Gangliosides improve a memory deficit in pentylenetetrazol-kindled rats.

Epileptic patients often show impairments in a number of cognitive functions. Kindling is considered to be a useful experimental model for human epilepsy. Recently we have demonstrated a learning impairment in a shuttle box experiment in pentylenetetrazol (PTZ)-kindled rats. This model offers the possibility to investigate the relation between repeated convulsions and their consequences on learning and on the other side to test the effectiveness of substances on both processes. Although systemic application of gangliosides has neither an effect on the development of seizures induced by repeated injections of PTZ, nor on seizures induced by PTZ in kindled animals, the treatment protects against the memory-impairing effect of convulsions. These findings suggest a new useful strategy in the therapy of epileptic patients with the aim of diminishing the psychosocial problems in persons with seizure disorders: a combination of the anticonvulsive basic therapy and gangliosides.     

Cysteamine suppresses kindled seizures in pentylenetetrazol-kindled rats

Rats were kindled by intraperitoneal injection of pentylenetetrazol (PTZ) (30 mg/kg) every 48 h. Once kindled, animals received a single injection of cysteamine (200 mg/kg) and subsequent responses to PTZ were observed. Cysteamine, an agent which depletes brain somatostatin and suppresses kindled seizures in amygdaloid-kindled rats, markedly suppressed the severity of PTZ-induced seizures in PTZ-kindled rats as well. However, it did not alter the convulsive response of non-kindled rats to a submaximal convulsive dose (50 mg/kg) of PTZ. The results support a role for somatostatin in kindling.     

Forced swimming stress induced alterations in ingestive behavior in rats.

The effects of forced swimming stress (15 minutes per day) on body weight, food intake, blood sugar, water intake, and urine output were studied in adult male Wistar rats on the first, seventh, fourteenth and 21st days in different subgroups. There was a significant initial decrease in the body weight up to 14 days followed by a regain in the body weight, which was sustained until 21 days. Though there was no change in the food intake initially for 7 days, after 14 days a significant increase in the food intake was observed. A significant hypoglycemia was observed throughout the entire period of stress. More significant fall in the blood sugar level was observed in the initial period of exposure of stress (1-7 days). There was a significant reduction in the water intake in the stressed animals. Urine output decreased significantly up to 7 days of stress, though it got marginally increased later. Thus, repeated stress may produce a reduction in body weight only initially, which is accompanied with an initial decrease in food and water intake also. The peak response to stress was seen after 7 days of stress exposure. There was a gradual recovery back to normal in the body weight, food intake, and water intake and urine output when stress period was prolonged to 14-21 days. This is suggestive of the adaptation of the organism to repeated exposure of similar kind of stress.     

Morphological changes induced in rats following prolonged exposure to stress.

Prolonged exposure of male C. S. F. rats to irregular signalled footshick from which they could escape for up to 71 days produced profound morphological changes. Retardation in growth, adrenal hypertrophy associated with an increase in the zona fasiculata a-nd zona reticularis, and changes in the microcirculation of the heart were observed. There was a significant degree of congestion and dilatation of the microcirculation which was most marked in large venules, collecting venules and veins. An increase in PAS +ve material marginated in the venous endothelium was observed also, together with a suggested increase in mast cells and presence of vacuoles in the intima-media of the coronary arterioles. No pathological changes were observed in the renal cortex and medulla or the gastric lining. The changes in the microcirculation of the heart are discussed in terms of an oedematous reaction and a histamine type leakage of the endothelial lining.     

胍丁胺对慢性应激大鼠海马神经元和星形胶质细胞的影响

目的在海马神经元和星形胶质细胞水平探讨胍丁胺抗抑郁作用机制。方法采用多种应激方式建立大鼠慢性应激抑郁模型,通过开场实验和蔗糖饮水实验观察模型组、阳性对照药氟西汀组(10 mg.kg-1,ig)和胍丁胺组(20 mg.kg-1,ig)大鼠的行为学变化;应用神经元标志物——微管相关蛋白2(microtubule-associated protein 2,MAP2)和星形胶质细胞标志物——胶质原纤维酸性蛋白(glial fibrillary acidicprotein,GFAP)免疫组织化学染色,观察各组大鼠海马神经元和星形胶质细胞形态改变。结果慢性应激模型组大鼠开场实验水平运动得分和垂直运动得分明显降低,蔗糖偏嗜度明显降低,氟西汀和胍丁胺可逆转此变化;免疫组化结果显示,慢性应激模型组MAP2和GFAP表达明显减弱,表现为海马神经元突起长度和数目以及星形胶质细胞的数量和突起数量明显降低,氟西汀和胍丁胺可改善此病理变化。结论海马神经元和星形胶质细胞共同参与抑郁症发生,胍丁胺可逆转慢性应激引起的细胞形态结构改变,发挥抗抑郁作用。     

Drug-induced changes in the maternal behavior of rats

The effect of chlorpromazine and amphetamine (3 mg/kg b.w. injected s.c.) on the maternal behavior of rats was observed on days 4, 5, 6, 8, and 10 after the birth of the young. Spontaneous behavior in the presence of the young and contacts with them were recorded in four different testing situations.Both drugs interfered with the maternal behavior of female rats and reduced the duration of contacts with the young. The level of behavioral manifestations depended on the type of experimental procedure.     

Muscimol changes hypoxia-induced impairment of behavior in rats

Muscimol, a selective agonist of GABA-A receptors, causes changes in behavioral activity. Hypoxia interferes with the GABAergic system and with the functions of GABA-A receptors. We used muscimol in Wistar rats to estimate its influence on locomotor activity in the open field test as well as on the processes of consolidation and retrieval, evaluated in the test of passive conditioned reflexes. Anxiolytic activity was examined in the elevated "plus" maze in physiological state and after hypoxia-induced amnesia. Following intraperitoneal administration of muscimol (1 mg/kg, ip), the animals showed a decrease in motility, in retrieval of skill reflexes and in a number of entries into open and closed arms in the elevated plus "maze". In animals exposed to hypoxia, we observed reduced motility in the open field, inhibition of retrieval and consolidation of passive conditioned reflexes, shortened time of sojourn in open arms and decreased number of entries into open and closed arms. In the group of animals which underwent hypoxia and then received muscimol, we observed no effect of hypoxia on muscimol activity in the open field test, except rearing when muscimol action was significantly reduced. Muscimol improved consolidation but not retrieval in comparison with the hypoxic saline-treated group of rats. In the elevated "plus" maze test, treatment of rats with muscimol after hypoxia significantly prolonged the time spent in open arms and increased the number of entries into open arms, while shortened the time spent in closed arms. In conclusion, muscimol in hypoxia-exposed group of rats exerted beneficial effect on consolidation in passive avoidance situation and exerted anxiolytic activity. Changes in the activity of muscimol under hypoxia may have significant clinical implications.     

One-year time-sequence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver

Wistar rats were exposed to atmospheres containing 0 (control) or 5000 ppm vinyl chloride monomer (VCM), 7 h/day, 5 days/week, for a period of 52 weeks. After 4, 13, 26 and 52 weeks each time 10 rats/sex/group were killed and subjected to extensive examinations. The present paper describes the morphological changes found in the liver. The major parenchymal changes comprised swelling and malformation of mitochondria, an increased amount of smooth endoplasmic reticulum, necrosis, nuclear and cellular polymorphism of hepatocytes, "foci of cellular alteration", neoplastic nodules and hepatocellular carcinomas. A reduced glucose-6-phosphatase activity in hepatocytes and a strong sinusoidal activity of alkaline phosphatase were found within "foci of cellular alteration". The non-parenchymal alterations included focal dilatation of sinusoids, focal proliferation of atypical sinusoidal cells and multicentric angiosarcomas. The effects of VCM on the hepatic parenchyma seemed to precede those on the hepatic stroma.     

Action of enpiprazole on emotional behavior induced by hypothalamic stimulation in rats and cats

Action of enpiprazole on emotional behavior elicited by hypothalamic stimulation in rats and cats was investigated and comparisons were made with effects of diazepam. Two behavioral patterns were elicited by stimulation of the postero-medial part of the hypothalamus in rats: a food-carrying response beginning with exploratory movement and an analogue of fear. Enpiprazole frequently changed the food-carrying response into food-taking response and occasionally analogues of fear into food-carrying and/or food-taking responses. Thresholds for these behaviors were also elevated. Diazepam showed the same effects on the thresholds as enpiprazole, having but little effect on the behavioral patterns.In cats, enpiprazole elevated the thresholds for affective-defensive responses induced by hypothalamic stimulation in 6 of 8 cases, but lowered them in 2 cases. This suggests that enpiprazole has a biphasic effect in the central nervous system. By contrast, diazepam consistently elevated thresholds. Comparing the action of enpiprazole with that of diazepam it can be presumed that the former is a different type of anxiolytic drug than the latter.     

Effects of acetyl-L-carnitine on the brain lipofuscin content and emotional behavior in aged rats

The effects of long-term dosing with acetyl-L-carnitine (ALC) were examined in aged rats, and they were compared with those in young rats. ALC significantly reduced the lipofuscin deposition in the brain of aged rats. Emotional parameters such as locomotor activity and rearing behavior are lower in aged rats than in young rats, and these behaviors decreased in both age groups during the experiments. ALC diminished the decrease of these emotional behaviors, especially in rearing behavior in the aged rats. Furthermore, ALC had no effect on body weight gain. These results might reflect one of the main beneficial pharmacological mechanisms of ALC in clinical use.     

Nonlinear changes in activity and emotional reactivity scores following central noradrenergic lesions in rats

Two levels of permanent central norepinephrine depletion were obtained in rats by lesioning these neurons with small quantities of intraventricularly-applied 6-hydroxydopamine, and the effects of these lesions on a variety of standard tests of activity and emotional reactivity were studied. Both lesioned groups showed altered emotional reactivity; however, only the animals with less extensive lesions were hyperactive in running wheels, showed heightened shock-elicited aggression, were hyper-responsive to handling, and had a potentiated amphetamine-activation effect. It is suggested that these exaggerated behaviors reflected the sensitization and regeneration of partially lesioned noradrenergic circuits. These data are discussed in terms of the catecholamine hypothesis of depression.These data were part of Ph. D. dissertation by C.A.S. submitted to the Department of Psychology, U.C.L.A.     

Benzodiazepine receptors of the neurons and astrocytes]

Ultrastructural investigations of different parts of rat brain after diazepam administration revealed benzodiazepine receptors on the neuronal surface and plasma membrane of astrocytes of the sensorimotor cortex, hippocampus and central grey substance. Subsuperficial cisternae that replenish deficit of plasma membrane required for coated vesicles formation were only seen in the neurons and were absent from the astrocytes. The fate of internalized diazepam in the nerve and glial cells were different: in the neurons, ligand is destroyed in lysosomes and multivesicular bodies, while in the astrocytes, exceptionally in lysosomes.     

Liver mitochondria alterations in chloroform-treated Sprague-Dawley rats.

The formation of a chloroform adduct produced by the reaction of the oxidative chloroform metabolite phosgene with two molecules of phosphatidylethanolamine has been previously demonstrated in liver mitochondria of phenobarbital-pretreated Sprague-Dawley (SD) rats. The aim of our study was to assess the influence of chloroform adduct mitochondrial accumulation on the hepatic mitochondria morphology. Liver mitochondrial ultrastructural alterations were analyzed by electron microscopy in SD rats administered with increasing doses of chloroform. Variation in the morphology of mitochondria, consisting of an increase of intertwined organelles, only rarely seen in control specimens, was observed at the lowest chloroform dose (180 mg/kg). At higher doses, mitochondrial damage progressed with swelling of the organelles and formation of megamitochondria. These megamitochondria were characterized by a dilution of the matrix, and often membranous whorls were found inside the matrix. The two distinct forms of cell death, necrosis and apoptosis, were first observed at 300 mg/kg of chloroform. Our results suggest that the formation and the accumulation of a chloroform-modified phosphatidylethanolamine in mitochondria induce ultrastructural modifications of these organelles. In conclusion, mitochondria are involved in chloroform-induced hepatotoxicity.     

Lithium- and valproate-induced alterations in circadian locomotor behavior in Drosophila.

Lithium and valproate are commonly used mood stabilizers, but their action pathways are not clearly understood. They also suffer from multiple toxic effects that limit their utility. Elucidating their action mechanisms could lead to newer agents and better understanding of the etiopathogenesis of bipolar disorder. We have expanded the study of signaling mechanisms of lithium and valproate by using Drosophila circadian locomotor activity as a robust behavioral assay that is amenable to genetic manipulations. We demonstrate that lithium affects the circadian system of Drosophila similarly to what has been reported in the mammalian studies. We show that lithium and valproate share effects on the circadian locomotor activity of Drosophila: they lengthen the period of circadian rhythms and increase arrhythmicity. Valproate exerts these effects in a weaker fashion than does lithium. We also tested the circadian alterations in multiple mutant lines of Drosophila bearing defects in the GSK-3beta gene and other clock genes in response to lithium administration. We show that lithium partially rescues the shortening of circadian period when the GSK-3beta gene is overexpressed only in specific circadian pacemaker neurons, thus implicating GSK-3beta as a component in lithium's effect on the circadian oscillator. Moreover, lithium also lengthens the period in GSK-3beta heterozygous mutants and doubletime long mutants. These results establish a basis for using Drosophila genetics to investigate more fully lithium and valproate action mechanisms.     

Renal extracellular matrix alterations in lead-treated rats.

Although the nephrotoxic effects of lead are well documented, the subcellular mechanisms of its action on the kidney remain unclear. The aim of the present work was to investigate the effects of chronic lead exposure on the expression of laminin-1 and fibronectin in the kidney of lead-treated rats. Western immunoblotting of the kidney extracts revealed that experimental exposure to lead resulted in a marked decrease in the intensity of the bands corresponding to laminin-1 and an increase in the intensity of the band corresponding to fibronectin. Immunohistochemical studies demonstrated a weak labelling to laminin-1 and a strong labelling to fibronectin in all renal basement membranes together with a decrease in their thickness. Other ultrastructural alterations found were a diminution in the amount of endothelial fenestrae, an increased fusion of foot processes in epithelial cells of the glomerulus and the presence of intranuclear inclusion bodies in the proximal tubule cells. Lead intoxication might be responsible for the above alterations in the renal extracellular matrix that could play an important role in the pathogenesis of lead nephropathy.     

星形胶质细胞转分化为神经元的研究进展

近年来, 转分化技术在干细胞和再生学领域迅速发展, 具有较大的研究价值。研究发现, 随着转分化诱导条件的成熟, 可以改变其他细胞的谱系来获得神经元。并且, 星形胶质细胞 （As） 广泛分布于中枢神经系统的灰质和白质中, 其过度增生会形成胶质纤维瘢痕, 是阻碍神经功能恢复的关键。因此, As 转分化为神经元成为目前研究的热点。As 的转分化既可以阻止胶质瘢痕的形成, 又能获得新的神经元。本文就 As 的功能及其转分化为神经元的相关研究进行综述。