小鼠脑缺血后的能量代谢改变和药物的作用

应用部分结扎小鼠颈总动脉(包括迷走神经)及小鼠断头法引起脑缺血后,脑组织的ATP和磷酸肌酸明显降低,乳酸明显升高。部分结扎颈动脉出现四肢无力、转圈及昏睡等症状,其严重程度与脑能量代谢改变相平行。皮下注射尼莫地平、硝苯吡啶、尼卡地平和三七皂甙对脑缺血有一定保护作用。苯巴比妥钠能改善正常和脑缺血小鼠的脑能量代谢,人参皂甙Rb₁可降低正常小鼠脑乳酸含量。     

环胞素A加强尼莫地平对脑损伤保护作用

目的:研究P-精蛋白(P-gp)抑制剂环胞素A(CsA)是否加强尼莫地平(NMD)对脑损害的保护作用.方法:(1)小鼠ip NMD或合用CsA后,分别记录断头小鼠的喘气持续时间和ip NaNO_2后的小鼠生存时间;(2)大鼠ip NMD或合用CsA后,用双侧颈总动脉结扎加低血压模型造成前脑缺血20 min,再灌1h后,测定皮层中丙二醛(MDA)、乳酸(LA)浓度和乳酸脱氢酸(LDH)活性.(3)测定单用NMD和合用CsA后,脑内NMD的浓度.结果:NMD对三种药理模型均显示一定的药理活性.与单用NMD比较,合用CsA,使断头小鼠和ip NaNO_2后小鼠生存时间显著延长.在脑缺血/再灌损伤模型大鼠中,与单用NMD比较,合用CsA后,皮层中MDA、LA和LDH水平显著改善.合用CsA使脑内NMD浓度显著增加.结论:P-gp抑制剂CsA可加强NMD对脑损害的保护作用.     

Carbofuran-induced alterations (in vivo) in high-energy phosphates,creatine kinase (CK) and CK isoenzymes

Male Sprague-Dawley rats administered with an acute sublethal dose of carbofuran (1.5 mg/kg, s.c.) developed the signs of peak hypercholinergic activity during 30–60 min. At this time, in hemidiaphragm muscle, a significant decrease in ATP (28%) and phosphocreatine (PC) (29%) occurred without concurrent change in AMP and creatine (CR). A significant decrease in the levels of total adenine nucleotides (ATP + ADP + AMP) (20%) and total creatine compounds (PC + CR) (17%) was evident. The decline in the corresponding ratios of ATP/ADP (26%), ATP/AMP (39%), and PC/CR (20%) was therefore suggestive of greater utilization of ATP and PC in response to their increased demand for high-frequency muscle fasciculations. The energy charge=ATP + 1/2 ADP/(ATP + ADP + AMP), an index of high-energy phosphate adequacy in hemidiaphragm, remained unchanged. A significant (p<0.01) increase in serum magnesium with no concurrent change in calcium was also evident. The observed higher activity (152%) of total CK (EC 2.7.3.2) in the serum induced by carbofuran was possibly a reflection of more than a twofold increase in CK-BB isoenzyme (CK-1) and 141% increase in CK-MM isoenzyme (CK-3), which also strengthens our findings of enhanced synthesis of ATP and PC. Increased levels of CK-MM isoenzyme in the brain (253%) and hemidiaphragm (195%); and depletion of CK-BB isoenzyme in the hemidiaphragm (0%), heart (42%), and brain (77%), and of CK-MB isoenzyme (CK-2) in the brain (4%) and hemidiaphragm (14%), appeared to be the major contributory factors leading to enhanced serum CK activity.Presented in part at the 29th Annual Meeting of Society of Toxicology, February 12–16, 1990, Miami Beach, Florida.     

The effects of phenobarbitone, leptazol, dexamphetamine, iproniazid, imipramine, LSD, chlorpromazine, reserpine and hydroxyzine on the in vivo levels of adenine nucleotides and phosphocreatine in the rat brain

1. Enzymic and ion-exchange chromatographic analyses were used to measure adenosine triphosphate (ATP), diphosphate (ADP) and monophosphate (AMP) in brain extracts from rats treated with a wide range of centrally acting drugs. Phosphocreatine (PC) was assayed by the acid molybdate method.2. An anaesthetic dose of phenobarbitone caused an increase in brain levels of ATP and PC, and a reduction in ADP and AMP. A convulsant dose of leptazol gave rise to precisely opposite effects. Subanaesthetic (hypnotic) and subconvulsive doses of the two drugs, respectively, produced no alterations in brain nucleotide levels.3. Among the psychotropic drugs, dexamphetamine, LSD and hydroxyzine, at the doses used, caused no changes in brain levels of the adenine nucleotides. Iproniazid and imipramine caused slight increases in the ATP level and ATP / ADP ratio, respectively. Chlorpromazine failed to give rise to any effect in the nucleotides 3 hr after administration, but produced a rise in brain ATP after 6 hr. Reserpine, on the other hand, caused a fall in the ATP/ADP ratio 6 hr after injection.4. These results indicate that some psychotropic drugs can cause small changes in the rat brain ATP/ADP ratio but do not support claims by certain workers that such changes correlate closely with the behavioural effects of these drugs.     

丁基苯酞对小鼠全脑缺血的保护作用

观察了丁基苯酞(NBP)对小鼠全脑缺血脑保护作用和脑能量代谢的影响。用Lowry法测定脑乳酸,ATP和磷酸肌酸(PCr)的含量。结果表明,NBP112.5或250mg·kg^-1sc能明显延长断头或iv饱和MgCl₂后喘息的时间;NBP15O或200mg·kg^-1sc能明显减少断头缺血后乳酸的升高和ATP及PCr的降低。实验结果提示,NBP对缺血脑有保护和改善脑能量代谢的作用。     

急性吗啡依赖大鼠脑内G_(i2)蛋白的表达

目的研究急性吗啡成瘾后大鼠腹侧背盖区(Ventral tegmental area,VTA)、伏隔核(Nucleus accumbens,NAc)、前额皮质(Prefrontal cortex,PC)、海马(Hippocampus)及去甲肾上腺能神经中枢蓝斑(Locus coeruleus,LC)五个脑区Gi2蛋白的改变,探讨急性吗啡成瘾的可能机制。方法18只SD大鼠随机分为三组,每组6只,分别是急性吗啡成瘾组、急性吗啡戒断组、空白对照组。吗啡成瘾组和戒断组腹腔注射吗啡,直到吗啡成瘾模型建立。戒断组腹腔注射纳络酮5mg/kg,作用30min后断头处死各组大鼠。取出脑组织,进行冰冻切片。用免疫组化技术检测NAc、PC、LC、VTA和Hippocampus五个脑区相对Gi2蛋白水平。结果急性吗啡成瘾组和急性戒断组与空白对照组相比,NAc区Gi2蛋白水平有明显降低(P<0.01),其它脑区则未发现明显的改变。结论急性吗啡成瘾可引起大鼠脑内Gi2蛋白水平发生改变,NAc区Gi2蛋白水平有明显降低,其它脑区则未发现明显的改变。Gi2蛋白水平的改变可能是吗啡耐受和依赖潜在的分子机制。     

和厚朴酚通过抑制脑MPTP开放和调节PARP-1活性保护全脑缺血的作用研究

目的研究和厚朴酚微乳剂对全脑缺血的影响,探讨其可能的作用机制。方法用断头法制备小鼠急性全脑缺血模型;用分光光度法观察脑线粒体通透性转换孔(MPTP)开放程度;用荧光法测定聚腺苷二磷酸核糖聚合酶-1(PARP-1)活性;用MTT法侧细胞活力。结果和厚朴酚(7～70μg.kg-1)单次静注可剂量依赖地增加小鼠断头后喘息次数、降低小鼠脑匀浆液中乳酸的含量,升高脑匀浆液中ATP的含量。和厚朴酚(2.5μmol.L-1～10μmol.L-1)可浓度依赖地降低脑组织MPTP的开放,它可浓度依赖地抑制聚腺苷二磷酸核糖聚合酶(PARP-1)活性,其IC50=76.82μmol.L-1,和厚朴酚可明显提高缺氧损伤的PC12细胞存活率。结论和厚朴酚对全脑缺血有保护作用,该作用与其可能减轻缺血状态、抑制能量耗竭和乳酸堆积有关,可能与抑制神经细胞MPTP开放、抑制PARP-1的活性、从而保护神经细胞有关。这些结果为其治疗全脑缺血提供了实验依据。     

丹酚酸B拮抗大鼠缺血再灌注引起的脑损伤(英文)

目的:研究丹酚酸B对缺血再灌注脑损伤的拮抗作用。方法:采用大鼠局灶性脑缺血再灌注模型。以行为学实验评价中枢神经系统的损伤。采用比色法检测脑匀浆液中超氧化物歧化酶(SOD)的活性,以及还原型谷胱苷肽(GSH)、丙二醛(MDA)、三磷酸腺苷(ATP)和乳酸(LA)的含量。结果:局灶性脑缺血再灌注可造成行为学异常,丹酚酸B 10 mg·kg~(-1)可减轻此种异常。同时,丹酚酸B 10mg·kg~(-1)可以改善由于脑缺血再灌注所造成的SOD、GSH、和ATP含量降低以及MDA和LA含量增加。结论:丹酚酸B对脑缺血再灌注脑损伤具有保护作用,其作用机制与减轻脂质过氧化、促进自由基的清除以及改善能量代谢有关。     

Sotalol and mexiletine: combination of rate-dependent electrophysiological effects.

The rate-dependent electrophysiological effects of sotalol (30 microM), mexiletine (10 and 18 microM), and their coadministration were examined in isolated dog cardiac Purkinje fibers following abrupt changes in pacing cycle length. Combination of 30 microM sotalol with 10 microM mexiletine significantly lengthened premature action potential durations at diastolic intervals of less than 50 ms while the basic action potential duration evoked at a stimulus frequency of 2 Hz was not affected. This effect on the premature action potential duration was attenuated when the higher mexiletine concentration (18 microM) was coadministered with sotalol. The fast time constant for restitution of the action potential duration was significantly slowed by either combination. Coadministration of sotalol and mexiletine, like mexiletine alone, produced a rate-dependent depression of Vmax that displayed a second slow time component during recovery. This slow component for recovery of Vmax was not distinguished in the absence of drug or in the presence of sotalol alone. Sotalol-induced lengthening of the action potential duration observed at slow pacing frequencies was also attenuated by addition of mexiletine; and, under these conditions, Purkinje fiber early afterdepolarizations were prevented. In addition, the range of premature action potential durations was significantly decreased by mexiletine and by the combination, while sotalol alone increased this range slightly. These results indicate that coadministration of sotalol and mexiletine may provide beneficial electrophysiological effects expected to provide enhanced antiarrhythmic efficacy and fewer proarrhythmic complications in patients.