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Microglia and the immune pathology of Alzheimer disease

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AMERICAN JOURNAL OF HUMAN GENETICS 1999年第1期65卷 13-18页

作者： Giulian, D Baylor Coll Med Dept Neurol Alzheimers Dis Res Ctr Houston TX 77030 USA

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Protection by 2-deoxy-D-glucose against β,β′-iminodipropionitrile-induced neurobehavioral toxicity in mice

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EXPERIMENTAL NEUROLOGY 1999年第1期158卷 229-233页

作者： Tariq, M Khan, HA Al Moutaery, K Al Deeb, S Armed Forces Hosp Neurosci Res Grp Riyadh 11159 Saudi Arabia

This investigation was undertaken to study the effect of a-deoxy-D-glucose (2-DG) on beta,beta'-iminodipropionitrile (IDPN)-induced neurobehavioral toxicity in mice. Animals were divided into five groups of nine animals each. One of the groups served as control and received vehicle only, whereas the remaining four groups were treated with IDPN (250 mg/kg, ip) daily for 11 days, 2-DG was injected intraperitoneally in the doses of 0 (vehicle only), 100, 300, and 600 mg/kg daily 30 min before IDPN administration. The animals were observed for dyskinetic behavior including vertical (retrocollis) and horizontal (laterocollis) head movements and circling. Twenty-four hours after the last dose of IDPN, the animals were sacrificed by decapitation and striata were isolated from the brain for the analysis of serotonin (5-HT). Our results showed that 2-DG significantly and dose dependently attenuated the incidence and severity of IDPN-induced neurobehavioral toxicity. Administration of 2-DC: also protected mice against IDPN-induced increase in striatal 5-HT levels. Further studies are warranted to investigate the neuroprotective mechanism of 2-DG;against IDPN-induced neurotoxicity. (C) 1999 Academic Press.

关键词：抗代谢药/药理学行为动物/药物作用血糖/药物作用脱氧葡萄糖/药理学注射腹腔内小鼠近交系运动活动/药物作用运动障碍/病因学神经毒素类/代谢神经毒素类/毒性腈类/代谢腈类/毒性动物小鼠

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Subunit interface selectivity of the α-neurotoxins for the nicotinic acetylcholine receptor

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第14期274卷 9581-9586页

作者： Osaka, H Malany, S Kanter, JR Sine, SM Taylor, P Univ Calif San Diego Dept Pharmacol 0636 La Jolla CA 92093 USA Mayo Clin & Mayo Fdn Dept Physiol & Biophys Receptor Biol Lab Rochester MN 55905 USA

Peptide toxins selective for particular subunit interfaces of the nicotinic acetylcholine receptor have proven invaluable in assigning candidate residues located in the two binding sites and for determining probable orientations of the bound peptide. We report here on a short alpha-neurotoxin from Naja mossambica mossambica (NmmI) that, similar to other alpha-neurotoxins, binds with high affinity to alpha gamma and alpha delta subunit interfaces (K-D similar to 100 pM) but binds with markedly reduced affinity to the alpha epsilon interface (K-D similar to 100 nM). By constructing chimeras composed of portions of the gamma and epsilon subunits and coexpressing them with wild type alpha, beta, and delta subunits in HEK 293 cells, we identify a region of the subunit sequence responsible for the difference in affinity. Within this region, gamma Pro-175 and gamma Glu-176 confer high affinity, whereas Thr and Ala, found at homologous positions in epsilon, confer low affinity. To identify an interaction between gamma Glu-176 and residues in NmmI, we have examined cationic residues in the central loop of the toxin and measured binding of mutant toxin-receptor combinations. The data show strong pairwise interactions or coupling between gamma Glu-176 and Lys-27 of NmmI and progressively weaker interactions with Arg-33 and Arg-36 in loop II of this three-loop toxin, Thus, loop II of NmmI, and in particular the face of this loop closest to loop III, appears to come into close apposition with Glu-176 of the gamma subunit surface of the binding site interface.

关键词：氨基酸取代环蛇毒素类/代谢细胞系眼镜蛇神经毒素蛋白质类/化学眼镜蛇神经毒素蛋白质类/遗传学眼镜蛇神经毒素蛋白质类/代谢谷氨酰胺/遗传学谷氨酰胺/代谢模型分子诱变定点神经毒素类/化学神经毒素类/遗传学神经毒素类/代谢脯氨酸/遗传学脯氨酸/代谢蛋白质构象受体烟碱/代谢重组融合蛋白质类/代谢构效关系人类

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In vitro studies of striatal vesicles containing the vesicular monoamine transporter (VMAT2): Rat versus mouse differences in sequestration of 1-methyl-4-phenylpyridinium

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期293卷 329-335页

作者： Staal, RGW Hogan, KA Liang, CL German, DC Sonsalla, PK Univ Med & Dent New Jersey Robert Wood Johnson Med Sch Dept Neurol Piscataway NJ 08854 USA Univ Texas SW Med Ctr Dept Psychiat Dallas TX USA

Significant differences exist in the sensitivity of mice and rats to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that cannot be explained by differences in exposure to or uptake of 1-methyl-4-phenylpyridinium (MPP+) into dopamine (DA) neurons. MPP+ is also a substrate for the brain vesicular monoamine transporter (VMAT2), and sequestration into synaptic vesicles may be one mechanism of protection against MPP+ toxicity. A greater sequestration of MPP+ into vesicles of DA neurons in rats versus mice could explain the lower vulnerability of DA neurons in the rat to MPP+ toxicity. To test this hypothesis, the kinetics of uptake for [H-3]MPP+ and [H-3]DA as well as [H-3]dihydrotetrabenazine binding to VMAT2 were compared in vesicles isolated from the striata of rats and mice. The K-m value of [H-3]MPP+ transport was similar in the two species. In contrast, the maximal transport rate (V-max) was 2-fold greater in vesicles from rats than in those from mice. Likewise, the K-m value for [H-3]DA transport was similar in both preparations, but the V-max value was 2-fold greater in rat than in mouse vesicles. The B-max value for [H-3]dihydrotetrabenazine binding was also 2-fold greater in striatal vesicles from rats than in those from mice. Electron micrographs demonstrated that vesicles isolated from rats and mice were approximately the same size. Based on these observations, we propose that striatal vesicles from rats have more VMAT2 than vesicles from mice and that this species difference in VMAT2 density may help explain the reduced vulnerability of rat DA neurons to MPP+ neurotoxicity.

关键词： 1-甲基-4-苯基吡啶/代谢可卡因/类似物和衍生物可卡因/代谢多巴胺药/代谢多巴胺摄取抑制剂/代谢指示剂和试剂动力学膜糖蛋白类/代谢膜转运蛋白质类显微镜检查电子新纹状体/药物作用新纹状体/代谢新纹状体/超微结构神经肽类神经毒素类/代谢神经递质药/代谢大鼠 Sprague-Dawley 种特异性突触小泡/药物作用突触小泡/代谢突触小泡/超微结构囊泡生物胺转运蛋白质类囊泡单胺转运蛋白质类动物男(雄)性小鼠大鼠

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Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin

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NATURE NEUROSCIENCE 1998年第8期1卷 668-674页

作者： Chuang, RSI Jaffe, H Cribbs, L Perez-Reyes, E Swartz, KJ NINDS Mol Physiol & Biophys Unit NIH Bethesda MD 20892 USA NINDS Prot Peptide Sequencing Facil NIH Bethesda MD 20892 USA Loyola Univ Med Ctr Dept Physiol Maywood IL 60153 USA

The biophysical properties of T-type voltage-gated calcium channels are well suited to pacemaking and to supporting calcium flux near the resting membrane potential in both excitable and nonexcitable cells. We have identified a new scorpion toxin (kurtoxin) that binds to the alpha(1G) T-type calcium channel with high affinity and inhibits the channel by modifying voltage-dependent gating. This toxin distinguishes between alpha(1G) T-type calcium channels and other types of voltage-gated calcium channels, including alpha(1A), alpha(1B), alpha(1C) and alpha(1E). Like the other alpha-scorpion toxins to which it is related, kurtoxin also interacts with voltage-gated sodium channels and slows their inactivation. Kurtoxin will facilitate characterization of the subunit composition of T-type calcium channels and help determine their involvement in electrical and biochemical signaling.

关键词：结合竞争性/生理学钙通道/药物作用钙通道/代谢钙通道 T型电生理学离子通道闸门/药物作用离子通道闸门/生理学神经毒素类/代谢神经毒素类/药理学卵母细胞/代谢蝎毒液类/代谢蝎毒液类/药理学钠通道/药物作用钠通道/代谢光滑爪蟾动物女(雌)性

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The putative bioactive surface of insect-selective scorpion excitatory neurotoxins

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第9期274卷 5769-5776页

作者： Froy, O Zilberberg, N Gordon, D Turkov, M Gilles, N Stankiewicz, N Pelhate, M Loret, E Oren, DA Shaanan, B Gurevitz, M Tel Aviv Univ Dept Plant Sci George S Wise Fac Life Sci IL-69978 Tel Aviv Israel CE Saclay Dept Ingn & Etudes Proteines Commissariat Energie Atom F-91191 Gif Sur Yvette France Univ Angers Fac Med Neurophysiol Lab F-49045 Angers France CNRS LIDSM IBSM UPR 9027 F-13402 Marseille France Hebrew Univ Jerusalem Inst Life Sci Wolfson Ctr Appl Struct Biol IL-91904 Jerusalem Israel Hebrew Univ Jerusalem Inst Life Sci Dept Biol Chem IL-91904 Jerusalem Israel

Scorpion neurotoxins of the excitatory group show total specificity for insects and serve as invaluable probes for insect sodium channels. However, despite their significance and potential for application in insect-pest control, the structural basis for their bioactivity is still unknown. We isolated, characterized, and expressed an atypically long excitatory toxin, Bj-xtrIT, whose bioactive features resembled those of classical excitatory toxins, despite only 49% sequence identity. With the objective of clarifying the toxic site of this unique pharmacological group, Bj-xtrIT was employed in a genetic approach using point mutagenesis and biological and structural assays of the mutant products. A primary target for modification was the structurally unique C-terminal region, Sequential deletions of C-terminal residues suggested an inevitable significance of Ile(73) and Ile(74) for toxicity. Based on the bioactive role of the C-terminal region and a comparison of Bj-xtrIT with a Bj-xtrIT-based model of a classical excitatory toxin, AaHIT, a conserved surface comprising the C terminus is suggested to form the site of recognition with the sodium channel receptor.

关键词：氨基酸序列碱基序列圆二色性克隆分子蜚蠊目/药物作用 DNA引物双翅目/药物作用昆虫蛋白质类膜电位模型分子分子序列数据神经毒素类/化学神经毒素类/遗传学神经毒素类/代谢蛋白质构象蝎毒液类/化学序列同源性氨基酸动物

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Attenuation of NMDA receptor activity and neurotoxicity by nitroxyl anion, NO^-

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NEURON 1999年第2期24卷 461-469页

作者： Kim, WK Choi, YB Rayudu, PV Das, P Asaad, W Arnelle, DR Stamler, JS Lipton, SA Brigham & Womens Hosp Cerebrovasc & Neurosci Res Inst Boston MA 02115 USA Harvard Univ Sch Med Program Neurosci Boston MA 02115 USA Duke Univ Med Ctr Howard Hughes Med Inst Dept Med Durham NC 27710 USA Duke Univ Med Ctr Dept Cell Biol Durham NC 27710 USA

Recent evidence indicates that the NO-related species, nitroxyl anion (NO-), is produced in physiological systems by several redox metal-containing proteins, including hemoglobin, nitric oxide synthase (NOS), superoxide dismutase, and S-nitrosothiols (SNOs), which have recently been identified in brain. However, the chemical biology of NO- remains largely unknown. Here, we show that NO--unlike NO., but reminiscent of NO+ transfer (or S-nitrosylation) - reacts mainly with Cys-399 in the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor to curtail excessive Ca2+ influx and thus provide neuroprotection from excitotoxic insults. This effect of NO- closely resembles that of NOS, which also downregulates NMDA receptor activity under similar conditions in culture.

关键词：阴离子/代谢细胞培养的大脑皮质/细胞学 N-甲基天冬氨酸/药理学神经元/代谢神经毒素类/代谢一氧化氮/药理学一氧化氮供体/药理学一氧化氮合酶/代谢氧化氮类/代谢卵母细胞大鼠 Sprague-Dawley 受体 N-甲基-D-天冬氨酸/化学受体 N-甲基-D-天冬氨酸/药物作用受体 N-甲基-D-天冬氨酸/代谢受体 N-甲基-D-天冬氨酸/生理学巯基化合物/化学巯基化合物/代谢光滑爪蟾动物女(雌)性大鼠

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EXCITATORY AMINO-ACID RECEPTORS IN HUMAN SPINAL-CORD - EVALUATION IN AMYOTROPHIC-LATERAL-SCLEROSIS PATIENTS

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1992年第1期648卷 260-262页

作者： ALLAOUA, H CHAUDIEU, I BOKSA, P PERRY, TL KRIEGER, C QUIRION, R FAC MED VANCOUVER VANCOUVER V6T 1W5BCCANADA MCGILL UNIV DEPT PSYCHIATVERDUN H4H 1R3QUEBECCANADA

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神经生物学

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中国学术期刊文摘 2006年第11期12卷 7页

Nurr1基因与干细胞多巴胺能表型分化的研究进展;肉毒神经毒素受体的研究进展。[编者按]

关键词：肉毒毒素类/代谢神经毒素类/代谢神经生物学

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