Cannabinoid receptor 1 in the vagus nerve is dispensable for body weight homeostasis but required for normal gastrointestinal motility

The cannabinoid receptor 1 (CB(1)R) is required for body weight homeostasis and normal gastrointestinal motility. However, the specific cell types expressing CB(1)R that regulate these physiological functions are unknown. CB(1)R is widely expressed, including in neurons of the parasympathetic branches of the autonomic nervous system. The vagus nerve has been implicated in the regulation of several aspects of metabolism and energy balance (e.g., food intake and glucose balance), and gastrointestinal functions including motility. To directly test the relevance of CB(1)R in neurons of the vagus nerve on metabolic homeostasis and gastrointestinal motility, we generated and characterized mice lacking CB(1)R in afferent and efferent branches of the vagus nerve (Cnr1(flox/flox); Phox2b-Cre mice). On a chow or on a high-fat diet, Cnr1(flox/flox); Phox2b-Cre mice have similar body weight, food intake, energy expenditure, and glycemia compared with Cnr1(flox/flox) control mice. Also, fasting-induced hyperphagia and after acute or chronic pharmacological treatment with SR141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] (CB(1)R inverse agonist) paradigms, mutants display normal body weight and food intake. Interestingly, Cnr1(flox/flox); Phox2b-Cre mice have increased gastrointestinal motility compared with controls. These results unveil CB(1)R in the vagus nerve as a key component underlying normal gastrointestinal motility.     

Intracerebral pneumatocele: CT findings

Two cases of intracerebral pneumatocele following trauma are presented. One to two months after initial treatment both patients had deteriorating neurologic status. The diagnosis was made by radiography. When a pneumatocele is suspected clinically, computed tomography can play a vital role in determining the precise location of the gas collection, its relationship to the fracture site, and the amount of mass effect on the brain.     

Differential expression of orexin receptors 1 and 2 in the rat brain

Orexins (hypocretins) are neuropeptides synthesized in the central nervous system exclusively by neurons of the lateral hypothalamus. Orexin-containing neurons have widespread projections and have been implicated in complex physiological functions including feeding behavior, sleep states, neuroendocrine function, and autonomic control. Two orexin receptors (OX(1)R and OX(2)R) have been identified, with distinct expression patterns throughout the brain, but a systematic examination of orexin receptor expression in the brain has not appeared. We used in situ hybridization histochemistry to examine the patterns of expression of mRNA for both orexin receptors throughout the brain. OX(1)R mRNA was observed in many brain regions including the prefrontal and infralimbic cortex, hippocampus, paraventricular thalamic nucleus, ventromedial hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. OX(2)R mRNA was prominent in a complementary distribution including the cerebral cortex, septal nuclei, hippocampus, medial thalamic groups, raphe nuclei, and many hypothalamic nuclei including the tuberomammillary nucleus, dorsomedial nucleus, paraventricular nucleus, and ventral premammillary nucleus. The differential distribution of orexin receptors is consistent with the proposed multifaceted roles of orexin in regulating homeostasis and may explain the unique role of the OX(2)R receptor in regulating sleep state stability.     

高效液相色谱法测定炎痛净乳膏中双氯芬酸钠和苯佐卡因的含量

目的：测定炎痛净乳膏中双氯芬酸钠和苯佐卡因的含量。方法：高效液想象以谱法，甲醇为提取溶剂，地西泮为内标，No-va-PakC18色谱柱，甲醇-水-冰醋酸（80：20：0.5)为流动相，检测波长为283nm。结果：双氯芬酸钠和苯佐卡因在5μg/ml-40μg/ml范围内，其浓度与峰面积均呈良好的线性关系（r=0.9999)，平均回收率分别为101.0%,RSD=1.21%,99.8%,RSD=0.62%。结论：本法专属性强，操作简便，结果准确。     

HIV-1tat induced apoptosis of T-cells is not mediated by TGF-β

Recent reports have demonstrated that the HIV-1 transactivator protein,tat, induces apoptosis in T-lymphocyte cell lines, as well as in peripheral blood mononuclear cells, and stimulates a cascade of events resulting in up-regulation of the potent immunosuppressive cytokine, transforming growth factor-β (TGF-β). In this study we evaluated the ability of TGF-β to mediatetat induced apoptosis in T-lymphocyte cell lines. T-cells treated exogenously with either TGF-β1 or a combination of tat and pan-specific TGF-β neutralizing antibodies showed little change in the amount of apoptosis. When treated with pan-specific TGF-β neutralizing antibodies, Jurkat cells that stably expresstat protein (Jurkat-tat) showed only a modest decrease in apoptosis, while CEM-TART cells (CEM T-cells expressing both HIV-1tat andrev) demonstrated little change in the amount of apoptosis. In conclusion, we have demonstrated that TGF-β does not play a significant role in mediatingtat induced T-cell apoptosis.     

Distribution of the novel antifolate pemetrexed to the brain

Pemetrexed disodium is a novel antifolate that exhibits potent inhibitory effects on multiple enzymes in folate metabolism. Phase II/III clinical trials have shown that pemetrexed is effective against various solid tumors. Like methotrexate, pemetrexed may be useful in treatment of primary and secondary brain tumors. In this study, we examined the central nervous system (CNS) distribution of pemetrexed and the interaction with an organic anion transport inhibitor indomethacin. Male Wistar rats were administered pemetrexed by either single intravenous bolus or constant intravenous infusion. Unbound pemetrexed in blood and brain was measured by simultaneous arterial blood and frontal cortex microdialysis sampling. In the i.v. bolus experiments, indomethacin was administered by i.v. bolus (10 mg/kg) followed by i.v. infusion (0.1 mg/kg/h) in a crossover manner. In the infusion experiments, the same dose of indomethacin was administered after a steady state was reached for pemetrexed. CNS distributional kinetics was analyzed by compartmental and noncompartmental methods. Both bolus and infusion studies showed that pemetrexed has a limited CNS distribution. The mean area under concentration-time curve (AUC)(brain)/AUC(plasma) ratio of unbound pemetrexed was 0.078 +/- 0.038 in the i.v. bolus study. The pemetrexed steady-state brain-to-plasma unbound concentration ratio after i.v. infusion was 0.106 +/- 0.054. The distributional clearance into the brain was approximately 10% of the clearance out of the brain in both the compartmental and noncompartmental analyses. Indomethacin had no effect on either the brain-to-plasma AUC ratio or the steady-state brain-to-plasma concentration ratio. The distribution of pemetrexed into the brain is limited, and an efflux clearance process, such as an efflux transporter, may be involved.     

Galanin and its receptors in neurological disorders

Galanin is a highly inducible neuropeptide, showing distinct up-regulation after pathological disturbance within the nervous system. Significant increase in galanin expression is observed after peripheral nerve injury, in the basal forebrain in Alzheimer’s disease (AD), during neuronal development, and after stimulation with estrogen, while seizure activity deplete galanin in the hippocampus. A wide distribution of galanin and its receptors is seen in the nervous system, often in co-localization with classical neurotransmitters and other neuromodulators. Galanin acts predominantly as an inhibitory, hyperpolarizing neuromodulator on neurotransmitter and glucose-induced insulin release and stimulates growth hormone and prolactin secretion. Galanin has been implicated in several higher order physiological functions including cognition, feeding, nociception, mood regulation, and neuroendocrine modulation. The effects of galanin are mediated via three G protein-coupled receptors with different functional coupling. Moderate to low pharmacological effects are seen by galanin under physiological conditions, in contrast to its dramatic effects on the nervous system after neuronal disturbance. This pathophysiological heavy function of the galaninergic system renders it an interest for disorders such as AD, depression, and epilepsy in terms of side effects. Some properties of the galaninergic system are of particular importance in the context of neurodegeneration. Galanin is highly inducible, 10- to 100-fold, upon nerve injury, whereas most neuropeptides are induced 1.5- to 2-fold. Galanin is strongly neurotrophic during development as well as subsequent to injury. Whereas other neurotrophic neuropeptides like VIP and PACAP activate cAMP synthesis, galanin suppresses its synthesis, yet it is a strong neurotrophic as well as neuroprotective agent. As we delineate which galanin receptor subtype mediates neuroprotective and neurotrophic effects and which mediates synaptic inhibition, pharmacological use of receptor-selective galaninergic ligands for treatment in neurodegenerative diseases are coming closer.     

Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells

Several multidrug resistance-associated protein (MRP) homologs are expressed in brain microvessel endothelial cells forming the blood-brain barrier (BBB). The influence of these MRP transporters on BBB permeability will be dependent on their localization within the brain microvessel endothelial cells. Using two different and complementary approaches, the localization of various MPR homologs (MRP1, MRP4, and MRP5) was examined in primary cultured bovine brain microvessel endothelial cells (BBMECs). The first approach involved centrifugal separation of apical and basolateral plasma membranes of cultured BBMECs. The membrane fractions were then subjected to Western blot analysis for MRPs. The second approach used confocal laser scanning microscopy to determine membrane localization of MRPs in BBMECs. Results show a predominantly apical plasma membrane distribution for MRP1 and MRP5, and an almost equal distribution of MRP4 on the apical and basolateral plasma membrane of BBMECs. These studies provide the first demonstration of the localization of MRP1, MRP4, and MRP5 homologs in brain microvessel endothelial cells. The present studies also indicate that the localization of MRPs in the endothelial cells forming the BBB is different from that observed in polarized epithelial cells and thus may contribute to the reduced entry and enhanced elimination of organic anions and nucleotides in the brain.