized the neurological deficit; these effects were associated with a decreased VEGFA expression and an increased claudin-5 expression. Members of the Src PTK family may be critical targets for the protection of the BBB following cerebral ischemia. PMID:25269821

Bai, Yongsheng; Xu, Guanghui; Xu, Mengxue; Li, Qi; Qin, Xinyue



Neither Milk Production, Milk Transfer Nor Pup Growth Hormone Account for Reduced Body Weights of Rat Pups Reared In Hypergravity  

NASA Technical Reports Server (NTRS)

Studies spanning the gravity continuum from 0 to 2-g are revealing new insights into how mammalian reproduction and development may proceed in the microgravity of space. Rat pups reared from either conception or midgestation in hypergravity (hg) weigh 6-15% less than 1-g controls. In the present study we analyzed maternal and pup factors that may account for reduced body weight of hg reared pups. Beginning on Gestational day (G)11 of the rats' 22 day pregnancy, rat dams and their litters were continuously exposed to either 1.5-g, 1.75-g or 2.0-g. Prolaction (Prl) and oxytocin (OT) were measured in hg-exposed dams during either pregnancy (G20) or lactation (Postnatal day [P] 10). Gravity related differences in Prl were not observed whereas OT was depressed during lactation in hg dams relative to controls (p less than 0.05). Milk transfer measured during a discrete suckling episode was actually increased in hg-reared litters and comparable numbers of milk-letdowns were observed in the two conditions. Recent reports using dwarfing phenotypes in mouse mutants have provided evidence for postnatal dependence on growth hormone (GH) and insulin-like growth factors (IGFs). Plasma GH measured in P10 pups using enzyme immunoassay (EIA) was significantly elevated in hg pups relative to 1-g controls (mean +/- sd., ng/ml: 2.0-g, 10.6 [3.0], 1.5-g 8.9 [4.0], 1.0-g, 7.95 [3.1]). Together, these findings suggest that neither milk production, milk transfer nor pup GH play significant roles in reduced body weights of hg-reared pups. Studies underway are focused on insulin-like growth factors.

Bear, L. A.; Chowdhury, J. H.; Grindeland, R. E.; Wade, C. E.; Ronca, A. E.; Dalton, Bonnie (Technical Monitor)



Arsenic reduces the antipyretic activity of paracetamol in rats: modulation of brain COX-2 activity and CB? receptor expression.  


We examined whether subacute arsenic exposure can reduce paracetamol-mediated antipyretic activity by affecting COX pathway and cannabinoid CB1 receptor regulation. Rats were preexposed to elemental arsenic (4 ppm) as sodium arsenite through drinking water for 28 days. Next day pyrexia was induced with lipopolysaccharide and paracetamol's (200 mg/kg, oral) antipyretic activity was assessed. The activities of COX-1 and COX-2, the levels of PGE?, TNF-? and IL-1? and expression of CB? receptors were assessed in brain. Arsenic inhibited paracetamol-mediated antipyretic activity. COX-1 activity was not affected by any treatments. Paracetamol decreased COX-2 activity, levels of PGE?, TNF-? and IL-1? and caused up-regulation of CB1 receptors. Arsenic caused opposite effects on these parameters. In the arsenic-preexposed rats, paracetamol-mediated effects were attenuated, while CB? receptor up-regulation was reversed to down-regulation. Results suggest that elevated COX-2 activity and reduced CB? expression could be involved in the arsenic-mediated attenuation of the antipyretic activity of paracetamol. PMID:24448467

Vijayakaran, Karunakaran; Kannan, Kandasamy; Kesavan, Manickam; Suresh, Subramaniyam; Sankar, Palanisamy; Tandan, Surendra Kumar; Sarkar, Souvendra Nath



Angiopoietin-1 gene-modified human mesenchymal stem cells promote angiogenesis and reduce acute pancreatitis in rats  

PubMed Central

Mesenchymal stem cells (MSCs) can serve as a vehicle for gene therapy. Angiopoietin-1 (ANGPT1) plays an important role in the regulation of endothelial cell survival, vascular stabilization, and angiogenesis. We hypothesized that ANGPT1 gene-modified MSCs might be a potential therapeutic approach for severe acute pancreatitis (SAP) in rats. Human umbilical cord-derived MSCs with or without transfection with lentiviral vectors containing the ANGPT1 gene were delivered through the tail vein of rats 12 h after induction of SAP. Administration of MSCs alone significantly reduced pancreatic injury and inflammation, as reflected by reductions in pancreatitis severity scores and serum amylase and lipase levels as well as reducing the serum levels of proinflammatory cytokines (TNF-?, IFN-?, IL-1?, and IL-6). Furthermore, administration of ANGPT1-transfected MSCs resulted in not only further reductions in pancreatic injury and serum levels of proinflammatory cytokines, but also promotion of pancreatic angiogenesis. These results suggest that MSCs and ANGPT1 have a synergistic role in the treatment of SAP. ANGPT1 gene-modified MSCs may be developed as a potential novel therapy strategy for the treatment of SAP. PMID:25120736

Hua, Jie; He, Zhi-Gang; Qian, Dao-Hai; Lin, Sheng-Ping; Gong, Jian; Meng, Hong-Bo; Yang, Ting-Song; Sun, Wei; Xu, Bin; Zhou, Bo; Song, Zhen-Shun



Role of Reactive Oxygen Species in Hypertension Produced by Reduced Uterine Perfusion in Pregnant Rats  

PubMed Central

BACKGROUND Although recent studies indicate preeclampsia (PE) is associated with increased oxidative stress, the role of reactive oxygen species in the hypertension associated with PE remains unclear. We sought to test the hypothesis that placental ischemia increases oxidative stress which in turn, contributes to hypertension. METHODS Reduction in uterine perfusion pressure (RUPP) was induced by placing silver clips on the abdominal aorta and the ovarian arteries on day 14 of pregnancy. On day 20 of pregnancy, mean arterial pressure (MAP) was measured and oxidative stress was assessed in renal and placental tissues whereas systemic administration of tempol, a superoxide dismutase (SOD) mimetic, was used to evaluate the contribution of reactive oxygen species on RUPP-induced hypertension. RESULTS MAP (120 ± 2 mm Hg vs.106 ± 3 mm Hg), placental levels of 8-isoprostane (1.9 ± 0.4 ng/g tissue vs. 0.8 ± 0.1 ng/g tissue), and malondialdehyde (MDA) (6.9 ± 0.6 ?mol/g tissue vs. 3.9 ± 0.4 ?mol/g tissue) were increased, whereas renal cortical SOD activity was decreased in RUPP rats (1.2 ± 0.1 units/mg protein vs. 1.6 ± 0.1 units/ mg protein) at day 20 of gestation (20 dG) compared to controls. Chronic treatment with tempol attenuated the hypertension (RUPP + tempol 112 ± 2 mm Hg vs. RUPP, 120 ± 2 mm Hg) associated with RUPP, whereas tempol had no effect on MAP (NP, 106 ± 3 vs. NP + tempol, 108 ± 2) in control rats. CONCLUSION The results of this study indicate that placental ischemia decreases innate antioxidant activity resulting in elevated oxidative stress which appears to play a role in mediating hypertension associated with chronic RUPP in pregnant rats. PMID:18670418

Sedeek, Mona; Gilbert, Jeffrey S.; LaMarca, Babbette B.; Sholook, Myssara; Chandler, Derrick L.; Wang, Yuping; Granger, Joey P.



Regional blood flows in the established stage of reduced renal mass (RRM) hypertension in rats  

SciTech Connect

Regional blood flows were measured with 15 /sup 153/Gd-labelled microspheres in 21 anesthetized (pentobarbital-50 mg/kg, i.p.) male Sprague Dawley rats 5-6 weeks after a 75% reduction in renal mass and in 6 sham operated controls (SOC). RRM rats were maintained on either a high salt (HS-RRM) diet, i.e., choice of 1% NaCl or tap water (n = 11), or on a salt-restricted (SR-RRM) diet (n = 10). Mean arterial blood pressure was significantly elevated (mean +/- SE) in the HS-RRM (168 +/- 5 mmHg) vs. either the SR-RRM (147 +/- 6 mmHg) or the SOC (138 +/- 4 mmHg). Although blood flow to the skin and femur were elevated in HS-RRM and SR-RRM relative to SOC, there were no significant differences in blood flow to skeletal muscle, spleen, liver, small intestine, stomach or testes between any of the groups. Absolute renal blood flow and renal blood flow/gm of tissue were significantly lower in HS-RRM (7.2 +/- 0.7 ml/min or 3.4 +/- 0.5 ml/min/gm) and SR-RRM (6.3 +/- 0.6 ml/min or 3.2 +/- 0.3 ml/min/gm) than in SOC (15.1 +/- 0.97 ml/min or 5.5 +/- 0.2 ml/min/gm). The present results suggest that regional blood flow is unchanged in most vascular beds during the established stage of RRM hypertension in rats.

Smits, G.J.; Lombard, J.H.



Sialic acid reduces acute endotoxemia-induced liver dysfunction in the rat.  


Endotoxemia caused by LPS is a life-threatening and inflammatory condition contributing to multiple organ failure. Viruses or bacteria require sialic acid (SA) for target-cell binding. We suggest that exogenous SA through masking or mediating the binding of LPS to the target cells may attenuate LPS-induced liver dysfunction and cecal ligation and puncture-induced shock. We found that SA can directly scavenge O2-, H2O2, and NO activity by a chemiluminescence analyzer and bind to LPS with high affinity using surface plasmon resonance. Intravenous SA significantly increased plasma SA concentration within 4 h. We then assessed the potential effect of SA on LPS-induced acute endotoxemia in the rat. Intravenous LPS (10-50 mg/kg) dose-dependently increased plasma endotoxin and reactive oxygen species in the blood, bile, and liver and increased plasma alanine aminotransferase and aspartate aminotransferase levels as well as TNF-alpha, monocyte chemoattractant protein 1, tissue inhibitor of metalloproteinase 1, IL-1beta, and IL-6 levels in the rats. Thirty minutes after LPS stimulation, SA decreased LPS-enhanced endotoxin level, oxidative stress, alanine aminotransferase and aspartate aminotransferase levels, and cytokine concentration and ameliorated histopathologic alteration in the liver. We found that SA increased LPS-depressed Mn-superoxide dismutase, CuZn-superoxide dismutase, and heat shock protein 70 and decreased LPS-enhanced iNOS and proapoptotic Bax protein expression in the liver by Western blot. Sialic acid was given after treatment to rats subjected to cecal ligation and puncture, and the hypotensive effect was blunted for 6 h. In conclusion, SA treatment can counteract LPS-enhanced acute endotoxemia and oxidative injury via a direct scavenging reactive oxygen species activity and neutralization potential. PMID:19060786

Ho, Chien-Hsing; Hsu, Su-Ping; Yang, Chih-Chin; Lee, Yi-Huey; Chien, Chiang-Ting



Exercise training reduces PGE2 levels and induces recovery from steatosis in tumor-bearing rats.  


The effects of endurance training on PGE (2) levels and upon the maximal activity of hepatic carnitine palmitoyltransferase (CPT) system were studied in rats bearing the Walker 256 carciosarcoma. Animals were randomly assigned to a sedentary control (SC), sedentary tumor-bearing (ST), exercised control (EC), and as an exercised tumor-bearing (ET) group. Trained rats ran on a treadmill (60% VO (2) max) for 60 min/day, 5 days/week, for 8 weeks. We examined the mRNA expression (RT-PCR) and maximal activity (radioassay) of the carnitine palmitoyltransferase system enzymes (CPT I and CPT II), as well as the gene expression of fatty-acid-binding protein (L-FABP) in the liver. PGE (2) content was measured in the serum, in tumor cells, and in the liver (ELISA). CPT I and CPT II maximal activity were decreased (p<0.01) in ST when compared with SC. In contrast, serum PGE (2) was increased (p<0.05) in cachectic animals as compared with SC. In the liver, PGE (2) content was also increased (p<0.05) when compared with SC. Endurance training restored maximal CPT I and CPT II activity in the tumor-bearing animals (p<0.0001). Exercise training induced PGE (2) levels to return to control values in the liver of tumor-bearing training rats (p<0.05) and decreased the eicosanoid content in the tumor (p<0.01). In conclusion, endurance training was capable of reestablishing liver carnitine palmitoyltransferase (CPT) system activity associated with decreased PGE (2) levels in cachectic tumor-bearing animals, preventing steatosis. PMID:21064006

Lira, F S; Yamashita, A; Carnevali, L C; Gonçalves, D C; Lima, W P; Rosa, J C; Caperuto, E C; Rosa, L F C; Seelaender, M



Fluoroquinolones reduce carrageenan-induced edema in rats and the involvement of the glucocorticoid receptor system.  


We studied the effect of fluoroquinolones (FQs) on carrageenan-induced edema in the rat footpad. Ciprofloxacin, gatifloxacin, sparfloxacin, norfloxacin, and enoxacin (s.c., 100 mg/kg), which have piperazinyl and/or cyclopropyl groups, inhibited carrageenan-induced edema, whereas levofloxacin, tosufloxacin, and pazufloxacin did not. The reduction of edema by ciprofloxacin, sparfloxacin, and enoxacin was abolished by pretreatment with mifepristone, an antagonist of the glucocorticoid receptor. These results suggest that FQs with piperazinyl and/or cyclopropyl groups can modify biological responses through enhancing the glucocorticoid-glucocorticoid receptor system. PMID:19396522

Ogino, Hiromi; Yamada, Kaori; Yuhara, Mizuki; Tsuchida, Saori; Maezawa, Kayoko; Kizu, Junko; Hori, Seiji



Dietary taurine enhances cholesterol degradation and reduces serum and liver cholesterol concentrations in rats fed a high-cholesterol diet.  


The effect of taurine on hypercholesterolemia induced by feeding a high-cholesterol (HC) diet (10g/kg) to rats was examined. When various amounts of taurine (0.25, 0.5, 1, 2.5, 5, 10, 20, 30, 40 or 50 g/kg diet) were supplemented to HC for 2 wk, serum total cholesterol gradually and significantly decreased in a dose-dependent manner and normalized at the dose of 10 g taurine/kg, compared with the control (cholesterol free) diet group. By contrast, serum HDL-cholesterol was elevated by taurine supplementation. The HC diet caused a significant decrease in the concentration of taurine in serum, liver and heart compared to that in the control group, and the effective dose of supplemental taurine to improve its reduction was 2.5 g/kg diet. In the hypercholesterolemic rats fed the HC diet, the excretion of fecal bile acids and hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) activity and its mRNA level increased significantly, and the supplementation of taurine further enhanced these indexes, indicating an increase in cholesterol degradation. The abundance of mRNA for Apo A-I, one of the main components of HDL, was reduced by HC and recovered by taurine supplementation. Agarose gel electrophoresis revealed that, in hypercholesterolemic rats fed the HC diet, the serum level of the heavier VLDL increased significantly, but taurine repressed this increase and normalized this pattern. Significant correlations were observed between the time- and dose-dependent increases of CYP7A1 gene expression and the decrease of blood cholesterol concentration in rats fed the HC diet supplemented with taurine (time, r = -0.538, P < 0.01, n = 32; dose, r = -0.738, P < 0.001, n = 20). These results suggest that the hypocholesterolemic effects of taurine observed in the hypocholesterolemic rats fed the HC diet were mainly due to the enhancement of cholesterol degradation and the excretion of bile acid. PMID:10460208

Yokogoshi, H; Mochizuki, H; Nanami, K; Hida, Y; Miyachi, F; Oda, H



Effects of reducing agents and oxidants on excitation-contraction coupling in skeletal muscle fibres of rat and toad.  

PubMed Central

1. The mechanically skinned fibre technique was used to examine the role of oxidation-reduction in the control of Ca2+ release and contraction in rat and toad skeletal muscle fibres under physiological conditions of myoplasmic [Mg2+] and [ATP] and sarcoplasmic reticulum (SR) Ca2+ load. 2. None of the reducing agents, dithiothreitol (DTT, 10 mM), glutathione (GSH, 10 mM) or cysteine (1 and 5 mM), had any detectable effect on the peak force, duration or the total number of depolarization-induced responses that could be elicited in skinned fibres from either toad or rat muscle, except for a slight alteration in one case (GSH on the duration of the response in rat fibres) caused by an effect of the agent of the Ca2+ sensitivity of the contractile apparatus. 3. Application of the reactive disulphide, 2,2'-dithiodipyridine (DTDP, 100 microM), a potent oxidizing agent, never induced any measurable force response or noticeable depletion of SR Ca2+ in any fibre under the conditions used. When all Ca2+ uptake was prevented, DTDP treatment of rat fibres was found to cause a 2- to 3-fold increase in the low rate of Ca2+ "leak' from the SR. DTDP treatment also increased the responsiveness of toad muscle fibres to 1 or 2 mM caffeine. These effects could be largely reversed by treatment with DTT. These results indicate that oxidation of the Ca2+ release channel does not cause substantial channel opening under physiological conditions. 4. Depolarization-induced force responses in both rat and toad fibres were rapidly abolished in the presence of DTDP (10 or 100 microM), in a manner favoured by inactivation of the voltage sensors. The relatively impermeant oxidant, 5,5'-dithionitrobenzoic acid (DTNB, 100 microM), had an effect very similar to DTDP if applied intracellularly, but unlike DTDP, had little or no effect if applied extracellularly (at 5 mM) before skinning. Depolarization-induced responses could be restored by treatment with DTT (10 mM). Intracellular application of the sulfhydryl-alkylating agent, N-ethylmaleimide (NEM, 100 microM), had effects very similar to DTDP and DTNB. 5. These results are not consistent with the proposal that excitation-contraction coupling in skeletal muscle primarily involves the oxidative linkage of the voltage sensors to the Ca2+ release channels, but do show that oxidation of an intracellularly accessible site can interfere with the coupling, in a process made more sensitive by voltage sensor inactivation. PMID:8930846

Posterino, G S; Lamb, G D



Developmental Exposure to Polychlorinated Biphenyls Reduces Amphetamine Behavioral Sensitization in Long-Evans Rats  

PubMed Central

PCBs have long been known to affect dopamine (DA) function in the brain. The current study used an amphetamine behavioral sensitization paradigm in rats developmentally exposed to PCBs. Long-Evans rats were given perinatal exposure to 0, 3, or 6 mg/kg/day PCBs and behavioral sensitization to d-amphetamine (AMPH) was assessed in one adult male and female/litter. Non-exposed (control) males showed increasing locomotor activity to repeated injections of 0.5 mg/kg AMPH, typical of behavioral sensitization. PCB-exposed males showed greater activation to the initial acute AMPH injection, but sensitization occurred later and was blunted relative to controls. Sensitization in control females took longer to develop than in the males, but no exposure-related differences were observed. Analysis of whole brain and serum AMPH content following a final IP injection of 0.5 mg/kg revealed no differences among the exposure groups. Overall, these results indicated developmental PCB-exposure can alter the motor-stimulating effects of repeated AMPH injections. Males developmentally exposed to PCBs appeared to be pre-sensitized to AMPH, but quickly showed behavioral tolerance to the same drug dose. Results also revealed the behavioral effect was not due to exposure-induced alterations in AMPH metabolism following PCB exposure. PMID:23623962

Poon, Emily; Monaikul, Supida; Kostyniak, Paul J.; Chi, Lai Har; Schantz, Susan L.; Sable, Helen J. K.



Calcium and ?-tocopherol suppress cured-meat promotion of chemically induced colon carcinogenesis in rats and reduce associated biomarkers in human volunteers123  

PubMed Central

Background: Processed meat intake has been associated with increased colorectal cancer risk. We have shown that cured meat promotes carcinogen-induced preneoplastic lesions and increases specific biomarkers in the colon of rats. Objectives: We investigated whether cured meat modulates biomarkers of cancer risk in human volunteers and whether specific agents can suppress cured meat–induced preneoplastic lesions in rats and associated biomarkers in rats and humans. Design: Six additives (calcium carbonate, inulin, rutin, carnosol, ?-tocopherol, and trisodium pyrophosphate) were added to cured meat given to groups of rats for 14 d, and fecal biomarkers were measured. On the basis of these results, calcium and tocopherol were kept for the following additional experiments: cured meat, with or without calcium or tocopherol, was given to dimethylhydrazine-initiated rats (47% meat diet for 100 d) and to human volunteers in a crossover study (180 g/d for 4 d). Rat colons were scored for mucin-depleted foci, putative precancer lesions. Biomarkers of nitrosation, lipoperoxidation, and cytotoxicity were measured in the urine and feces of rats and volunteers. Results: Cured meat increased nitroso compounds and lipoperoxidation in human stools (both P < 0.05). Calcium normalized both biomarkers in rats and human feces, whereas tocopherol only decreased nitro compounds in rats and lipoperoxidation in feces of volunteers (all P < 0.05). Last, calcium and tocopherol reduced the number of mucin-depleted foci per colon in rats compared with nonsupplemented cured meat (P = 0.01). Conclusion: Data suggest that the addition of calcium carbonate to the diet or ?-tocopherol to cured meat may reduce colorectal cancer risk associated with cured-meat intake. This trial was registered at as NCT00994526. PMID:24025632

Martin, Océane CB; Santarelli, Raphaelle L; Taché, Sylviane; Naud, Nathalie; Guéraud, Françoise; Audebert, Marc; Dupuy, Jacques; Meunier, Nathalie; Attaix, Didier; Vendeuvre, Jean-Luc; Mirvish, Sidney S; Kuhnle, Gunter CG; Cano, Noel; Corpet, Denis E




EPA Science Inventory

DEHP is a plasticizer that alters sexual differentiation in the male rat by reducing fetal Leydig cell testosterone synthesis and insl3 mRNA levels. When exposure includes the pubertal stage of life, DEHP and other phthalates delay puberty and reduce androgen-dependent tissue wei...


Skeletal Muscle Aging in F344BN F1Hybrid Rats: II. Improved Contractile Economy in Senescence Helps Compensate for Reduced ATP-Generating Capacity  

Microsoft Academic Search

We used a pump-perfused rat hind-limb preparation to compare young adult (YA: 8-9- month- old), late middle-aged (LMA: 28-29-month-old), and senescent (SEN: 36-month-old) rats at similar rates of convective O2 delivery during a 4-minute contraction bout. We hypothesized that not only would _ VO2 and lactate production be reduced, but also that contractile economy would be altered with aging. Peak

Russell T. Hepple; Jason L. Hagen; Daniel J. Krause; David J. Baker


[Estrogen reduced myocardial damage by regulating G?s-cAMP pathway in isoprenaline injured rats].  


The aim of the present study is to explore the mechanism of estrogen on regulating cardiac function disorder by adjusting the stimulating adenylate cyclase G ? protein (G?s)-cycle adenosine monophosphate (cAMP) signal pathway. Adult female rats were randomly divided into five groups: sham group, ovariectomized group (OVX), OVX and 17?-estradiol given group (OVX+E2), OVX and isoprenaline injected group (OVX+ISO), OVX and 17?-estradiol, isoprenaline injected group (OVX+E2+ISO). Rats were ovariectomized, and two weeks later, OVX+E2 group was injected with E2, OVX+ISO group was injected with ISO, OVX+E2+ISO group was injected with E2 and ISO. Another four weeks later, the hemodynamic parameters were monitored by carotid artery intubation: left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximal differentials of left ventricular developed pressure (+dp/dtmax), and minimal differentials of left ventricular developed pressure (-dp/dtmax). Brain natriuretic peptide (BNP) and cAMP concentration in plasma were determined; G?s protein expression in myocardium was determined. The results showed that the hemodynamic parameters, the concentration of BNP and cAMP in plasma had no significant changes after ovariectomy compared with sham group. But after isoprenaline injection in ovariectomized rats, LVSP and +dp/dtmax declined (P < 0.01), LVEDP and -dp/dtmax elevated (P < 0.01); plasma BNP concentration increased (P < 0.01); plasma cAMP concentration decreased (P < 0.01), compared with OVX group. Further estrogen supplements improved the heart function treated by isoprenaline: LVSP and +dp/dtmax elevated (P < 0.01), LVEDP and -dp/dtmax declined (P < 0.05, P < 0.01); the plasma BNP concentration decreased (P < 0.01); the plasma cAMP concentration increased (P < 0.01). Estrogen had no significant influence on G?s protein expression. The results suggest that estrogen can alleviate myocardial injury and regulate cardiac function disorder by increasing cAMP level, finally improved the excessive suppression of myocardium. PMID:25332004

Sang, Li-Li; Zhou, Chun-Le; Fu, Lu; Chong, Jing-Min; Zhang, Lin; Cao, Xian-Cun; Sun, Hong



Organization of the forelimb area in squirrel monkey motor cortex: representation of digit, wrist, and elbow muscles  

Microsoft Academic Search

The EMG in 8 to 14 hand, forearm, and arm muscles evoked by intracortical electrical stimulation was recorded at 433 sites in layer V in the region of the forelimb area of the primary motor cortex (MI) of three squirrel monkeys during ketamine anesthesia. At each site, the EMG was recorded at movement threshold (T) and at 1.5T and 2T

J. P. Donoghue; S. Leibovic; J. N. Sanes



Resveratrol reduces steroidogenesis in rat ovarian theca-interstitial cells: the role of inhibition of Akt/PKB signaling pathway.  


Polycystic ovary syndrome is characterized by theca-interstitial hyperplasia and increased expression of steroidogenic genes, leading to excessive androgen production. Resveratrol, a natural polyphenol, promotes apoptosis and reduces rat theca-interstitial cell growth, in part by inhibiting the mevalonate pathway and decreasing the availability of substrates of isoprenylation [farnesyl-pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP)]. This study evaluated the effect of resveratrol on rat theca-interstitial cell steroidogenesis. Because resveratrol may activate sirtuins, this study also investigated whether steroidogenesis was affected by sirtuin inhibitors (nicotinamide, sirtinol). Theca-interstitial cells were cultured with or without resveratrol (1-10 ?m), GGPP (30 ?m), FPP (30 ?m), nicotinamide (1 mm), and/or sirtinol (10 ?m). Resveratrol did not affect progesterone levels but reduced androgen production in a concentration-dependent fashion (androstenedione by up to 78% and androsterone by up to 76%). This inhibitory effect correlated with a decrease in mRNA expression of genes regulating androgen production, especially Cyp17a1 (by up to 73%). GGPP and FPP had no effect on androgen levels and Cyp17a1 mRNA levels and did not alter the effects induced by resveratrol. Similarly, sirtuin inhibitors did not reverse resveratrol-induced inhibition of steroidogenesis. However, resveratrol decreased activity of serine-threonine kinase/protein kinase B pathway, a cell-signaling pathway involved in ovarian steroidogenesis. The present findings indicate that resveratrol reduces androgen production primarily by inhibiting Cyp17a1 mRNA expression, and this inhibition may be mediated, in part, by blocking the activity of the serine-threonine kinase/protein kinase B pathway. These findings may be of clinical relevance to conditions associated with excessive production of androgens by theca cells, such as polycystic ovary syndrome. PMID:22719052

Ortega, Israel; Villanueva, Jesus A; Wong, Donna H; Cress, Amanda B; Sokalska, Anna; Stanley, Scott D; Duleba, Antoni J



A low-carbohydrate/high-fat diet reduces blood pressure in spontaneously hypertensive rats without deleterious changes in insulin resistance  

PubMed Central

Previous studies reported that diets high in simple carbohydrates could increase blood pressure in rodents. We hypothesized that the converse, a low-carbohydrate/high-fat diet, might reduce blood pressure. Six-week-old spontaneously hypertensive rats (SHR; n = 54) and Wistar-Kyoto rats (WKY; n = 53, normotensive control) were fed either a control diet (C; 10% fat, 70% carbohydrate, 20% protein) or a low-carbohydrate/high-fat diet (HF; 20% carbohydrate, 60% fat, 20% protein). After 10 wk, SHR-HF had lower (P < 0.05) mean arterial pressure than SHR-C (148 ± 3 vs. 159 ± 3 mmHg) but a similar degree of cardiac hypertrophy (33.4 ± 0.4 vs. 33.1 ± 0.4 heart weight/tibia length, mg/mm). Mesenteric arteries and the entire aorta were used to assess vascular function and endothelial nitric oxide synthase (eNOS) signaling, respectively. Endothelium-dependent (acetylcholine) relaxation of mesenteric arteries was improved (P < 0.05) in SHR-HF vs. SHR-C, whereas contraction (potassium chloride, phenylephrine) was reduced (P < 0.05). Phosphorylation of eNOSSer1177 increased (P < 0.05) in arteries from SHR-HF vs. SHR-C. Plasma glucose, insulin, and homoeostatic model of insulin assessment were lower (P < 0.05) in SHR-HF vs. SHR-C, whereas peripheral insulin sensitivity (insulin tolerance test) was similar. After a 10-h fast, insulin stimulation (2 U/kg ip) increased (P < 0.05) phosphorylation of AktSer473 and S6 in heart and gastrocnemius similarly in SHR-C vs. SHR-HF. In conclusion, a low-carbohydrate/high-fat diet reduced blood pressure and improved arterial function in SHR without producing signs of insulin resistance or altering insulin-mediated signaling in the heart, skeletal muscle, or vasculature. PMID:23604708

Bosse, John D.; Lin, Han Yi; Sloan, Crystal; Zhang, Quan-Jiang; Abel, E. Dale; Pereira, Troy J.; Dolinsky, Vernon W.; Symons, J. David



The Reduced Cochlear Output and the Failure to Adapt the Central Auditory Response Causes Tinnitus in Noise Exposed Rats  

PubMed Central

Tinnitus is proposed to be caused by decreased central input from the cochlea, followed by increased spontaneous and evoked subcortical activity that is interpreted as compensation for increased responsiveness of central auditory circuits. We compared equally noise exposed rats separated into groups with and without tinnitus for differences in brain responsiveness relative to the degree of deafferentation in the periphery. We analyzed (1) the number of CtBP2/RIBEYE-positive particles in ribbon synapses of the inner hair cell (IHC) as a measure for deafferentation; (2) the fine structure of the amplitudes of auditory brainstem responses (ABR) reflecting differences in sound responses following decreased auditory nerve activity and (3) the expression of the activity-regulated gene Arc in the auditory cortex (AC) to identify long-lasting central activity following sensory deprivation. Following moderate trauma, 30% of animals exhibited tinnitus, similar to the tinnitus prevalence among hearing impaired humans. Although both tinnitus and no-tinnitus animals exhibited a reduced ABR wave I amplitude (generated by primary auditory nerve fibers), IHCs ribbon loss and high-frequency hearing impairment was more severe in tinnitus animals, associated with significantly reduced amplitudes of the more centrally generated wave IV and V and less intense staining of Arc mRNA and protein in the AC. The observed severe IHCs ribbon loss, the minimal restoration of ABR wave size, and reduced cortical Arc expression suggest that tinnitus is linked to a failure to adapt central circuits to reduced cochlear input. PMID:23516401

Matsumoto, Masahiro; Lee, Sze Chim; Zuccotti, Annalisa; Zimmermann, Ulrike; Jaumann, Mirko; Rohbock, Karin; Xiong, Hao; Knipper, Marlies



Sabiporide Reduces Ischemia-Induced Arrhythmias and Myocardial Infarction and Attenuates ERK Phosphorylation and iNOS Induction in Rats  

PubMed Central

The aim of the present study was to investigate the effects of sabiporide, a potent and selective NHE1 inhibitor, on myocardial ischemia-induced arrhythmias and myocardial infarction and the possible pathways related to the cardioprotection afforded by sabiporide treatment. Anesthetized rats were subjected to myocardial ischemia via left main coronary artery occlusion for 30 minutes, followed by 2 hours of reperfusion. Administration of sabiporide (0.01–3.0?mg/kg) prior to coronary artery occlusion dose-dependently reduced ischemia-induced arrhythmias and infarct size with an ED50 value of 0.14?mg/kg. Administration of sabiporide (1.0?mg/kg) prior to reperfusion also reduced infarct size by 38.6%. The reduction in infarct size was accompanied by a decrease in circulating levels of creatine phosphokinase and troponin I. In addition, sabiporide (1.0?mg/kg) given prior to coronary artery occlusion or immediately before reperfusion significantly reduced phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and the expression of the inducible nitric oxide synthase (iNOS) following myocardial ischemia-reperfusion. This study demonstrates that sabiporide is a potent and effective cardioprotective agent during myocardial ischemia and reperfusion, by reducing serious ventricular arrhythmias and myocardial infarct size. The cardioprotection afforded by sabiporide is attributed in part to inhibition of ERK1/2 phosphorylation and suppression of iNOS expression. PMID:23484128

Doods, Henri; Wu, Dongmei



Role of glucocorticoids in the response of rat leg muscles to reduced activity  

NASA Technical Reports Server (NTRS)

Adrenalectomy did not prevent atrophy of rat soleus muscle during 6 days of tail cast suspension. Cortisol treatment enhanced the atrophy and caused atrophy of the weight-bearing soleus and both extensor digitorum longus (EDL) muscles. Unloading led to increased sarcoplasmic protein concentration in the soleus but cortisol administration increased the myhofibrillar (+stromal) protein concentration in both muscles. Suspension of hindlimbs of adrenalectomized animals led to faster protein degradation, slower sarcoplasmic protein degradation, and faster myofibrillar protein synthesis in the isolated soleus, whereas with cortisol-treated animals, the difference in synthesis of myofibrillar proteins was enhanced and that of sarcoplasmic proteins was abolished. Both soleus and EDL of suspended, cortisol-treated animals showed faster protein degradation. It is unlikely that any elevation in circulating glucocorticoids was solely responsible for atrophy of the soleus in this model, but catabolic amounts of glucocorticoids could alter the response of muscle to unloading.

Jaspers, Stephen R.; Tischler, Marc E.



Grape seed procyanidin extract reduces the endotoxic effects induced by lipopolysaccharide in rats.  


Acute inflammation is a response to injury, infection, tissue damage, or shock. Bacterial lipopolysaccharide (LPS) is an endotoxin implicated in triggering sepsis and septic shock, and LPS promotes the inflammatory response, resulting in the secretion of proinflammatory and anti-inflammatory cytokines such as the interleukins (IL-6, IL-1?, and IL-10) and tumor necrosis factor-? by the immune cells. Furthermore, nitric oxide and reactive oxygen species levels increase rapidly, which is partially due to the activation of inducible nitric oxide synthase in several tissues in response to inflammatory stimuli. Previous studies have shown that procyanidins, polyphenols present in foods such as apples, grapes, cocoa, and berries, have several beneficial properties against inflammation and oxidative stress using several in vitro and in vivo models. In this study, the anti-inflammatory and antioxidant effects of two physiological doses and two pharmaceutical doses of grape seed procyanidin extract (GSPE) were analyzed using a rat model of septic shock by the intraperitoneal injection of LPS derived from Escherichia coli. The high nutritional (75mg/kg/day) and the high pharmacological doses (200mg/kg/day) of GSPE showed anti-inflammatory effects by decreasing the proinflammatory marker NOx in the plasma, red blood cells, spleen, and liver. Moreover, the high pharmacological dose also downregulated the genes Il-6 and iNos; and the high nutritional dose decreased the glutathione ratio (GSSG/total glutathione), further illustrating the antioxidant capability of GSPE. In conclusion, several doses of GSPE can alleviate acute inflammation triggered by LPS in rats at the systemic and local levels when administered for as few as 15 days before the injection of endotoxin. PMID:23439188

Pallarès, Victor; Fernández-Iglesias, Anabel; Cedó, Lídia; Castell-Auví, Anna; Pinent, Montserrat; Ardévol, Anna; Salvadó, Maria Josepa; Garcia-Vallvé, Santiago; Blay, Mayte



Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats  

PubMed Central

The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis. PMID:24519128

Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J.



Folic acid supplementation reduces oxidative stress and hepatic toxicity in rats treated chronically with ethanol  

PubMed Central

Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = 0.612**), AST (r = 0.652*), CD (r = 0.495*), and TRAP (r = -0.486*). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress. PMID:22259676

Lee, Soo-Jung; Kang, Myung-Hee



Genetic regulation of canine skeletal traits: trade-offs between the hind limbs and forelimbs in the fox and dog.  


Genetic variation in functionally integrated skeletal traits can be maintained over 10 million years despite bottlenecks and stringent selection. Here, we describe an analysis of the genetic architecture of the canid axial skeleton using populations of the Portuguese Water Dog Canis familiaris) and silver fox (Vulpes vulpes). Twenty-one skeletal metrics taken from radiographs of the forelimbs and hind limbs of the fox and dog were used to construct separate anatomical principal component (PC) matrices of the two species. In both species, 15 of the 21 PCs exhibited significant heritability, ranging from 25% to 70%. The second PC, in both species, represents a trade-off in which limb-bone width is inversely correlated with limb-bone length. PC2 accounts for approximately 15% of the observed skeletal variation, approximately 30% of the variation in shape. Many of the other significant PCs affect very small amounts of variation (e.g., 0.2-2%) along trade-off axes that partition function between the forelimbs and hind limbs. These PCs represent shape axes in which an increase in size of an element of the forelimb is associated with a decrease in size of an element of the hind limb and vice versa. In most cases, these trade-offs are heritable in both species and genetic loci have been identified in the Portuguese Water Dog for many of these. These PCs, present in both the dog and the fox, include ones that affect lengths of the forelimb versus the hind limb, length of the forefoot versus that of the hind foot, muscle moment (i.e., lever) arms of the forelimb versus hind limb, and cortical thickness of the bones of the forelimb versus hind limb. These inverse relationships suggest that genetic regulation of the axial skeleton results, in part, from the action of genes that influence suites of functionally integrated traits. Their presence in both dogs and foxes suggests that the genes controlling the regulation of these PCs of the forelimb versus hind limb may be found in other tetrapod taxa. PMID:18458753

Kharlamova, Anastasia V; Trut, Lyudmila N; Carrier, David R; Chase, Kevin; Lark, Karl G



Administration of structured lipid composed of MCT and fish oil reduces net protein catabolism in enterally fed burned rats.  

PubMed Central

The effects of enteral feeding with safflower oil or a structured lipid (SL) derived from 60% medium-chain triglyceride (MCT) and 40% fish oil (MCT/fish oil) on protein and energy metabolism were compared in gastrostomy-fed burned rats (30% body surface area) by measuring oxygen consumption, carbon dioxide production, nitrogen balance, total liver protein, whole-body leucine kinetics, and rectus muscle and liver protein fractional synthetic rates (FSR, %/day). Male Sprague-Dawley rats (195 +/- 5g) received 50 ml/day of an enteral regimen containing 50 kcal, 2 g amino acids, and 40% nonprotein calories as lipid for three days. Protein kinetics were estimated by using a continuous L-[1-14C] leucine infusion technique on day 2. Thermally injured rats enterally fed MCT/fish oil yielded significantly higher daily and cumulative nitrogen balances (p less than or equal to 0.025) and rectus muscle (39%) FSR (p less than or equal to 0.05) when compared with safflower oil. MCT/fish oil showed a 22% decrease (p less than or equal to 0.005) in per cent flux oxidized and a 7% (p less than or equal to 0.05) decrease in total energy expenditure (TEE) versus safflower oil. A 15% increase in liver FSR was accompanied by a significant elevation (p less than or equal to 0.025) in total liver protein with MCT/fish oil. This novel SL shares the properties of other structured lipids in that it reduces the net protein catabolic effects of burn injury, in part, by influencing tissue protein synthetic rates. The reduction in TEE is unique to MCT/fish oil and may relate to the ability of fish oil to diminish the injury response. PMID:2500898

Teo, T C; DeMichele, S J; Selleck, K M; Babayan, V K; Blackburn, G L; Bistrian, B R



Electrographic seizures are significantly reduced by in vivo inhibition of neuronal uptake of extracellular glutamine in rat hippocampus  

PubMed Central

Summary Rats were given unilateral kainate injection into hippocampal CA3 region, and the effect of chronic electrographic seizures on extracellular glutamine (GLNECF) was examined in those with low and steady levels of extracellular glutamate (GLUECF). GLNECF, collected by microdialysis in awake rats for 5 h, decreased to 62 ± 4.4% of the initial concentration (n = 6). This change correlated with the frequency and magnitude of seizure activity, and occurred in the ipsilateral but not in contralateral hippocampus, nor in kainate-injected rats that did not undergo seizure (n = 6). Hippocampal intracellular GLN did not differ between the Seizure and No-Seizure Groups. These results suggested an intriguing possibility that seizure-induced decrease of GLNECF reflects not decreased GLN efflux into the extracellular fluid, but increased uptake into neurons. To examine this possibility, neuronal uptake of GLNECF was inhibited in vivo by intrahippocampal perfusion of 2-(methylamino)isobutyrate, a competitive and reversible inhibitor of the sodium-coupled neutral amino acid transporter (SNAT) subtypes 1 and 2, as demonstrated by 1.8 ± 0.17 fold elevation of GLNECF (n = 7). The frequency of electrographic seizures during uptake inhibition was reduced to 35 ± 7% (n = 7) of the frequency in pre-perfusion period, and returned to 88 ± 9% in the post-perfusion period. These novel in vivo results strongly suggest that, in this well-established animal model of temporal-lobe epilepsy, the observed seizure-induced decrease of GLNECF reflects its increased uptake into neurons to sustain enhanced glutamatergic epileptiform activity, thereby demonstrating a possible new target for anti-seizure therapies. PMID:24070846

Kanamori, Keiko; Ross, Brian D.



Diallyl trisulfide attenuates carbon tetrachloride-caused liver injury and fibrogenesis and reduces hepatic oxidative stress in rats.  


Liver fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with accumulation of extracellular matrix (ECM) components in the liver. Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrogenesis. The process of HSC activation is accompanied by enhanced expression of a series of marker proteins and pro-fibrogenic signal molecules. Natural products have been an important source of antifibrotic remedies. The present study aims to evaluate the in vivo effects of diallyl trisulfide (DATS), the primary component derived from garlic, on carbon tetrachloride (CCl4)-induced injury and fibrosis in rats. Our results showed that DATS improved liver histological architecture and decreased hepatic enzyme levels, but did not significantly affect cytochrome P450 2E1 activity in vivo. DATS also attenuated collagen deposition and inhibited HSC activation in the rat fibrotic liver demonstrated by reduced expression of ?-smooth muscle actin, ?1(I) procollagen, and fibronectin-three key markers of HSC activation-and by downregulation of transforming growth factor-? receptor 1, platelet-derived growth factor-? receptor, and epidermal growth factor receptor-three key receptors transmitting pro-fibrogenic pathways. In addition, DATS ameliorated hepatic oxidative stress by diminishing the levels of lipid peroxides and malondialdehyde and enhancing glutathione content. These data collectively revealed that DATS protected the rat liver from CCl4-caused injury and fibrogenesis in vivo, which was associated with inhibition of HSC activation and attenuation of oxidative stress. Our results suggested DATS as a promising antifibrogenic candidate for the prevention and treatment of liver fibrosis. PMID:24557053

Zhu, Xiaojing; Zhang, Feng; Zhou, Liang; Kong, Desong; Chen, Li; Lu, Yin; Zheng, Shizhong



Electrographic seizures are significantly reduced by in vivo inhibition of neuronal uptake of extracellular glutamine in rat hippocampus.  


Rats were given unilateral kainate injection into hippocampal CA3 region, and the effect of chronic electrographic seizures on extracellular glutamine (GLNECF) was examined in those with low and steady levels of extracellular glutamate (GLUECF). GLNECF, collected by microdialysis in awake rats for 5h, decreased to 62±4.4% of the initial concentration (n=6). This change correlated with the frequency and magnitude of seizure activity, and occurred in the ipsilateral but not in contralateral hippocampus, nor in kainate-injected rats that did not undergo seizure (n=6). Hippocampal intracellular GLN did not differ between the Seizure and No-Seizure Groups. These results suggested an intriguing possibility that seizure-induced decrease of GLNECF reflects not decreased GLN efflux into the extracellular fluid, but increased uptake into neurons. To examine this possibility, neuronal uptake of GLNECF was inhibited in vivo by intrahippocampal perfusion of 2-(methylamino)isobutyrate, a competitive and reversible inhibitor of the sodium-coupled neutral amino acid transporter (SNAT) subtypes 1 and 2, as demonstrated by 1.8±0.17 fold elevation of GLNECF (n=7). The frequency of electrographic seizures during uptake inhibition was reduced to 35±7% (n=7) of the frequency in pre-perfusion period, and returned to 88±9% in the post-perfusion period. These novel in vivo results strongly suggest that, in this well-established animal model of temporal-lobe epilepsy, the observed seizure-induced decrease of GLNECF reflects its increased uptake into neurons to sustain enhanced glutamatergic epileptiform activity, thereby demonstrating a possible new target for anti-seizure therapies. PMID:24070846

Kanamori, Keiko; Ross, Brian D



Anesthetized Long Evans rats show similar protein expression and long-term potentiation as Fischer 344 rats but reduced short-term potentiation in motor cortex  

Microsoft Academic Search

A number of studies describe strain-related differences in the motor behavior of rats. Inbred albino F344 rats are found to be impaired in procedural spatial learning, skilled reaching, and over ground locomotion in relation to pigmented out bred Long Evans (LE) rats. These deficits could be related to the functional differences in the motor cortex of the two strains, and

Paul Wawryko; Nicole L. Ward; Ian Q. Whishaw; Tammy L. Ivanco



Oxidative stress and reduced responsiveness of challenged circulating leukocytes following pulmonary instillation of metal-rich particulate matter in rats  

PubMed Central

Welding fume is an exposure that consists of a mixture of metal-rich particulate matter with gases (ozone, carbon monoxide) and/or vapors (VOCs). Data suggests that welders are immune compromised. Given the inability of pulmonary leukocytes to properly respond to a secondary infection in animal models, the question arose whether the dysfunction persisted systemically. Our aim was to evaluate the circulating leukocyte population in terms of cellular activation, presence of oxidative stress, and functionality after a secondary challenge, following welding fume exposure. Rats were intratracheally instilled (ITI) with PBS or 2 mg of welding fume collected from a stainless steel weld. Rats were sacrificed 4 and 24 h post-exposure and whole blood was collected. Whole blood was used for cellular differential counts, RNA isolation with subsequent microarray and Ingenuity Pathway Analysis, and secondary stimulation with LPS utilizing TruCulture technology. In addition, mononuclear cells were isolated 24 h post-exposure to measure oxidative stress by flow cytometry and confocal microscopy. Welding fume exposure had rapid effects on the circulating leukocyte population as identified by relative mRNA expression changes. Instillation of welding fume reduced inflammatory protein production of circulating leukocytes when challenged with the secondary stimulus LPS. The effects were not related to transcription, but were observed in conjunction with oxidative stress. These findings support previous studies of an inadequate pulmonary immune response following a metal-rich exposure and extend those findings showing leukocyte dysfunction occurs systemically. PMID:25123171



Diet supplementation with donkey milk upregulates liver mitochondrial uncoupling, reduces energy efficiency and improves antioxidant and antiinflammatory defences in rats.  


Dietary PUFA, mainly those of the n-3 family, are known to play essential roles in the maintenance of energy balance and in the reduction of body fat deposition through the upregulation of mitochondrial uncoupling that is the main source of reactive oxygen species. We hypothesized that rat supplementation with raw donkey's milk (DM), characterized by low-fat content and higher n3:n6 ratio, may affect energy balance, lipid metabolism, and prooxidant status as compared to animals treated with cow's milk. In the present study, the effects of drinking raw DM (for 4 weeks) on energy balance, lipid metabolism, antiinflammatory, and antioxidant/detoxifying defences was compared to that produced by rat intake of an iso-energetic amount of raw cow's milk. The hypolipidemic effect produced by DM paralleled with the enhanced mitochondrial activity/proton leakage and with the increased activity or expression of mitochondrial markers namely, carnitine palmitoyl transferase and uncoupling protein 2. The association of decreased energy efficiency with reduced proinflammatory signs (TNF-? and LPS levels) with the significant increase antioxidant (total thiols) and detoxifying enzyme activities (glutathione-S-transferase NADH quinone oxidoreductase) in DM-treated animals, indicated that beneficial effects were attributable, at least in part, to the activation of nuclear factor 2 erythroid-related factor 2 pathway. PMID:22930490

Lionetti, Lillà; Cavaliere, Gina; Bergamo, Paolo; Trinchese, Giovanna; De Filippo, Chiara; Gifuni, Giorgio; Gaita, Marcello; Pignalosa, Angelica; Donizzetti, Immacolata; Putti, Rosalba; Di Palo, Rossella; Barletta, Antonio; Mollica, Maria Pina



Crocetin reduces the oxidative stress induced reactive oxygen species in the stroke-prone spontaneously hypertensive rats (SHRSPs) brain  

PubMed Central

Crocetin is a natural carotenoid compound of gardenia fruits and saffron, which has various effects in biological systems. In this study, we investigated the antioxidant effects of crocetin on reactive oxygen species such as hydroxyl radical using in vitro X-band electron spin resonance and spin trapping. Crocetin significantly inhibited hydroxyl radical generation compared with the control. Moreover, we performed electron spin resonance computed tomography ex vivo with the L-band electron spin resonance imaging system and determined the electron spin resonance signal decay rate in the isolated brain of stroke-prone spontaneously hypertensive rats, a high-oxidative stress model. Crocetin significantly reduced oxidative stress in the isolated brain by acting as a scavenger of reactive oxygen species, especially hydroxyl radical, as demonstrated by in vitro and ex vivo electron spin resonance analysis. The distribution of crocetin was also determined in the plasma and the brain of stroke-prone spontaneously hypertensive rats using high-performance liquid chromatography. After oral administration, crocetin was detected at high levels in the plasma and the brain. Our results suggest that crocetin may participate in the prevention of reactive oxygen species-induced disease due to a reduction of oxidative stress induced by reactive oxygen species in the brain. PMID:22128217

Yoshino, Fumihiko; Yoshida, Ayaka; Umigai, Naofumi; Kubo, Koya; Lee, Masaichi-Chang-il



Etanercept Attenuates Traumatic Brain Injury in Rats by Reducing Brain TNF-? Contents and by Stimulating Newly Formed Neurogenesis  

PubMed Central

It remains unclear whether etanercept penetrates directly into the contused brain and improves the outcomes of TBI by attenuating brain contents of TNF-? and/or stimulating newly formed neurogenesis. Rats that sustained TBI are immediately treated with etanercept. Acute neurological and motor injury is assessed in all rats the day prior to and 7 days after surgery. The numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain injury that occurred during TBI were counted by immunofluorescence staining. Enzyme immunoassay for quantitative determination of TNF-? or etanercept in brain tissues is also performed. Seven days after systemic administration of etanercept, levels of etanercept can be detected in the contused brain tissues. In addition, neurological and motor deficits, cerebral contusion, and increased brain TNF-? contents caused by TBI can be attenuated by etanercept therapy. Furthermore, the increased numbers of the colocalizations of 5-bromodeoxyuridine and doublecortin specific markers in the contused brain tissues caused by TBI can be potentiated by etanercept therapy. These findings indicate that systemically administered etanercept may penetrate directly into the contused brain tissues and may improve outcomes of TBI by reducing brain contents of TNF-? and by stimulating newly formed neurogenesis. PMID:23710117

Cheong, Chong-Un; Chao, Chien-Ming; Cheng, Bor-Chih; Yang, Chung-Zhing; Chio, Chung-Ching



Treatment with Aqueous Extract from Croton cajucara Benth Reduces Hepatic Oxidative Stress in Streptozotocin-Diabetic Rats  

PubMed Central

Croton cajucara Benth is a plant found in Amazonia, Brazil and the bark and leaf infusion of this plant have been popularly used to treat diabetes and hepatic disorders. The present study was designed to evaluate the oxidative stress as well as the therapeutic effect of Croton cajucara Benth (1.5?mL of the C. cajucara extract i.g.) in rats with streptozotocin-induced diabetes. Croton cajucara Benth was tested as an aqueous extract for its phytochemical composition, and its antioxidant activity in vitro was also evaluated. Lipid peroxidation and superoxide dismutase, catalase, and glutathione reductase activities were measured in the hepatic tissue, as well as the presence activation of p65 (NF-?B), through western blot. Phytochemical screening of Croton cajucara Benth detected the presence of flavonoids, coumarins and alkaloids. The extract exhibited a significant antioxidant activity in the DPPH-scavenging and the hypoxanthine/xanthine oxidase assays. Liver lipid peroxidation increased in diabetic animals followed by a reduction in the Croton-cajucara-Benth-treated group. There was activation of p65 nuclear expression in the diabetic animals, which was attenuated in the animals receiving the Croton cajucara Benth aqueous extract. The liver tissue in diabetic rats showed oxidative alterations related to the streptozotocin treatment. In conclusion the Croton cajucara Benth aqueus extract treatment effectively reduced the oxidative stress and contributed to tissue recovery. PMID:22811599

Rodrigues, Graziella Ramos; Di Naso, Fabio Cangeri; Porawski, Marilene; Marcolin, Eder; Kretzmann, Nelson Alexandre; Ferraz, Alexandre de Barros Falcao; Richter, Marc Francois; Marroni, Claudio Augusto; Marroni, Norma Possa



Oxidative stress and reduced responsiveness of challenged circulating leukocytes following pulmonary instillation of metal-rich particulate matter in rats.  


Welding fume is an exposure that consists of a mixture of metal-rich particulate matter with gases (ozone, carbon monoxide) and/or vapors (VOCs). Data suggests that welders are immune compromised. Given the inability of pulmonary leukocytes to properly respond to a secondary infection in animal models, the question arose whether the dysfunction persisted systemically. Our aim was to evaluate the circulating leukocyte population in terms of cellular activation, presence of oxidative stress, and functionality after a secondary challenge, following welding fume exposure. Rats were intratracheally instilled (ITI) with PBS or 2 mg of welding fume collected from a stainless steel weld. Rats were sacrificed 4 and 24 h post-exposure and whole blood was collected. Whole blood was used for cellular differential counts, RNA isolation with subsequent microarray and Ingenuity Pathway Analysis, and secondary stimulation with LPS utilizing TruCulture technology. In addition, mononuclear cells were isolated 24 h post-exposure to measure oxidative stress by flow cytometry and confocal microscopy. Welding fume exposure had rapid effects on the circulating leukocyte population as identified by relative mRNA expression changes. Instillation of welding fume reduced inflammatory protein production of circulating leukocytes when challenged with the secondary stimulus LPS. The effects were not related to transcription, but were observed in conjunction with oxidative stress. These findings support previous studies of an inadequate pulmonary immune response following a metal-rich exposure and extend those findings showing leukocyte dysfunction occurs systemically. PMID:25123171

Erdely, Aaron; Antonini, James M; Young, Shih-Houng; Kashon, Michael L; Gu, Ja K; Hulderman, Tracy; Salmen, Rebecca; Meighan, Terence; Roberts, Jenny R; Zeidler-Erdely, Patti C



Cadmium-induced postaxial forelimb ectrodactyly: association with altered sonic hedgehog signaling.  


Administration of CdSO(4) to C57BL/6 mice at day 9.5 of gestation induces a high incidence of postaxial forelimb ectrodactyly in the offspring. We propose that Cd(2+) exposure impairs the process of anterior/posterior formation in the limb bud, a process that is directed by Sonic hedgehog (Shh) signaling. We show that exposure of the mouse embryo to Cd(2+) disrupts Shh signaling as measured by polarizing activity of mouse limb bud ZPA grafted to a host chick wing, and activity of a Gli:luciferase reporter exposed to limb bud lysates. Yet the expression of Shh and its translation are not affected by Cd(2+) exposure. We propose that teratogen exposure affects the processing of Shh in the cells in which it is made. PMID:15749261

Scott, William J; Schreiner, Claire M; Goetz, John A; Robbins, David; Bell, Sheila M



Evidence for reduced tonic levels of GABA in the hippocampus of an animal model of ADHD, the spontaneously hypertensive rat.  


Recent studies have investigated the role of ?-aminobutyric acid (GABA) in the behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD), specifically in behavioural disinhibition. Spontaneously hypertensive rats (SHR) are widely accepted as an animal model of ADHD, displaying core symptoms of the disorder. Using an in vitro superfusion technique, we have shown that glutamate-stimulated release of radio-actively labelled norepinephrine ([(3)H]NE) from prefrontal cortex and hippocampal slices is greater in SHR than in their normotensive control strain, Wistar-Kyoto rats (WKY), and/or a standard control strain, Sprague-Dawley rats (SD). In the present study, we investigated how the level of extracellular (tonic) GABA affects release of [(3)H]NE in hippocampal slices of male and female SHR, WKY and SD rats, in response to 3 glutamate stimulations (S1, S2, and S3). The hippocampal slices were prelabelled with [(3)H]NE and superfused with buffer containing 0?M, 1?M, 10?M, or 100?M GABA. Three consecutive glutamate stimulations were achieved by exposing slices to 3 pulses of glutamate (1mM), each separated by 10min. Increasing tonic levels of GABA increased basal and stimulated release of [(3)H]NE in all strains. When GABA was omitted from the superfusion buffer used to perfuse SHR hippocampal slices, but present at 100µM in the buffer used to perfuse WKY and SD hippocampal slices, glutamate-stimulated release of [(3)H]NE was similar in all three strains. In these conditions, the decrease in [(3)H]NE release from S1 to S2 and S3 was also similar in all three strains. These findings suggest that extracellular concentrations of GABA may be reduced in SHR hippocampus, in vivo, compared to WKY and SD. An underlying defect in GABA function may be at the root of the dysfunction in catecholamine transmission noted in SHR, and may underlie their ADHD-like behaviours. PMID:24161405

Sterley, Toni-Lee; Howells, Fleur M; Russell, Vivienne A



Involvement of central TRPV1 receptors in pentylenetetrazole and amygdala-induced kindling in male rats.  


Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel that is involved in modulation of diverse physiological processes. The role of this receptor in epilepsy has not been studied well. Therefore, we investigated the role of central TRPV1 receptors on the development of pentylenetetrazole (PTZ) and amygdala-induced kindling in rats. Male Wistar rats received subconvulsive dose of PTZ intraperitoneally, every other day. TRPV1 receptor agonist, OLDA and its antagonist, AMG-9810 were injected intracerebroventricularly 30 min prior to PTZ administration. In electrical kindling, stimulating and recording electrodes were implanted in the right amygdala of male rats. After kindling, the effect of TRPV1 receptor agonist or antagonist on afterdischarge duration (ADD), latency to the onset of bilateral forelimb clonuses (S4L) and duration of loss of equilibrium (stage 5 seizures, S5D) were measured. The results demonstrated that, OLDA at the doses of 0.01, 0.1 and 1 ?g/rat, significantly accelerated the incidence of all seizure stages, increased S5D and decreased S4L in the PTZ model of kindling. Also, in amygdala kindling, S5D and ADD were significantly reduced following the administration of AMG-9810. In contrast, OLDA significantly aggravated the indices of seizure in both models of epileptic seizure. This study demonstrated that central TRPV1 receptors may be involved in the development of electrical and PTZ-induced kindling. PMID:24577898

Shirazi, Mohsen; Izadi, Mahin; Amin, Masoud; Rezvani, Mohammad Ebrahim; Roohbakhsh, Ali; Shamsizadeh, Ali



Population Coding of Forelimb Joint Kinematics by Peripheral Afferents in Monkeys  

PubMed Central

Various peripheral receptors provide information concerning position and movement to the central nervous system to achieve complex and dexterous movements of forelimbs in primates. The response properties of single afferent receptors to movements at a single joint have been examined in detail, but the population coding of peripheral afferents remains poorly defined. In this study, we obtained multichannel recordings from dorsal root ganglion (DRG) neurons in cervical segments of monkeys. We applied the sparse linear regression (SLiR) algorithm to the recordings, which selects useful input signals to reconstruct movement kinematics. Multichannel recordings of peripheral afferents were performed by inserting multi-electrode arrays into the DRGs of lower cervical segments in two anesthetized monkeys. A total of 112 and 92 units were responsive to the passive joint movements or the skin stimulation with a painting brush in Monkey 1 and Monkey 2, respectively. Using the SLiR algorithm, we reconstructed the temporal changes of joint angle, angular velocity, and acceleration at the elbow, wrist, and finger joints from temporal firing patterns of the DRG neurons. By automatically selecting a subset of recorded units, the SLiR achieved superior generalization performance compared with a regularized linear regression algorithm. The SLiR selected not only putative muscle units that were responsive to only the passive movements, but also a number of putative cutaneous units responsive to the skin stimulation. These results suggested that an ensemble of peripheral primary afferents that contains both putative muscle and cutaneous units encode forelimb joint kinematics of non-human primates. PMID:23112841

Umeda, Tatsuya; Seki, Kazuhiko; Sato, Masa-aki; Nishimura, Yukio; Kawato, Mitsuo; Isa, Tadashi



Longitudinal development of equine forelimb conformation from birth to weaning in three different horse breeds.  


There is limited published data on conformational changes in the forelimbs of growing foals. This study was designed to describe the changes in conformation of the carpus and distal forelimb from birth to weaning in foals of three different breeds. Evaluation of the conformation of the carpus, fetlock, pastern and foot was carried out in 134 Thoroughbreds, 162 French Trotters and 98 Selle Français (French Warmblood) within 1 month of age and then at approximately 2 month intervals until weaning at approximately 6 months of age. The prevalence of limb deviations decreased from birth to weaning. Angular limb deformities were the predominant conditions in the first month (63.6% of all observed limb deviations) and flexural limb deformities were the most common abnormalities at weaning. The most frequent congenital abnormalities were carpal valgus (42.1% of the foals), fetlock valgus (31.2%), over-at-the-knee (30.8%) and dropped fetlocks (13.0%), with French Trotters and Thoroughbred foals being more affected than Selle Français foals. During the study period, the carpal and fetlock conformation became less valgus. The predominant abnormalities at weaning were fetlock valgus (19.1%), club feet (13.0%) and fetlock varus (11.2%). These observations show that carpal, fetlock and foot conformations changed substantially from birth and weaning. There were significant conformational differences between the three breeds, especially in the first months of life. An understanding of the peculiarities of specific breeds may be useful for the evaluation of individual foal conformation. PMID:24176280

Robert, C; Valette, J-P; Denoix, J-M



Combination of carvacrol with methotrexate suppresses Complete Freund's Adjuvant induced synovial inflammation with reduced hepatotoxicity in rats.  


The present study evaluated the therapeutic benefit of the combination of carvacrol, an isoprenoid having potential anti-inflammatory action, with methotrexate in suppressing Complete Freund's Adjuvant induced arthritis and attenuating methotrexate induced hepatic damage. Arthritis was induced in rats with Complete Freund's Adjuvant. Animals received methotrexate (2mg/kg) intraperitonealy once a week for 5 weeks alone and along with carvacrol orally (50 and 100mg/kg) respectively from the 10th to the 42nd day. Control and carvacrol alone group were also studied. Paw volume, hypernociception, and erythrocyte sedimentation rate were evaluated as arthritic markers. Hepatic marker enzymes in serum; myeloperoxidase, protein oxidation, and oxidative measures were determined in the liver homogenate. Liver histological assessments were also carried out. Methotrexate significantly controlled arthritis; however, liver damage was evident due to oxidative stress and rise in myeloperoxidase levels. Carvacrol suppressed the hyperalgesic response, significantly alleviated arthritis and reduced damage to the hepatocytes owing to a decline in the levels of myeloperoxidase and oxidative markers. High dose of the combination reduced the levels of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and alkaline phosphatase by 24.74%, 30.2% and 28.14% compared with methotrexate treatment. Histological assessment also revealed that carvacrol minimizes methotrexate induced liver toxicity. In combination, carvacrol promoted the anti-arthritic action of methotrexate, reduced neutrophils infiltration and peroxidative damage to the liver. Therefore, carvacrol can serve as a useful adjuvant and promote the safe use of methotrexate in the management of arthritis. PMID:24333217

Banji, Otilia J F; Banji, David; Soumya, N; Chilipi, Kiran Kumar; Kalpana, C H; Kranthi Kumar, C H; Annamalai, A R



Low-Level Laser Therapy (808 nm) Reduces Inflammatory Response and Oxidative Stress in Rat Tibialis Anterior Muscle After Cryolesion  

PubMed Central

Background and Objective Muscle regeneration is a complex phenomenon, involving coordinated activation of several cellular responses. During this process, oxidative stress and consequent tissue damage occur with a severity that may depend on the intensity and duration of the inflammatory response. Among the therapeutic approaches to attenuate inflammation and increase tissue repair, low-level laser therapy (LLLT) may be a safe and effective clinical procedure. The aim of this study was to evaluate the effects of LLLT on oxidative/nitrative stress and inflammatory mediators produced during a cryolesion of the tibialis anterior (TA) muscle in rats. Material and Methods Sixty Wistar rats were randomly divided into three groups (n = 20): control (BC), injured TA muscle without LLLT (IC), injured TA muscle submitted to LLLT (IRI). The injured region was irradiated daily for 4 consecutive days, starting immediately after the lesion using a AlGaAs laser (continuous wave, 808 nm, tip area of 0.00785 cm2, power 30 mW, application time 47 seconds, fluence 180 J/cm2; 3.8 mW/cm2; and total energy 1.4 J). The animals were sacrificed on the fourth day after injury. Results LLLT reduced oxidative and nitrative stress in injured muscle, decreased lipid peroxidation, nitrotyrosine formation and NO production, probably due to reduction in iNOS protein expression. Moreover, LLLT increased SOD gene expression, and decreased the inflammatory response as measured by gene expression of NF-k? and COX-2 and by TNF-? and IL-1? concentration. Conclusion These results suggest that LLLT could be an effective therapeutic approach to modulate oxidative and nitrative stress and to reduce inflammation in injured muscle. PMID:23001637

Assis, Livia; Moretti, Ana I.S.; Abrahao, Thalita B.; Cury, Vivian; Souza, Heraldo P.; Hamblin, Michael R.; Parizotto, Nivaldo A.



Inactivation of the Dorsal Raph? Nucleus Reduces the Anxiogenic Response of Rats Running an Alley for Intravenous Cocaine  

PubMed Central

Rats traversing a straight alley once a day for delivery of a single i.v. injection of cocaine develop over trials an ambivalence about entering the goal box. This ambivalence is characterized by the increasing occurrence of “retreat behaviors” where animals leave the start box and run quickly to the goal box, but then stop at the entry point and “retreat” back toward the start box. This unique pattern of retreat behavior has been shown to reflect a form of “approach-avoidance conflict” that stems from the animals’ concurrent positive (cocaine reward) and negative (cocaine-induced anxiety) associations with the goal box. Cocaine blocks reuptake of the serotonergic (5-HT) transporter and serotonin has been implicated in the modulation of anxiety. It was therefore of interest to determine whether inactivation of the serotonergic cell bodies residing in the dorsal raphé nucleus (DRN) and projecting to brain areas critical for the modulation of anxiety, would alter the anxiogenic state exhibited by rats running an alley for single daily i.v. injections of 1.0 mg/kg cocaine. Reversible inactivation of the DRN was accomplished by intracranial application of a mixed solution of the GABA agonists baclofen and muscimol. While DRN inactivation had no impact on the subjects’ motivation to initiate responding (i.e., latencies to leave the start box were unaffected) it reliably reduced the frequency of approach-avoidance retreat behaviors (conflict behavior). These data suggest that inactivation of the dorsal raphé reduces the conflict/anxiety otherwise present in experienced cocaine-seeking animals. PMID:21108959

Ettenberg, Aaron; Ofer, Oren A.; Mueller, Carl L.; Waldroup, Stephanie; Cohen, Ami; Ben-Shahar, Osnat



Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat.  

PubMed Central

We have shown that osteogenic protein-1 (OP-1) (bone morphogenetic protein-7) is responsible for the induction of nephrogenic mesenchyme during embryonic kidney development. Gene knock-out studies showed that OP-1 null mutant mice die of renal failure within the first day of postnatal life. In the present study, we evaluated the effect of recombinant human OP-1 for the treatment of acute renal failure after 60 min bilateral renal artery occlusion in rats. Bioavailability studies in normal rats indicate that approximately 1.4 microg OP-1/ml is available in the circulation 1 min after intravenous administration of 250 microg/kg, which then declines steadily with a half life of 30 min. About 0.5% of the administered OP-1 dose/g tissue is targeted for OP-1 receptors in the kidney. We show that OP-1 preserves kidney function, as determined by reduced blood urea nitrogen and serum creatinine, and increased survival rate when administered 10 min before or 1 or 16 h after ischemia, and then at 24-h intervals up to 72 h after reperfusion. Histochemical and molecular analyses demonstrate that OP-1: (a) minimizes infarction and cell necrosis, and decreases the number of plugged tubules; (b) suppresses inflammation by downregulating the expression of intercellular adhesive molecule, and prevents the accumulation and activity of neutrophils; (c) maintains the expression of the vascular smooth muscle cell phenotype in pericellular capillaries; and (d) reduces programmed cell death during the recovery. Collectively, these data suggest that OP-1 prevents the loss of kidney function associated with ischemic injury and may provide a basis for the treatment of acute renal failure. PMID:9649574

Vukicevic, S; Basic, V; Rogic, D; Basic, N; Shih, M S; Shepard, A; Jin, D; Dattatreyamurty, B; Jones, W; Dorai, H; Ryan, S; Griffiths, D; Maliakal, J; Jelic, M; Pastorcic, M; Stavljenic, A; Sampath, T K



Perfusion of the mechanically compressed lumbar ganglion with lidocaine reduces mechanical hyperalgesia and allodynia in the rat.  


The rat L(5) dorsal root ganglion (DRG) was chronically compressed by inserting a hollow perforated rod into the intervertebral foramen. The DRG was constantly perfused through the hollow rod with either lidocaine or normal saline delivered by a subcutaneous osmotic pump. Behavioral evidence for neuropathic pain after DRG compression involved measuring the incidence of hindlimb withdrawals to both punctate indentations of the hind paw with mechanical probes exerting different bending forces (hyperalgesia) and to light stroking of the hind paw with a cotton wisp (tactile allodynia). Behavioral results showed that for saline-treated control rats: the withdrawal thresholds for the ipsilateral and contralateral paws to mechanical stimuli decreased significantly after surgery and the incidence of foot withdrawal to light stroking significantly increased on both ipsilateral and contralateral hind paws. Local perfusion of the compressed DRG with 2% lidocaine for 7 days at a low flow-rate (1 microl/h), or for 1 day at a high flow-rate (8 microl/h) partially reduced the decrease in the withdrawal thresholds on the ipsilateral foot but did not affect the contralateral foot. The incidence of foot withdrawal in response to light stroking with a cotton wisp decreased significantly on the ipsilateral foot and was completely abolished on the contralateral foot in the lidocaine treatment groups. This study demonstrated that compression of the L(5) DRG induced a central pain syndrome that included bilateral mechanical hyperalgesia and tactile allodynia. Results also suggest that a lidocaine block, or a reduction in abnormal activity from the compressed ganglia to the spinal cord, could partially reduce mechanical hyperalgesia and tactile allodynia. PMID:10938306

Zhang, J M; Li, H; Brull, S J



Resveratrol Treatment Reduces Cardiac Progenitor Cell Dysfunction and Prevents Morpho-Functional Ventricular Remodeling in Type-1 Diabetic Rats  

PubMed Central

Emerging evidence suggests that both adult cardiac cell and the cardiac stem/progenitor cell (CSPC) compartments are involved in the patho-physiology of diabetic cardiomyopathy (DCM). We evaluated whether early administration of Resveratrol, a natural antioxidant polyphenolic compound, in addition to improving cardiomyocyte function, exerts a protective role on (i) the progenitor cell pool, and (ii) the myocardial environment and its impact on CSPCs, positively interfering with the onset of DCM phenotype. Adult Wistar rats (n?=?128) with streptozotocin-induced type-1 diabetes were either untreated (D group; n?=?54) or subjected to administration of trans-Resveratrol (i.p. injection: 2.5 mg/Kg/day; DR group; n?=?64). Twenty-five rats constituted the control group (C). After 1, 3 or 8 weeks of hyperglycemia, we evaluated cardiac hemodynamic performance, and cardiomyocyte contractile properties and intracellular calcium dynamics. Myocardial remodeling and tissue inflammation were also assessed by morphometry, immunohistochemistry and immunoblotting. Eventually, the impact of the diabetic “milieu” on CSPC turnover was analyzed in co-cultures of healthy CSPCs and cardiomyocytes isolated from D and DR diabetic hearts. In untreated animals, cardiac function was maintained during the first 3 weeks of hyperglycemia, although a definite ventricular remodeling was already present, mainly characterized by a marked loss of CSPCs and adult cardiac cells. Relevant signs of ventricular dysfunction appeared after 8 weeks of diabetes, and included: 1) a significant reduction in ±dP/dt in comparison with C group, 2) a prolongation of isovolumic contraction/relaxation times, 3) an impaired contraction of isolated cardiomyocytes associated with altered intracellular calcium dynamics. Resveratrol administration reduced atrial CSPC loss, succeeded in preserving the functional abilities of CSPCs and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function. These findings indicate that RSV can constitute an adjuvant therapeutic option in DCM prevention. PMID:22768138

Delucchi, Francesca; Berni, Roberta; Frati, Caterina; Cavalli, Stefano; Graiani, Gallia; Sala, Roberto; Chaponnier, Christine; Gabbiani, Giulio; Calani, Luca; Rio, Daniele Del; Bocchi, Leonardo; Lagrasta, Costanza; Quaini, Federico; Stilli, Donatella



Excessive zinc intake increases systemic blood pressure and reduces renal blood flow via kidney angiotensin II in rats.  


This study investigated the effects of excess zinc intake on the mean arterial pressure (MAP), renal blood flow (RBF), inulin clearance (IC), serum zinc level, serum angiotensin-converting enzyme (ACE) activity, and kidney angiotensin II (AT II) levels in rats. Experiments were performed on male Sprague-Dawley rats maintained for 4 weeks on a diet containing either 5 mg/100 g (control group), 50 mg/100 g (Zn50 group), or 200 mg/100 g (Zn200 group) zinc carbonate. Serum zinc levels significantly increased to 126.5 % in the Zn50 group and 198.1 % in the Zn200 group compared with controls. MAP significantly increased to 107.8 % in the Zn50 group and 114.5 % in the Zn200 group again compared with controls. Although the difference in serum ACE activity was independent of the serum zinc levels, the kidney AT II levels increased significantly to 137.2 % in the Zn50 group and 174.4 % in the Zn200 group compared with the controls. RBF was decreased significantly to 74.4 % in the Zn50 group and 69.7 % in the Zn200 group compared with the controls. IC values were significantly decreased to 69.6 % in the Zn50 group and 52.7 % in the Zn200 group as compared with control levels. Combined together, these results show that excessive Zn intake reduced IC and RBF and increased MAP and kidney AT II levels, suggesting that excessive Zn intake reduces renal function. PMID:22752877

Kasai, Miyoko; Miyazaki, Takashi; Takenaka, Tsuneo; Yanagisawa, Hiroyuki; Suzuki, Hiromichi



Cystatin A expression reduces bile salt-induced apoptosis in a rat hepatoma cell line.  


We have previously demonstrated abrogation of bile salt-induced apoptosis by cathepsin B inhibitors. However, caspases have been strongly implicated in apoptosis, and the mechanistic interface between caspase and cathepsin B activation is unclear. Thus our aims were to determine the mechanistic relationship between caspases and cathepsin B in bile salt-induced apoptosis in a rat hepatoma cell line. Expression of cystatin A was used to inhibit cathepsin B, whereas Z-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) was used to inhibit caspases. Cystatin A expression prevented cathepsin B activation and apoptosis during treatment with glycochenodeoxycholate (GCDC), a toxic bile salt. Caspase N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin (DEVD-AMC) hydrolytic activity increased in both wild-type and cystatin A-transfected cells treated with GCDC, demonstrating caspase activation despite inhibition of cathepsin B. In contrast, Z-VAD-FMK blocked both DEVD-AMC hydrolytic activity and cathepsin B activity during GCDC treatment. Our data demonstrate that 1) bile salt-induced apoptosis can be inhibited by the cystatin A transgene and 2) caspase and cathepsin B activation are linked mechanistically with cathepsin B downstream of caspases. PMID:9756503

Jones, B; Roberts, P J; Faubion, W A; Kominami, E; Gores, G J



Reduced Hippocampal Dendritic Spine Density and BDNF Expression following Acute Postnatal Exposure to Di(2-Ethylhexyl) Phthalate in Male Long Evans Rats  

PubMed Central

Early developmental exposure to di(2-ethylhexyl) phthalate (DEHP) has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats. PMID:25295592

Smith, Catherine A.; Holahan, Matthew R.



Reduced GABAAR-mediated tonic inhibition in aged rat auditory thalamus  

PubMed Central

Age-related deficits in detecting and understanding speech, which can lead to social withdrawal and isolation, have been linked to changes in the central auditory system. Many of these central age-related changes involve altered mechanisms of inhibitory neurotransmission, essential for accurate and reliable auditory processing. In sensory thalamus, GABA mediates fast (phasic) inhibition via synaptic GABAAR and long-lasting (tonic) inhibition via high affinity (extrasynaptic) GABAARs which provide a majority of the overall inhibitory tone in sensory thalamus. Due to a delicate balance between excitation and inhibition, alteration of normal thalamic inhibitory function with age and a reduction of tonic GABAAR-mediated inhibition may disrupt normal adult auditory processing, sensory gating, thalamocortical rhythmicity and slow-wave sleep. The present study examined age-related homeostatic plasticity of GABAAR function in auditory thalamus or medial geniculate body (MGB). Using thalamic slices from young adult (3–8 months) and aged (28–32 months) rats, these studies found a 45.5% reduction in GABAAR density and a 50.4% reduction in GABAAR-mediated tonic whole cell Cl? currents in the aged MGB. Synaptic GABAAR-mediated inhibition appeared differentially affected in aged lemniscal and non-lemniscal MGB. Except for resting membrane potential, basic properties were unaltered with age, including neuronal Cl? homeostasis determined using the gramicidin perforated patch-clamp method. Results demonstrate selective significant age-dependent deficits in the tonic inhibitory tone within the MGB. These data suggest that selective GABAAR subtype agonists or modulators might be used to augment MGB inhibitory neurotransmission, improving speech understanding, sensory gating and slow-wave sleep for a subset of elderly individuals. PMID:23325258

Richardson, Ben D.; Ling, Lynne L.; Uteshev, Victor V.; Caspary, Donald M.




PubMed Central

BACKGROUND This study examined whether prazosin reduces alcohol drinking over the course of prolonged treatment and whether it blocks initiation of alcohol drinking in rats with a genetic predisposition toward high alcohol drinking, i.e, alcohol-preferring (P) rats. METHODS In study one, alcohol-experienced P rats that had been drinking alcohol 2 hrs/day for several months were treated daily with prazosin (0, 0.5, 1.0 or 2.0 mg/kg BW) for 7 weeks. In study two, alcohol-naïve P rats were treated daily with prazosin (0, 1.0 or 2.0 mg/kg BW) for two weeks prior to, or concomitantly with, initiation of alcohol access and throughout 3 weeks of alcohol availability. Prazosin treatment and alcohol access were then discontinued for 2 weeks followed by reinstatement of alcohol access without prazosin treatment for 4 weeks, followed by resumption of daily prazosin treatment (2.0 mg/kg BW) for 3 weeks. RESULTS Prazosin reduced alcohol drinking throughout 7 weeks of treatment in P rats accustomed to drinking alcohol. Following termination of prazosin treatment, alcohol drinking slowly returned to pretreatment baseline. Reduced alcohol intake was accompanied by increased water intake. In alcohol-naïve P rats, prazosin administration prior to the first opportunity to drink alcohol and throughout 3 weeks of alcohol access retarded acquisition of alcohol drinking and reduced the amount of alcohol consumed. When prazosin was administered concomitantly with the first opportunity to drink alcohol, it abolished acquisition of alcohol drinking. Discontinuation of prazosin treatment allowed expression of a genetic predisposition toward high alcohol drinking to gradually emerge. Prazosin retained the ability to reduce alcohol intake with repeated treatments. CONCLUSIONS Prazosin decreased alcohol drinking during prolonged treatment and may be useful for treating alcoholism and alcohol use disorders. Prazosin may also be useful for deterring initiation of drinking in individuals with a family history of alcoholism. PMID:23731093

Froehlich, Janice C; Hausauer, Brett J; Federoff, David L; Fischer, Stephen M; Rasmussen, Dennis D



Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging  

PubMed Central

The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW) throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6–42 months) were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning, and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL) male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR) prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR) rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn), an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non-obese aging rats. PMID:24847259

Ménard, Caroline; Quirion, Rémi; Bouchard, Sylvain; Ferland, Guylaine; Gaudreau, Pierrette



Reduced anti-contractile effect of perivascular adipose tissue on mesenteric small arteries from spontaneously hypertensive rats: role of Kv7 channels.  


Perivascular adipose tissue (PVAT) has been shown to produce vasoactive substances and regulate vascular tone. This function of PVAT has been reported to be altered in hypertension. However, the underlying mechanisms are not fully understood. In this study we used age-matched normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) as well as Sprague-Dawley rats and tested effects of PVAT on mesenteric small arteries. Vessels were mounted in a Mulvany-Halpern myograph and cumulative concentration-response relations to noradrenaline were determined in the presence or absence of PVAT. We found that PVAT has an anti-contractile effect on mesenteric small vessels, irrespective of strains. A reduced effect of PVAT was observed in SHR compared to WKY rats; the difference between strains was eliminated by 10 ?M XE991, a blocker of Kv7 (KCNQ) voltage-dependent potassium channels. The anti-contractile effect of PVAT was not affected by depolarizing smooth muscle cells with high K(+) solution. Sensitivities to exogenous vasodilators acetylcholine or sodium nitroprusside were not potentiated but reduced in vessels with PVAT. Our results suggest that the reduced anti-contractile effect of PVAT in SHR correlates with a deficiency in Kv7 channels. Diffusion hindrance of PVAT is also a factor that should be considered in investigations on rat mesenteric small arteries. PMID:23059186

Li, Rui; Andersen, Ingrid; Aleke, Josefin; Golubinskaya, Veronika; Gustafsson, Helena; Nilsson, Holger



Reduced conduction reserve in the diabetic rat heart: role of iPLA2 activation in the response to ischemia.  


Hearts from streptozotocin (STZ)-induced diabetic rats have previously been shown to have impaired intercellular electrical coupling, due to reorganization (lateralization) of connexin43 proteins. Due to the resulting reduction in conduction reserve, conduction velocity in diabetic hearts is more sensitive to conditions that reduce cellular excitability or intercellular electrical coupling. Diabetes is a known risk factor for cardiac ischemia, a condition associated with both reduced cellular excitability and reduced intercellular coupling. Activation of Ca(2+)-independent phospholipase A(2) (iPLA(2)) is known to be part of the response to acute ischemia and may contribute to the intercellular uncoupling by causing increased levels of arachidonic acid and lysophosphatidyl choline. Normally perfused diabetic hearts are known to exhibit increased iPLA(2) activity and may thus be particularly sensitive to further activation of these enzymes. In this study, we used voltage-sensitive dye mapping to assess changes in conduction velocity in response to acute global ischemia in Langendorff-perfused STZ-induced diabetic hearts. Conduction slowing in response to ischemia was significantly larger in STZ-induced diabetic hearts compared with healthy controls. Similarly, slowing of conduction velocity in response to acidosis was also more pronounced in STZ-induced diabetic hearts. Inhibition of iPLA(2) activity using bromoenol lactone (BEL; 10 ?M) had no effect on the response to ischemia in healthy control hearts. However, in STZ-induced diabetic hearts, BEL significantly reduced the amount of conduction slowing observed beginning 5 min after the onset of ischemia. BEL treatment also significantly increased the time to onset of sustained arrhythmias in STZ-induced diabetic hearts but had no effect on the time to arrhythmia in healthy control hearts. Thus, our results suggest that iPLA(2) activation in response to acute ischemia in STZ-induced diabetic hearts is more pronounced than in control hearts and that this response is a significant contributor to arrhythmogenic conduction slowing. PMID:21037228

Rahnema, Parisa; Shimoni, Yakhin; Nygren, Anders



The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: Synergism with the benzodiazepine diazepam  

SciTech Connect

Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of ?-aminobutyric acid A (GABA{sub A}) receptors. However, seizure activity itself causes the endocytosis of GABA{sub A} receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-D-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20 mg/kg, im) and DZP (10 mg/kg, sc), administered both separately and in combination, at 10, 20 or 30 min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD{sub 50}; 132 ?g/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2 mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20–30 min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity. -- Highlights: ? Soman (GD) produced seizure activity resulting in neuropathology in rats. ? Tx: caramiphen (CED) and/or diazepam (DZP) @ 10, 20 or 30 min after seizure onset. ? CED/DZP showed superior anticonvulsant and neuroprotective capacity. ? Physostigmine (PHY) was examined as an adjunct post-exposure therapy. ? PHY attenuated GD-induced seizure development, but not seizure duration.

Schultz, M.K.; Wright, L.K.M.; Stone, M.F.; Schwartz, J.E.; Kelley, N.R.; Moffett, M.C.; Lee, R.B.; Lumley, L.A., E-mail:



Brain BDNF levels elevation induced by physical training is reduced after unilateral common carotid artery occlusion in rats.  


We investigated the contribution of blood flow elevation in the cerebrovasculature to physical training-induced brain-derived neurotrophic factor (BDNF) levels elevation in the brain. Brain-derived neurotrophic factor protein levels were measured in the motor cortex 24?h after the last session of a forced treadmill walking (30?minutes a day, 18?m/minute for 7 consecutive days). Unilateral common carotid artery occlusion and modulation of exercise intensity (0 versus -10% inclination of the treadmill) were used as strategies to reduce the (normal) elevation of flow in the cerebrovasculature occurring during exercise. Administration of N-nitro-L-arginine methyl ester (L-NAME, 60?mg/kg before each exercise sessions) and genetic hypertension (spontaneously hypertensive rats) were used as approaches to reduce stimulation of nitric oxide production in response to shear stress elevation. Vascular occlusion totally and partially abolished the effect of physical training on BDNF levels in the hemisphere ipsilateral and contralateral to occlusion, respectively. BDNF levels were higher after high than low exercise intensity. In addition, both genetic hypertension and L-NAME treatment blunted the effects of physical training on BDNF. From these results, we propose that elevation of brain BDNF levels elicited by physical training involves changes in cerebral hemodynamics. PMID:25052557

Banoujaafar, Hayat; Hoecke, Jacques Van; Mossiat, Claude M; Marie, Christine



21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia.  


U74006F is a member of a new family of steroid drugs called 21-aminosteroids, which are potent inhibitors of lipid peroxidation with little or no glucocorticoid or mineralocorticoid activity. We investigated the effects of U74006F on the early ionic edema produced by middle cerebral artery occlusion in rats. Intravenous doses of 3 mg/kg U74006F were given 10 minutes and 3 hours after occlusion. Tissue concentrations of Na+, K+, and water at and around the infarct site were measured by atomic absorption spectroscopy and by wet-dry weight measurements 24 hours after occlusion. Compared with vehicle treatment, U74006F treatment reduced brain water entry, Na+ accumulation, K+ loss, and net ion shift by 25-50% in most brain areas sampled in the frontal and parietal cortex. However, reductions of ionic edema were most prominent and reached significance (p less than 0.005, unpaired two-tailed t test) mostly in the frontoparietal and parietal cortex areas adjacent to the infarct site. Our findings suggest that a steroid drug without glucocorticoid or mineralocorticoid activity can reduce edema in cerebral ischemia but that the effects are largely limited to tissues in which collateral blood flow may be present. PMID:3400099

Young, W; Wojak, J C; DeCrescito, V



Exogenous antenatal glucocorticoid treatment reduces susceptibility for hippocampal kindled and maximal electroconvulsive seizures in infant rats.  


Dexamethasone (DEX) and betamethasone (BETA) are synthetic glucocorticoids used clinically to reduce morbidity and mortality in infants at risk of premature birth. While their main role is to facilitate lung development, their effect on the developing nervous system and seizure susceptibility is unclear. The present study tested the hypothesis that antenatal DEX or BETA treatment would alter seizure thresholds and spread of epileptiform activity in the brains of infant offspring. Pregnant dams received once daily injections with DEX, BETA, or vehicle on gestation days 15 to 18. Physical appearance, litter size, and weight of the pups were assessed postnatally. Seizure thresholds were determined on postnatal day 14 using electroconvulsive shock delivered through ear clips (i.e., generalized seizure) or kindling stimulation of the left hippocampus through indwelling electrodes (i.e., partial seizure). The rate of acquisition of kindled seizures was determined on postnatal days 14 and 15. Pups from dams treated with DEX and BETA were growth restricted. Antenatal BETA treatment increased seizure threshold for both models. Antenatal DEX treatment increased kindling threshold, but not electroconvulsive shock threshold. Kindling rate was unaffected by either antenatal treatment. In summary, repeated glucocorticoid treatments had adverse effects on weight, skin and litter size, raised seizure thresholds, and reduced seizure vulnerability. Although these effects are seemingly desirable with respect to seizure susceptibility, they suggest that the functional organization of the nervous system is altered with antenatal synthetic glucocorticoid treatment. PMID:16445912

Young, Nicole A; Teskey, G Campbell; Henry, Luke C; Edwards, Heather E



Transplantation of Bone Marrow Stromal Cells Enhances Nerve Regeneration of the Corticospinal Tract and Improves Recovery of Neurological Functions in a Collagenase-Induced Rat Model of Intracerebral Hemorrhage  

PubMed Central

The reorganization of brain structures after intracerebral hemorrhage (ICH) insult is crucial to functional outcome. Although the pattern of neuronal rewiring is well-documented after ischemic stroke, the study of brain plasticity after ICH has been focusing on the enhancement of dendritic complexity. Here we hypothesized that functional restoration after ICH involves brain reorganization which may be favorably modulated by stem cell transplantation. In this study, bone marrow stromal cells (BMSCs) were transplanted into the perilesional sites of collagenase-induced ICH in adult rats one day after ICH injury. Forelimb functional recovery was monitored with modified limb placing and vibrissae-elicited forelimb placement tests. Anterograde and retrograde tracing were used to assess the reorganization of bilateral forelimb areas of the sensorimotor cortex. We found that in rats transplanted with BMSCs after ICH injury, axonal sprouting occurred in the contralateral caudal forelimb area of the cortex, and was significantly higher than in ICH rat models that received only the vehicle (P < 0.01). The number of positive neurons in the ipsilateral rostral forelimb area of the cortex of the BMSC group was 1.5– to 4.5-fold greater than in the vehicle group (P < 0.05). No difference was found between the BMSC and vehicle groups in hemispheric atrophy or labeled neurons in the ipsilateral caudal forelimb area (P = 0.193). Scores for improved functional behavior in the BMSC group were in accord with the results from histology. Neuronal plasticity of the denervated corticospinal tract at bilateral forelimb areas of the cortex in the collagenase-induced ICH rat models was significantly enhanced by BMSC transplantation. BMSC transplantation may facilitate functional recovery after ICH injury. PMID:23807046

Liang, Hongsheng; Yin, Yibo; Lin, Tie; Guan, Dong; Ma, Bowen; Li, Changyu; Wang, Yuehua; Zhang, Xiangtong



Reduced brain corticotropin-releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats.  


The brain corticotropin-releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety-related behaviour or non-selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF-R) antagonist D-Phe to manipulate CRF-R1/2 non-specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation-specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D-Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D-Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF-R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour. PMID:23742269

Klampfl, Stefanie M; Neumann, Inga D; Bosch, Oliver J



AVE3085, an enhancer of endothelial nitric oxide synthase, restores endothelial function and reduces blood pressure in spontaneously hypertensive rats  

PubMed Central

BACKGROUND AND PURPOSE Nitric oxide (NO) plays an important role in endothelial function, and impaired NO production is involved in hypertension. Therefore, compounds that regulate endothelial NO synthase (eNOS) may be of therapeutic benefit. A novel, low molecular weight compound AVE3085 is a recently developed compound with the ability to enhance eNOS transcription. The present study investigated the effects of AVE3085 in endothelial dysfunction associated with hypertension. EXPERIMENTAL APPROACH Spontaneously hypertensive rats (SHRs) were treated with AVE 3085 (10 mg·kg·day?1, orally) for 4 weeks. Isometric force measurement was performed on rings of isolated aortae in organ baths. Protein expression of eNOS, phosphorylated-eNOS and nitrotyrosine in the aortae were examined by Western blotting. mRNA for eNOS in rat aortae were examined by reverse-transcriptase polymerase chain reaction (RT-PCR). KEY RESULTS AVE3085 greatly improved endothelium-dependent relaxations in the aortae of SHRs. This functional change was accompanied by up-regulated expression of eNOS protein and mRNA, enhanced eNOS phosphorylation and decreased formation of nitrotyrosine. Furthermore, AVE3085 treatment reduced the blood pressure in SHR without affecting that of hypertensive eNOS?/? mice. CONCLUSIONS AND IMPLICATIONS The eNOS-transcription enhancer AVE3085 restored impaired endothelial function in a hypertensive model. The present study provides a solid basis for the potential development of eNOS-targeting drugs to restore down-regulated eNOS, as a new strategy in hypertension. PMID:21385179

Yang, Qin; Xue, Hong-Mei; Wong, Wing-Tak; Tian, Xiao-Yu; Huang, Yu; Tsui, Stephen KW; Ng, Patrick KS; Wohlfart, Paulus; Li, Huige; Xia, Ning; Tobias, Silke; Underwood, Malcolm John; He, Guo-Wei



Intrathecal Administration of Mesenchymal Stem Cells Reduces the Reactive Oxygen Species and Pain Behavior in Neuropathic Rats  

PubMed Central

Background Neuropathic pain induced by spinal or peripheral nerve injury is very resistant to common pain killers, nerve block, and other pain management approaches. Recently, several studies using stem cells suggested a new way to control the neuropatic pain. In this study, we used the spinal nerve L5 ligation (SNL) model to investigate whether intrathecal rat mesenchymal stem cells (rMSCs) were able to decrease pain behavior, as well as the relationship between rMSCs and reactive oxygen species (ROS). Methods Neuropathic pain of the left hind paw was induced by unilateral SNL in Sprague-Dawley rats (n = 10 in each group). Mechanical sensitivity was assessed using Von Frey filaments at 3, 7, 10, 12, 14, 17, and 24 days post-ligation. rMSCs (10 µl, 1 × 105) or phosphate buffer saline (PBS, 10 µl) was injected intrathecally at 7 days post-ligation. Dihydroethidium (DHE), an oxidative fluorescent dye, was used to detect ROS at 24 days post-ligation. Results Tight ligation of the L5 spinal nerve induced allodynia in the left hind paw after 3 days post-ligation. ROS expression was increased significantly (P < 0.05) in spinal dorsal horn of L5. Intrathecal rMSCs significantly (P < 0.01) alleviated the allodynia at 10 days after intrathecal injection (17 days post-ligation). Intrathecal rMSCs administration significantly (P < 0.05) reduced ROS expression in the spinal dorsal horn. Conclusions These results suggest that rMSCs may modulate neuropathic pain generation through ROS expression after spinal nerve ligation. PMID:25031809

Zhang, En Ji; Ko, Young Kwon