The Effect of Adenosine A2A Receptor Antagonists on Hydroxyl Radical, Dopamine, and Glutamate in the Striatum of Rats with Altered Function of VMAT2

It has been shown that a decreased vesicular monoamine transporter (VMAT2) function and the disruption of dopamine (DA) storage is an early contributor to oxidative damage of dopamine neurons in Parkinson’s disease (PD). In our previous study, we demonstrated that adenosine A2A receptor antagonists suppressed oxidative stress in 6-hydroxydopamine-treated rats suggesting that this effect may account for neuroprotective properties of drugs. In the present study, rats were injected with reserpine (10 mg/kg sc) and 18 h later the effect of the adenosine A2A receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on extracellular DA, glutamate and hydroxyl radical formation was studied in the rat striatum using in vivo microdialysis. By disrupting VMAT2 function, reserpine depleted DA stores, and increased glutamate and hydroxyl radical levels in the rat striatum. CSC (1 mg/kg) but not ZM 241385 (3 mg/kg) increased extracellular DA level and production of hydroxyl radical in reserpinised rats. Both antagonists decreased the reserpine-induced increase in extracellular glutamate. l-3,4-Dihydroxyphenylalanine (L-DOPA) (25 mg/kg) significantly enhanced extracellular DA, had no effect on reserpine-induced hydroxyl radical production and decreased extracellular glutamate concentration. CSC but not ZM 241385 given jointly with L-DOPA increased the effect of L-DOPA on extracellular DA and augmented the reserpine-induced hydroxyl radical production. CSC and ZM 241385 did not influence extracellular glutamate level, which was decreased by L-DOPA. It seems that by decreasing the MAO-dependent DA metabolism rate, CSC raised cytosolic DA and by DA autoxidation, it induced hydroxyl radical overproduction. Thus, the methylxanthine A2A receptor antagonists bearing properties of MAO-B inhibitor, like CSC, may cause a risk of oxidative stress resulting from dysfunctional DA storage mechanism in early PD

Effect of Adenosine A2A Receptor Antagonists and l-DOPA on Hydroxyl Radical, Glutamate and Dopamine in the Striatum of 6-OHDA-Treated Rats

A2A adenosine receptor antagonists have been proposed as a new therapy of PD. Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A2A adenosine receptor antagonists 8-(-3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on hydroxyl radical generation, and glutamate (GLU) and dopamine (DA) extracellular level using a microdialysis in the striatum of 6-OHDA-treated rats. CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly for 14 days decreased the production of hydroxyl radical and extracellular GLU level, both enhanced by prior 6-OHDA treatment in dialysates from the rat striatum. CSC and ZM 241385 did not affect DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) extracellular levels in the striatum of 6-OHDA-treated rats. l-DOPA (6 mg/kg) given twice daily for two weeks in the presence of benserazide (3 mg/kg) decreased striatal hydroxyl radical and glutamate extracellular level in 6-OHDA-treated rats. At the same time, l-DOPA slightly but significantly increased the extracellular levels of DOPAC and HVA. A combined repeated administration of l-DOPA and CSC or ZM 241385 did not change the effect of l-DOPA on hydroxyl radical production and glutamate extracellular level in spite of an enhancement of extracellular DA level by CSC and elevation of extracellular level of DOPAC and HVA by ZM 241385. The data suggest that the 6-OHDA-induced damage of nigrostriatal DA-terminals is related to oxidative stress and excessive release of glutamate. Administration of l-DOPA in combination with CSC or ZM 241385, by restoring striatal DA-glutamate balance, suppressed 6-OHDA-induced overproduction of hydroxyl radical

Selective mGluR1 Antagonist EMQMCM Inhibits the Kainate-Induced Excitotoxicity in Primary Neuronal Cultures and in the Rat Hippocampus

Abundant evidence suggests that indirect inhibitory modulation of glutamatergic transmission, via metabotropic glutamatergic receptors (mGluR), may induce neuroprotection. The present study was designed to determine whether the selective antagonist of mGluR1 (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM), showed neuroprotection against the kainate (KA)-induced excitotoxicity in vitro and in vivo. In in vitro studies on mouse primary cortical and hippocampal neuronal cultures, incubation with KA (150 μM) induced strong degeneration [measured as lactate dehydrogenase (LDH) efflux] and apoptosis (measured as caspase-3 activity). EMQMCM (0.1–100 μM) added 30 min to 6 h after KA, significantly attenuated the KA-induced LDH release and prevented the increase in caspase-3 activity in the cultures. Those effects were dose- and time-dependent. In in vivo studies KA (2.5 nmol/1 μl) was unilaterally injected into the rat dorsal CA1 hippocampal region. Degeneration was calculated by counting surviving neurons in the CA pyramidal layer using stereological methods. It was found that EMQMCM (5–10 nmol/1 μl) injected into the dorsal hippocampus 30 min, 1 h, or 3 h (the higher dose only) after KA significantly prevented the KA-induced neuronal degeneration. In vivo microdialysis studies in rat hippocampus showed that EMQMCM (100 μM) significantly increased γ-aminobutyric acid (GABA) and decreased glutamate release. When perfused simultaneously with KA, EMQMCM substantially increased GABA release and prevented the KA-induced glutamate release. The obtained results indicate that the mGluR1 antagonist, EMQMCM, may exert neuroprotection against excitotoxicity after delayed treatment (30 min to 6 h). The role of enhanced GABAergic transmission in the neuroprotection is postulated

Удосконалення хімічного складу бронзового промислового литва

Introduction. Interstate standard GOST 493 provides for the maximum allowable zinc content in bronze BrA9Zh3L not more than 1 (wt.) %. Zinc in aluminum-iron bronze composition has controversial influence on casting technological and mechanical properties. The specified element improves material castability, but, in certain amount, leads to product embrittlement. Problem statement. In the present work the problem of effective amount of zinc determination for casting bronze BrA9Zh3L properties improving without negative affecting the plastic and impact characteristics of foundry products has been solved. Purpose. The purpose of this study was an evaluation of Zn content influence on BrА9Zh3L bronze structure and mechanical properties and determination of its rational doping. Materials and Methods. Aluminum-iron bronze BrА9Ж3Л according to GOST 493, alloyed with zinc in an amount 0…4 (wt.) %. Fractography of destroyed impact samples surfaces and the products microstructure have been studied according to ASTM E3 − 11 (2017) requirements. Mechanical static tensile tests were carried out according to GOST 1497, impact toughness according to GOST 9454. Results. It has been established that the zinc content increasing over then 0,2 % by weight in bronze BrA9Zh3L composition effects not only on significant strength decreasing, but also on sharp ductility dropping. The reason for such regularity is the number of eutectoid component in BrA9Zh3L structure increasing. Conclusions. Active loosing of BrA9Zh3L bronze plasticity and ductility, associated with alloy structural state changing, has been recorded in the range of 0,2...0,6 (wt.) % Zn. For industrial cast products maximum Zn content in bronze BrA9Zh3L has been recommended to limit by 0,2 (wt.) % against normatively stipulated 1,0 (wt.) % as per GOST 493.Введение. Межгосударственный стандарт ГОСТ 493 предусматривает максимально допустимое содержание цинка в бронзе БрА9Ж3Л массовой долей не более 1 %. Цинк в составе алюминий-железной бронзы оказывает неоднозначное влияние на технологические и механические характеристики литья. Указанный элемент улучшает жидкотекучесть материала, но, в определенных количествах, приводит к охрупчиванию изделия. Проблематика. В настоящей работе решалась проблема выбора эффективного количества цинка, способствующего улучшению литейных свойств бронзы БрА9Ж3Л без негативного воздействия на пластические и ударные характеристики отливок. Цель исследования − оценка влияния Zn на структуру и механические свойства бронзы БрА9Ж3Л и определение рационального ее легирования. Материалы и методы. Алюминиево-железная бронза БрА9Ж3Л по ГОСТ 493, легированная цинком массовой долей от 0 до 4 %. Фрактографию поверхностей разрушения ударных образцов и микроструктуру изделий изучали по требованиям АSTM Е3 – 11 (2017). Механические испытания на статическое растяжение проводили по ГОСТ 1497, на ударный изгиб – по ГОСТ 9454. Результат. Установлено, что увеличение содержания цинка более 0,2 % в составе бронзы БрА9Ж3Л приводит не только к существенному уменьшению её прочности, но и к резкому уменьшению пластичности. Причина такой закономерности – увеличение в структуре БрА9Ж3Л количества эвтектоидной составляющей. Выводы. Активная потеря пластичности и вязкости бронзы БрА9Ж3Л, связанная с изменением структурного состояния сплава, зафиксирована в интервале 0,2…0,6 % Zn. Для литых деталей индустриального назначения максимальное содержание Zn в бронзе БрА9Ж3Л рекомендовано ограничить массовой долей 0,2 % против нормативно предусмотренного 1,0 %.Вступ. Міждержавний стандарт ГОСТ 493 передбачає максимально допустимий вміст цинку в бронзі БрА9Ж3л масовою часткою не більше 1 %. Цинк у складі алюмінієво-залізної бронзи має неоднозначний вплив на технологічні і механічні характеристики лиття. Зазначений елемент поліпшує рідкоплинність матеріалу, але, в певних кількостях, спричинює окрихчування виробу. Проблематика. У роботі вирішувалася проблема вибору ефективної кількості цинку, який сприяє поліпшенню ливарних властивостей бронзи БрА9Ж3Л без негативного впливу на пластичні й ударні характеристики виливків. Мета дослідження − оцінення впливу Zn на структуру і механічні властивості бронзи БрА9Ж3Л і визначення раціонального її легування. Матеріали і методи. Алюмінієво-залізна бронза БрА9Ж3Л по ГОСТ 493, легована цинком у кількості масової частки від 0 до 4 %. Фрактографію поверхонь руйнування ударних зразків і мікроструктуру виробів вивчали за вимогами АSTM Е3 − 11 (2017). Механічні випробування на статичний розтяг проводили за ГОСТ 1497, на ударний вигин за ГОСТ 9454. Результат. Установлено, що збільшення вмісту цинку понад 0,2 % в складі бронзи БрА9Ж3Л не тільки суттєво зменшує її міцність й різко зменшує пластичність. Причина такої закономірності − збільшення в структурі БрА9Ж3Л кількості евтектоїдной складової. Висновки. Активна втрата пластичності і в'язкості бронзи БрА9Ж3Л, пов'язана зі зміною структурного стану сплаву, зафіксована в інтервалі 0,2...0,6 % Zn. Для литих деталей індустріального призначення максимальний вміст Zn у бронзі БрА9Ж3Л рекомендовано обмежити масовою часткою 0,2 % проти нормативно передбаченого 1,0 %