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1.
Ingestion of the excitotoxic cycad seed amino acid beta-N-methylamino-L-alanine may be responsible for the neuronal degeneration associated with Guam amyotrophic lateral sclerosis-parkinsonism-dementia in man. However, the basis for the central neurotoxicity of beta-N-methylamino-L-alanine has been unclear, as it lacks the omega acidic (or equivalent electronegative) moiety characteristic of other excitatory amino acids. beta-N-methylamino-L-alanine produced neurotoxic and neuroexcitatory effects in murine cortical cell cultures only when physiological concentrations of bicarbonate were available in the extracellular bathing medium. Bicarbonate may interact noncovalently with beta-N-methylamino-L-alanine to produce, in combination, a molecular configuration that activates glutamate receptors.  相似文献   

2.
Spatially resolved measurements of intracellular free calcium and of the changes produced by excitatory amino acids were made in neurons isolated from adult mammalian brain. Extremely long-lasting (minutes) Ca2+ gradients were induced in the apical dendrites of hippocampal CA1 neurons after brief (1 to 3 seconds), local application of either glutamate or N-methyl-D-aspartate (NMDA). These gradients reflect the continuous flux of Ca2+ into the dendrite. The sustained gradients, but not the immediate transient response to the agonists, were prevented by prior treatment with the protein kinase C inhibitor sphingosine. Expression of the long-lasting Ca2+ gradients generally required a priming or conditioning stimulus with the excitatory agonist. The findings demonstrate a coupling between NMDA receptor activation and long-lasting intracellular Ca2+ elevation that could contribute to certain use-dependent modifications of synaptic responses in hippocampal CA1 neurons.  相似文献   

3.
1-Methyl-4-phenyl-1,2,5,6- tetrahydropyri dine ( MPTP ) is known to cause an irreversible destruction of the dopaminergic nigrostriatal pathway and symptoms of parkinsonism in humans and in monkeys. However, MPTP has been reported to act only minimally or not at all in several other animal species. When MPTP (30 milligrams per kilogram of body weight) was administered parenterally to mice, a decrease in concentrations of neostriatal dopamine and its metabolites, a decrease in the capacity of neostriatal synaptosomal preparations to accumulate [3H]dopamine, and a disappearance of nerve cells in the zona compacta of the substantia nigra were observed. In contrast, MPTP administration had no effect on neostriatal concentrations of serotonin and its metabolites. MPTP administration thus results in biochemical and histological changes in mice similar to those reported in humans and monkeys and similar to those seen in Parkinson's disease in humans. The mouse should prove to be a useful small animal with which to study the mode of action of MPTP .  相似文献   

4.
Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.  相似文献   

5.
Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons   总被引：30，自引：0，他引：30  
Large amounts of zinc are present in synaptic vesicles of mammalian central excitatory boutons and may be released during synaptic activity, but the functional significance of the metal for excitatory neurotransmission is currently unknown. Zinc (10 to 1000 micromolar) was found to have little intrinsic membrane effect on cortical neurons, but invariably produced a zinc concentration-dependent, rapid-onset, reversible, and selective attenuation of the membrane responses to N-methyl-D-aspartate, homocysteate, or quinolinate. In contrast, zinc generally potentiated the membrane responses to quisqualate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and often did not affect the response to kainate. Zinc also attenuated N-methyl-D-aspartate receptor-mediated neurotoxicity but not quisqualate or kainate neurotoxicity. The ability of zinc to specifically modulate postsynaptic neuronal responses to excitatory amino acid transmitters, reducing N-methyl-to-aspartate receptor-mediated excitation while often increasing quisqualate receptor-mediated excitation, is proposed to underlie its normal function at central excitatory synapses and furthermore could be relevant to neuronal cell loss in certain disease states.  相似文献   

6.
The possibility that neuronal damage due to hypoglycemia is induced by agonists acting on the N-methyl-D-aspartate (NMDA) receptor was investigated in the rat caudate nucleus. Local injections of an NMDA receptor antagonist, 2-amino-7-phosphonoheptanoic acid, were performed before induction of 30 minutes of reversible, insulin-induced, hypoglycemic coma. Neuronal necrosis in these animals after 1 week of recovery was reduced 90 percent compared to that in saline-injected animals. The results suggest that hypoglycemic neuronal damage is induced by NMDA receptor agonists, such as the excitatory amino acids or related compounds.  相似文献   

7.
The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy") is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.  相似文献   

8.
Exposure of cultures of cortical cells from mouse to either of the endogenous excitatory neurotoxins quinolinate or glutamate resulted in widespread neuronal destruction; but only in the cultures exposed to quinolinate, an N-methyl-D-aspartate agonist, was there a striking preservation of the subpopulation of neurons containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). Further investigation revealed that neurons containing NADPH-d were also resistant to the toxicity of N-methyl-D-aspartate itself but were selectively vulnerable to the toxicity of either kainate or quisqualate. Thus, neurons containing NADPH-d may have an unusual distribution of receptors for excitatory amino acids, with a relative lack of N-methyl-D-aspartate receptors and a relative preponderance of kainate or quisqualate receptors. Since selective sparing of neurons containing NADPH-d is a hallmark of Huntington's disease, the results support the hypothesis that the disease may be caused by excess exposure to quinolinate or some other endogenous N-methyl-D-aspartate agonist.  相似文献   

9.
Brain injury induced by fluid percussion in rats caused a marked elevation in extracellular glutamate and aspartate adjacent to the trauma site. This increase in excitatory amino acids was related to the severity of the injury and was associated with a reduction in cellular bioenergetic state and intracellular free magnesium. Treatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dextrophan or the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid limited the resultant neurological dysfunction; dextrorphan treatment also improved the bioenergetic state after trauma and increased the intracellular free magnesium. Thus, excitatory amino acids contribute to delayed tissue damage after brain trauma; NMDA antagonists may be of benefit in treating acute head injury.  相似文献   

10.
Rat brain N-methyl-D-aspartate receptors expressed in Xenopus oocytes   总被引：9，自引：0，他引：9  
N-methyl-D-aspartate (NMDA) activates a class of excitatory amino acid receptor involved in a variety of plastic and pathological processes in the brain. Quantitative study of the NMDA receptor has been difficult in mammalian neurons, because it usually exists with other excitatory amino acid receptors of overlapping pharmacological specificities. Xenopus oocytes injected with messenger RNA isolated from primary cultures of rat brain have now been used to study NMDA receptors. The distinguishing properties of neuronal NMDA receptors have been reproduced in this amphibian cell, including voltage-dependent block by magnesium, block by the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid, and potentiation by glycine. This preparation should facilitate the quantitative study of the regulation of NMDA receptor activation and serve as a tool for purification of the encoding messenger RNA.  相似文献   

11.
Thyrotropin (TSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are structurally related glycoprotein hormones, which bind to receptors that share a high degree of sequence similarity. However, comparison of the primary amino acid sequences of the TSH and LH-CG receptors reveals two unique insertions of 8 and 50 amino acids in the extracellular domain of the TSH receptor. The functional significance of these insertions were determined by site-directed mutagenesis. Deletion of the 50-amino acid tract (residues 317 to 366) had no effect on TSH binding or on TSH and thyroid-stimulating immunoglobulin (TSI) biological activities. In contrast, either deletion or substitution of the eight-amino acid region (residues 38 to 45) abolished these activities. This eight-amino acid tract near the amino terminus of the TSH receptor appears to be an important site of interaction for both TSH and TSI.  相似文献   

12.
Intracaudate injections of kainic acid destroy striatal neurons containing acetylcholine and gamma-aminobutyric acid but leave dopaminergic nerve terminals in this brain region intact. Rats injected with the drug are aphagic and adipsic, and have other behavioral abnormalities strikingly similar to those seen in animals with lesions in the dopaminergic nigrostriatal bundle.  相似文献   

13.
To investigate the effects of aluminium (Al) exposure on amino acid neurotransmitters, the chickens with different levels of subchronic Al poisoning were estabolished by continuous peritoneal injection...  相似文献   

14.
[目的]为提高曲霉菌种固态发酵产游离氨基酸水平。[方法]以11种豆类为固态发酵培养基,研究其对米曲霉、黑曲霉、毛霉产游离氨基酸的影响,同时设计正交试验优化米曲霉产氨基酸的培养条件。[结果]在以黄豆为培养基时,米曲霉产氨基酸最多,达64.65mg/g,其次是毛霉。11种豆类培养基在接种米曲霉后,其氨基酸的含量明显提高,尤其是黄豆、蚕豆、绿豆,相对提高率依次为824.9%、785.9%、761.3%。正交试验表明,培养时间对游离氨基酸产量的影响最大,其次是装料量,再次是接种量。[结论]最佳的生产工艺是接种量10%,装料量40 g,培养时间8 d。  相似文献   

15.
A new class of excitatory premotor interneurons that are important in the generation of locomotion in the lamprey has now been described. In the isolated spinal cord, these neurons act simultaneously with their postsynaptic motoneurons during fictive swimming. They are small and numerous, and they monosynaptically excite both motoneurons and inhibitory premotor interneurons. The excitatory postsynaptic potentials are depressed by an antagonist of excitatory amino acids. These interneurons receive reticulospinal input from the brain stem and polysynaptic input form skin afferents. A model of the network underlying locomotion based on the synaptic interactions of these neurons can now be proposed for the lamprey.  相似文献   

16.
Lasting modifications of the receptive fields of neurons in the visual cortex can be induced by pairing visual stimuli with iontophoretic application of the neuromodulators acetylcholine and noradrenaline or the excitatory amino acids N-methyl-D-aspartate (NMDA) and L-glutamate. The modifications are obtained in less than 1 hour and persist for more than 40 minutes. Thus, acetylcholine and norepinephrine have a permissive role in use-dependent neuronal plasticity. These results support the notion of a postsynaptic threshold for neuronal malleability that differs from that of sodium-dependent action potentials.  相似文献   

17.
Long-term treatment of rats with haloperidol produced an increased sensitivity to the locomotor and stereotypic effect of apomorphine. This behavioral dopaminergic supersensitivity was accompanied by increased binding of [3H] spiroperidol in the striatum. Rats treated concurrently with lithium and haloperidol failed to develop both behavioral sensitivity to apomorphine and increased striatal dopamine receptor binding. The ability of lighium to prevent recurrent manicdepressive episodes may be related, in part, to its ability to stabilize dopaminergic receptor sensitivity.  相似文献   

18.
采用不去盲肠的真代谢能（ＴＭＥ）法，测定了山东省内使用或生产的１３种蛋鸡饲料必需氨基酸真消化率，进一步证实了以可利用氨基酸为指标配制日粮的合理性。据本试验测定结果制定了山东省蛋鸡饲料可利用氨基酸含量表，为山东省以可利用氨基酸为基础设计日粮配方奠定了基础  相似文献   

19.
以GenBank上登载的猪的T细胞受体β(pTCR-β)基因为参考序列,用RT-PCR法从猪的外周血淋巴细胞中克隆了TCR-β链基因,并进行生物信息学分析.结果表明:pTCR-β基因含有一个完整的开放阅读框架(ORF),大小为849bp,编码283个氨基酸,且含有一段27个氨基酸的信号肽序列,与参考序列相比,在核苷酸序列上的同源性为80.4%,在氨基酸序列上的同源性为70.3%;生物信息学结构预测发现2个结构域,一个为IG结构域,由第32-138位共107个氨基酸残基组成;另一个为IG-LIKE结构域,由第164-211位共48个氨基酸残基组成.  相似文献   

20.
The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.  相似文献   

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