Exploring potential energy hypersurfaces for triple symmetric inversion in 3-azabicyclo[3.3.1]nonan-9-one and its N-methyl derivative

The potential energy hypersurfaces for the triple inversion, from chair to boat and α to β conformations, are explored theoretically in 3-azabicyclo[3.3.1]nonan-9-one and its N-methyl derivative, by using ab initio quantum-mechanical calculations. Both compounds are precursors of rigid analogs of the potential GABA_A and GABA_B receptor antagonists. In contrast to results from semiempirical calculations, the chair–chair β conformers are found to be, by far, the most stable structures for both the nonmethylated and N-methylated compounds. The inversion barriers are found to be relatively low, so that the conformers could be expected to exist in thermodynamic equilibrium at room temperature. A population analysis reveals, however, that, in the ab initio approach, the molecules seem to exist practically only in the chair–chair–β conformation. The theoretical results compare well with the available experimental data. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1567–1574, 1998     

作用于离子型γ-氨基丁酸受体的异噁唑啉类杀寄生虫剂

离子型GABA受体是一类重要的杀虫剂靶标,异噁唑啉类化合物是作用于该靶标的一类新型杀虫（寄生虫）剂。基于异噁唑啉类衍生物高效的杀虫活性和出色的安全性,自首个该类杀寄生虫剂氟雷拉纳被发现后,阿福拉纳、沙罗拉纳、洛替拉纳和氟噁唑酰胺等化合物相继被报道。本文主要综述了异噁唑啉类化合物在杀虫剂领域的最新研究进展,重点在化学结构、杀虫活性、作用机制、生物代谢和安全性等方面进行了总结和评述,同时探讨了异噁唑啉类杀虫（寄生虫）剂在应用上的局限性,对该类化合物在农业病虫害防治的应用前景和发展趋势作了展望。     

MRS定量检测活体γ-氨基丁酸浓度的研究现状

γ-氨基丁酸（GABA）是一种重要的脑代谢物, 磁共振频谱(MRS)技术可以非介入检测活体脑代谢物浓度. 但使用MRS定量检测活体GABA还是会遇到很多困难. 随着谱编辑技术的发展和频谱分析软件的出现, 已提出了很多方法用于定量检测活体GABA浓度. 本文简述了GABA的理论背景, 然后介绍了国内外MRS定量检测活体γ 氨基丁酸浓度的研究现状, 最后分析了MRS定量检测γ 氨基丁酸浓度的方向.      

Neuronal mechanism of epileptogenesis in EL mouse

The convulsions of the EL mouse (EL) were described by Imaizumi et al. in 1954 and were established as epilepsy by Suzuki in 1976. The EL mouse has been kept as an inbred strain and is considered one of the best animal models originated in Japan. The mode of inheritance is autosomal dominant, and environmental risk factors for seizure occurrence are hypothesised to contribute to the polygenic background. Paroxysmal activities in the EL brain arise from the parietal cortex (PCX) and are augmented in the hippocampus, demonstrated by electrophysiology and autoradiography using 2-deoxy glucose when clinical symptoms of seizures appeared. The neurons in the EL PCX, where GABA activity is lower than that of DDY PCX demonstrate increased excitability to proprioceptive sensory input. After repetitive seizure-provoking stimuli, seizures are more easily induced, eventually occurring spontaneously. This phenomenon of “abnormal plasticity” is also observed in the EEG, decreasing GABA activity, expression of the immediately early gene, and various biochemical and molecular processes. This phenomenon is similar to the learning or progressive process of certain neurological diseases.     

Synthesis of [5,6-3H](+/−) Gamma Vinyl GABA

Abstract

An efficient synthesis of [5,6-³H] (+/?) gamma vinyl GABA 5 from 4-aminohex-5-ynoic acid 3 is described.     

Accuracy and stability of measuring GABA, glutamate, and glutamine by proton magnetic resonance spectroscopy: a phantom study at 4 Tesla

Proton magnetic resonance spectroscopy has the potential to provide valuable information about alterations in gamma-aminobutyric acid (GABA), glutamate (Glu), and glutamine (Gln) in psychiatric and neurological disorders. In order to use this technique effectively, it is important to establish the accuracy and reproducibility of the methodology. In this study, phantoms with known metabolite concentrations were used to compare the accuracy of 2D J-resolved MRS, single-echo 30 ms PRESS, and GABA-edited MEGA-PRESS for measuring all three aforementioned neurochemicals simultaneously. The phantoms included metabolite concentrations above and below the physiological range and scans were performed at baseline, 1 week, and 1 month time-points. For GABA measurement, MEGA-PRESS proved optimal with a measured-to-target correlation of R(2)=0.999, with J-resolved providing R(2)=0.973 for GABA. All three methods proved effective in measuring Glu with R(2)=0.987 (30 ms PRESS), R(2)=0.996 (J-resolved) and R(2)=0.910 (MEGA-PRESS). J-resolved and MEGA-PRESS yielded good results for Gln measures with respective R(2)=0.855 (J-resolved) and R(2)=0.815 (MEGA-PRESS). The 30 ms PRESS method proved ineffective in measuring GABA and Gln. When measurement stability at in vivo concentration was assessed as a function of varying spectral quality, J-resolved proved the most stable and immune to signal-to-noise and linewidth fluctuation compared to MEGA-PRESS and 30 ms PRESS.     

Manganese Accumulation in the Brain via Various Transporters and Its Neurotoxicity Mechanisms

Manganese (Mn) is an essential trace element, serving as a cofactor for several key enzymes, such as glutamine synthetase, arginase, pyruvate decarboxylase, and mitochondrial superoxide dismutase. However, its chronic overexposure can result in a neurological disorder referred to as manganism, presenting symptoms similar to those inherent to Parkinson’s disease. The pathological symptoms of Mn-induced toxicity are well-known, but the underlying mechanisms of Mn transport to the brain and cellular toxicity leading to Mn’s neurotoxicity are not completely understood. Mn’s levels in the brain are regulated by multiple transporters responsible for its uptake and efflux, and thus, dysregulation of these transporters may result in Mn accumulation in the brain, causing neurotoxicity. Its distribution and subcellular localization in the brain and associated subcellular toxicity mechanisms have also been extensively studied. This review highlights the presently known Mn transporters and their roles in Mn-induced neurotoxicity, as well as subsequent molecular and cellular dysregulation upon its intracellular uptakes, such as oxidative stress, neuroinflammation, disruption of neurotransmission, α-synuclein aggregation, and amyloidogenesis.     

人脑GABA磁共振波谱测量中大分子影响的研究

J差分谱编辑技术已广泛用于人脑g-氨基丁酸(γ-amino butyric acid,GABA)的检测,利用MEGA-PRESS序列可以有效编辑GABA在δ_H 3.02处的信号.由于相近的化学位移和J耦合作用,大分子(macromolecule,MM)在δ_H 3.00的信号也同时被编辑,因此测量得到的GABA信号中包含一部分MM信号(GABA+MM,简称GABA+).对称谱编辑技术可以有效抑制大分子,但该方法对编辑脉冲的频率选择性要求较高,因此对称谱编辑技术中编辑脉冲持续时间一般较长.该研究将MEGA-PRESS序列中编辑脉冲持续时间由14 ms增加到20 ms,回波时间(echo time,TE)由68 ms增加到80 ms,分别测量GABA+与对称谱编辑技术抑制大分子后的GABA(简称GABA).结果发现,在较长编辑脉冲作用时间和较长TE条件下,GABA比GABA+含量低27%;长编辑脉冲持续时间可以有效提高编辑脉冲的频率选择性,更好地实现对称谱编辑技术抑制大分子,有助于分析人脑GABA含量测定中大分子信号干扰的影响.纯GABA含量测量,有助于更准确地分析GABA在人脑中的代谢过程,以及GABA含量与各种疾病和功能认知反应之间的相关性.     

Improving detection sensitivity of amino acids in thyroid tissues by using phthalic acid as a mobile phase additive in hydrophilic interaction chromatography-electrospray ionization-tandem mass spectrometry

In this work, 0.08 mmol L⁻¹ of phthalic acid was introduced as a mobile phase additive to quantify free amino acids (AAs) by hydrophilic interaction liquid chromatography (HILIC) coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS). The addition of phthalic acid significantly increased the signal intensity of protonated AA ions, resulting from the decrease of the relative abundance of AA sodium adducts. Meanwhile, the chromatographic peak shapes of AAs were optimized. As a consequence, there was a noticeable increase in the sensitivity of detection for AAs. The limits of detection (LOD) and quantification (LOQ) of the AAs ranged from 0.0500 to 20.0 ng mL⁻¹ and from 0.100 to 50.0 ng mL⁻¹, respectively, which were 4–50 times lower compared to the values measured without the addition of phthalic acid. The enhanced detection and separation of AAs were obtained by merely adding phthalic acid to the mobile phase without changing other conditions. Eventually, this simple method was validated and successfully applied to the analysis of twenty-four kinds of free AAs in human thyroid carcinoma and para-carcinoma tissues, demonstrating a significant increase of most AAs in thyroid carcinoma tissues (p < 0.05).