Glucocorticoid Receptor Antagonist Mifepristone Does Not Alter Innate Anxiety-Like Behavior in Genetically-Selected Marchigian Sardinian (msP) Rats

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 (CRF1) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.     

Alterations of regional cerebral blood flow after NMDA receptor antagonist administration in patients with alcohol‐related dementia

Although N‐methyl‐d ‐aspartate (NMDA) receptor antagonists may have beneficial influences on cognition in patients with alcohol‐related dementia (ARD), their effects on regional cerebral blood flow (rCBF) remain unknown. This study evaluated changes in rCBF in ARD patients after administration of NMDA receptor antagonist for 12 weeks using technetium‐99m ethyl cysteinate dimer (Tc‐99m ECD) single‐photon emission computed tomography (SPECT). Twenty‐eight ARD patients were administered memantine for 12 weeks and underwent clinical evaluations and brain SPECT scans at baseline and follow‐up. Whole‐brain changes in perfusion were examined on a voxel‐by‐voxel basis. At follow‐up, the patients showed reduced rCBF in the left medial frontal gyrus, left cingulate gyrus, left claustrum, right brainstem, left superior temporal gyrus, bilateral fusiform gyrus, and left cerebellum. On the other hand, increased rCBF was found in the bilateral uncus, left parahippocampal gyrus, bilateral superior frontal gyrus, right inferior parietal lobule, left cuneus, and left superior temporal gyrus. Perfusion increases in various brain areas including the superior frontal, parahippocampal, and inferior parietal areas, which may play important roles in the pathophysiology of ARD, suggest potential benefits of NMDA receptor antagonists on brain functions in patients with ARD.     

Blocking, Unblocking, and Overexpectation of Fear: A Role for Opioid Receptors in the Regulation of Pavlovian Association Formation.

Injection of the opioid receptor antagonist naloxone facilitated acquisition of fear to contextual and auditory conditioned stimuli (CSs) in Experiments 1A and 1B. Experiment 2 showed that prior conditioning to a distinctive context blocked conditioning to an auditory CS. Blocking of CS fear was prevented by administrations of naloxone or increases in footshock intensity. Blocking of CS fear was facilitated by decreases in footshock intensity in a naloxone-reversible manner. Experiment 3 showed that compound conditioning of two CSs, each previously and separately paired with shock, produced overexpectation of fear that was reversed by naloxone. These results are consistent with a role for opioid receptors controlling Pavlovian association formation by regulating the discrepancy (A--ΣV) described by R. A. Rescorla and A. R. Wagner (1972). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.     

Towards a Treatment for Neuroinflammation in Epilepsy: Interleukin-1 Receptor Antagonist,Anakinra, as a Potential Treatment in Intractable Epilepsy

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized its effects in 38 patients (32 patients with FIRES and six with DRE). Of the 22 patients with FIRES, 16 (73%) had at least short-term seizure control 1 week after starting anakinra, while the remaining six suspected anakinra-refractory cases were male and had poor prognoses. Due to the small sample size, an explanation for anakinra refractoriness was not evident. In all DRE patients, seizures disappeared or improved, and cognitive function improved in five of the six patients following treatment. Patients showed no serious side effects, although drug reactions with eosinophilia and systemic symptoms, cytopenia, and infections were observed. Thus, anakinra has led to a marked improvement in some cases, and functional deficiency of IL-1RA was indicated, supporting a direct mechanism for its therapeutic effect. This review first discusses the effectiveness of anakinra for intractable epileptic syndromes. Anakinra could become a new tool for intractable epilepsy treatment. However, it does not currently have a solid evidence base.     

咖啡酸、阿魏酸:新的非肽类内皮素拮抗剂1

目的 评价桂皮酸类化合物咖啡酸和阿魏酸对内皮素(ET-1)生物效应的拮抗作用并初步探讨其拮抗ET-1 的作用机理。方法 用咖啡酸与阿魏酸腹腔注射及静脉注射给药后观察其对ET-1 致小鼠急性死亡以及对大鼠升压效应、对离体主动脉条的收缩效应的拮抗作用;口服给药后考察其对醋酸去氧皮质酮(DOCA)-盐高血压大鼠ET-1 的作用, 并对DOCA-盐高血压动物模型ET-1 血浆浓度、血压和动物体重变化及心血管组织增生的影响;对ET-1、c-fos、热休克蛋白(HSP70)mRNA 基因表达的影响。结果 咖啡酸和阿魏酸腹腔注射给药后能显著延长ET-1 致小鼠急性死亡时间, 与对照组相比该作用具剂量依赖性;静脉注射给药后能拮抗ET-1 引起的正常大鼠升压效应;在离体器官上可观察到咖啡酸与阿魏酸能拮抗ET-1 的缩血管效应;咖啡酸和阿魏酸长期口服给药能降低DOCA-盐高血压模型大鼠的血压、对心脏和血管的组织增生有明显的抑制作用;可降低血浆中ET-1 的浓度并可减少ET-1 引起的c-fos、HSP70 mRNA 基因表达的增加;放射性受体-配体结合实验表明, 咖啡酸和阿魏酸可竞争性地抑制ET-1 与其受体结合。结论 咖啡酸和阿魏酸为新的非肽类ET-1 拮抗剂。     

Design and Experimental Evaluation of a Peptide Antagonist against Amyloid β(1–42) Interactions with Calmodulin and Calbindin-D28k

Amyloid β_1–42 (Aβ(1–42)) oligomers have been linked to the pathogenesis of Alzheimer’s disease (AD). Intracellular calcium (Ca²⁺) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity in AD. The Ca²⁺ binding proteins calmodulin (CaM) and calbindin-D28k, whose expression levels are lowered in human AD brains, have relevant roles in neuronal survival and activity. In previous works, we have shown that CaM has a high affinity for Aβ(1–42) oligomers and extensively binds internalized Aβ(1–42) in neurons. In this work, we have designed a hydrophobic peptide of 10 amino acid residues: VFAFAMAFML (amidated-C-terminus amino acid) mimicking the interacting domain of CaM with Aβ (1–42), using a combined strategy based on the experimental results obtained for Aβ(1–42) binding to CaM and in silico docking analysis. The increase in the fluorescence intensity of Aβ(1–42) HiLyte^TM-Fluor555 has been used to monitor the kinetics of complex formation with CaM and with calbindin-D28k. The complexation between nanomolar concentrations of Aβ(1–42) and calbindin-D28k is also a novel finding reported in this work. We found that the synthetic peptide VFAFAMAFML (amidated-C-terminus amino acid) is a potent inhibitor of the formation of Aβ(1–42):CaM and of Aβ(1–42):calbindin-D28k complexes.     

CRH? receptor antagonists for the treatment of depression and anxiety.

From basic and clinical studies, ample evidence has emerged that abnormalities of stress hormone regulation observed in depression and anxiety are caused by elevated secretion of hypothalamic corticotropin-releasing hormone (CRH). This neuropeptide acts through CRH? receptors to produce a number of anxiety- and depression-like symptoms, which has resulted in extensive validation of CRH? receptors as a potential drug target. A number of orally available nonpeptidergic small molecules that are able to pass the blood-brain barrier have been discovered. Some of these compounds have entered clinical development. The authors summarize results from clinical studies of 2 CRH? antagonists. One study designed as a safety and tolerability study also monitored amelioration of depression under 2 dose-escalation regimens. The compound studied, NBI-30775/R121919, was found to have a clinical profile comparable to that of paroxetine. In a second study the effect of another CRH? antagonist, NBI-34041, on stress hormone secretion in response to a psychosocial stressor was investigated. Administration of this compound to healthy controls was found to reduce the stress-elicited secretion of stress hormones. However, neither compound impaired the CRH-induced release of adrenocorticotropic hormone and cortisol, rejecting the possibility that the stress hormone system is impaired by CRH? antagonists. From these studies the authors conclude that both CRH? antagonists have psychotropic effects unrelated to their neuroendocrine action, in line with behavioral data obtained from transgenic mice with CRH? gene deletions. The psychotropic effects observed in the clinical studies underscore that CRH? antagonists constitute a novel treatment of depression and anxiety but may also serve to prevent negative sequelae of severe stressors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine D? receptor activation modulates perceived odor intensity.

Dopaminergic modulation affects odor detection thresholds and olfactory discrimination capabilities in rats. The authors show that dopamine D? receptor modulation affects odor discrimination capabilities in a manner similar to the modulation of stimulus intensity. Performance in a simultaneous odor discrimination task was systematically altered by manipulations of both odorant concentration and D? receptor activation (agonist quinpirole, 0.025-0.5 mg/kg; antagonist spiperone, 0.5 mg/kg). Rats' discrimination performance systematically improved at higher odor concentrations. Blockade of D? receptors improved performance equivalent to increasing odor concentration by 2 log units, whereas activation of D? receptors reduced odor discrimination performance in a dose-dependent manner. Bulbar dopamine release may serve a gain control function in the olfactory system, optimizing its sensitivity to changes in the chemosensory environment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

醋柳黄酮对血管平滑肌细胞胞内游离钙浓度的影响

目的:探讨醋柳总黄酮(TFH) 对血管平滑肌细胞胞内游离钙浓度([Ca²⁺]_i) 的影响。方法:采用新一代钙荧光探针Fluo-3/AM 检测在高钾、去甲肾上腺素(NE)、血管紧张素II(Ang Ⅱ) 刺激下单层兔主动脉平滑肌细胞内游离钙水平的改变, 并与传统的钙拮抗剂Verapamil (Ver) 进行对照研究。结果:TFH(100 mg·L^-1) 对静息状态的血管平滑肌细胞[Ca²⁺]_i 无明显影响;TFH(60 ～ 100 mg·L^-1) 呈剂量依赖性抑制高K⁺ 去极化引起的[Ca²⁺]_i 升高, 与Ver 作用相似, 但弱于Ver;TFH(80、100 mg·L^-1) 对NE、Ang Ⅱ通过受体介导引起[Ca²⁺]_i 升高均具有明显的抑制作用;在无细胞外Ca²⁺存在下, TFH(80、100 mg·L^-1) 对NE 引起的[Ca²⁺]_i 升高也具有一定程度的抑制效应。结论:醋柳总黄酮通过对电压依赖性钙通道和受体操纵型钙通道双重抑制降低血管平滑肌细胞内游离钙水平, 这可能是醋柳黄酮产生舒血管降压作用机制之一。