摘要:

AbstractGangliosides are being used therapeutically to treat a variety of nervous system disorders including peripheral neuropathies and stroke. Gangliosides (over 70 molecular species) are glycosphingolipids found in highest concentration in neural tissue. They are thought to be functional in such diverse biological processes as embryogenesis and cell death, and specifically in membrane‐mediated processes (cell‐cell interactions, ionic balance, synaptic transmission, and receptor‐mediated information transfer). Their distribution changes during neural development, indicative of differential roles for each molecular species at critical stages of development. Ganglioside distribution differs during abnormal development or after neural injury due to trauma or disease. In vivo and in vitro studies have shown that exogenous gangliosides can substitute (structrally and functionally) for the endogenous molecules. This has made it possible to investigate the molecular mechanisms of ganglioside function in situ. During the genesis of these studies it became clear that exogenous gangliosides were able to protect the chemical and morphological changes associated with neural (CNS and PNS) tissue injury (mechanical, ischemic, and neurotoxic). This protective effect has been characterized by facilitated functional recovery in a number of CNS injury paradigms. The mechanism(s) for the facilitative effect of ganglioside treatment is unidentified. Data support a number of hypotheses. One contends that gangliosides can acutely reduce the extent of CNS injury and pathology by protection of membrane structure/function, thereby leading to reduced functional deficits and therefore to increased potential for functional recovery. Another hypothesis supports the view that these glycosphingolipids may promote neuronal regeneration through modulation of trophic factors. Studying the effects of exogenous gangliosides on CNS injury is leading to further insight into the critical functions of endogenous gangliosides as well as focusing attention on the potential of exogenous gangliosides as a therapeutic treatment of traumatic and degenerative CNS diso

ISSN:0272-4391    

DOI:10.1002/ddr.430150402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractPeptide T, an octapeptide sequence found in the external evelope protein (gp 120) of the ARV isolate of human immunodeficiency virus (HIV), was investigated for its action in preventing neuronal death observed in mouse hippocampal cultures treated with purified gp 120. Cell counts of neuronspecific enolase‐identified neurons revealed that peptide T application completely and potently antagonized gp 120‐induced death. Analogs of the core pentapeptide sequence of pepptide T, TTNYT, found in the second variable region of all gp 120 isolates sequenced to date, were also tested and found to be similarly active. Investigations of structure activity relationships of related peptides suggested that the second and fourth positions in the core pentapeptide sequence were critical for biological activity in the neuronal survival assay. Antiserum against the peptide T sequence found in the the ARV isolate was found to prevent neuronal cell death in cultures treated with purified gp 120 from the IIIB isolate of HIV. These data indicate that the peptide T sequence is effective in preventing neuronal cell death associated with the envelope protein and provide a rationale for peptide T to be evaluated as a potential therapeutic agent for the neuropsychiatric and neurological sequelae of acquired immune deficiency syndr

ISSN:0272-4391    

DOI:10.1002/ddr.430150403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe HIV virus initiates its infectious cycle through a high‐affinity binding interaction between the envelope protein gp 120 and its receptor, the T4 (or CD4) molecule. An octapeptide sequence, termed peptide T, present in the second variable region of gp 120 from the ARV isolate, has been implicated as the attachement site. The core peptide required for activity has been further refined to a pentapeptide, and homologous pentapeptides are similarly positioned in 21 other sequenced HIV isolates. Utilizing a novel direct binding assay of3H‐D‐ala1‐peptide T, we now report that synthetic peptides derived from these other isolates are potent competitors of peptide T binding to T4‐positive lymphocytes and brain membranes. Direct peptide T binding is also competable by purified virion gp 120, indicating that these ligands are interactive at the same receptor. Peptide T has sequence relatedness to the peptide vasoactive intestinal peptide (VIP), and VIP and its relevant homologous pentapeptide, VIP[7–11], are also potent inhibitors of peptide T binding. To determine the essential structural features responsible for receptor activity we have studied a series of synthetic peptides substituted with single D‐amino acid residues. These data reveal that the tyrosine of position 7 in peptide T, present in all natural viral isolates, is obligate for receptor activity. Structure/function analysis for a large number of analogs is presented. Significantly, this binding assay is highly correlated with peptide bioactivity in several independent systems, indicating that this methodology can be used for rapid screening of novel, potential anti‐AIDS therapeutics whose target is inhibition of viru

ISSN:0272-4391    

DOI:10.1002/ddr.430150404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe binding of the putative affinity ligand α‐flupenthixyl chloride (FPT‐Cl), a derivative of the neuroleptic α‐flupenthixol (FPT), to rat striatal dopamine, α1‐adrenergic, and muscarinic cholinergic recognition sites, as well as to serotonin (5‐HT) receptors and to the presynaptic 5‐HT transport complex, was examined in vitro. FPT and FPT‐Cl were relatively potent at inhibiting the binding of [3H]‐flupenthixol and [3H]‐spiroperidol in striatal tissue preparations as well as [3H]/spiroperidol and [3H]‐WB‐4101 in cortex with Kivalues in the 10–20 nM range. With the exception of the muscarinic cholinergic sites (3H‐quinuclidinyl‐benzilate [3H‐QNB]), where FPT‐Cl was more potent than FPT, the Kivalues for FPT‐Cl were, in general, slightly greater than those for FPT for other neuro‐receptors tested. FPT‐Cl was found to be essentially inactive at 5‐HT binding sites labeled with [3H]‐LSD and at the 5‐HT transport complex labeled with [3H]‐imipramine, with lC50values for both exceeding 5μM. It is concluded that the transformation of FPT to FPT‐Cl is not severely detrimental to its dopamine receptor binding characteristics, suggesting that in the presence of appropriate antagonists for masking other receptors, FPT‐Cl may represent

ISSN:0272-4391    

DOI:10.1002/ddr.430150405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractA new potential antihypertensive drug, irindalone (Lu 21‐098;(+)‐(1R,3S)‐1‐[2‐[4‐[3‐(p‐fluorophenyl)‐1‐indanyl]‐1‐piperazinyl]‐ethyl]‐2‐imidazolidinone), has been characterized by a series of in vitro methods. Irindalone competitively inhibits peripheral and central serotonin2(5‐HT2) receptors as measured by 5‐HT‐induced contractions of rabbit pulmonary artery and receptor binding methodology with3H‐ketanserin as a ligand. The inhibitory effect on 5‐HT receptors is confirmed using other organs in vitro (rat stomach fundus, rat jugular vein, guinea pig trachea). Irindalone has lower affinity for α1‐adrenoceptors and histamine‐H1receptors and only negligible affinity for α2‐adrenoceptors and muscarine cholinergic receptors. No inhibition of the uptake of noradrenaline (NA), dopamine (DA), or 5‐HT is seen. The neurochemical profile resembles that of ketanserin, which has slightly higher affinity for 5‐HT2receptors. In the rat fundus, irindalone inhibits 5‐HT‐induced contractions, differing in this respect from ketanserin and cinanserin. Irindalone clearly deviates from the neuroleptics haloperidol and tefludazine, and from prazosin with which irindalone has been compared. The (‐)enantiomer of irindalone, Lu 21‐099, is considerably weaker than irindalone in the different test systems. Due to the strong blockade of 5‐HT2receptors and the somewhat weaker blockade of α‐adrenoceptors, irindalone is expected to lower blood pressure po

ISSN:0272-4391    

DOI:10.1002/ddr.430150406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe effects of clonidine, rilmenidine, and guanfacine were studied in the holeboard and elevated‐plus maze tests in rats. In the holeboard test, clonidine had a profound effect on locomotor activity, significantly (P<0.05) reducing this measure at all but one of the doses tested (0.005–0.25 mg/kg). In contrast, rilmenidine and guanfacine only markedly affected locomotor activity at 2.5 mg/kg or higher. The ED50

ISSN:0272-4391    

DOI:10.1002/ddr.430150407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractThe effects of loperamide and loperamide‐oxide were studied in rats trained to discriminate 0.04 mg/kg, fentanyl from saline. After oral pretreatment with the doses of 0.63, 2.50, 10.0, and 40.0 mg/kg, neither loperamide nor loperamide‐oxide produced any generalization with fentanyl. Both compounds depressed the response rate at 10 and 40 mg/kg. These results indicate that loperamide and loperamide‐oxide produce no fentanyl generalization in rats up to doses at least 250 times their antidiarrheal dose and that both drugs are expected to be devoid of an opiate‐like addiction liability

ISSN:0272-4391    

DOI:10.1002/ddr.430150408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

摘要:

AbstractA diagram is presented that evaluates results from clinical and biological studies in which two treatments are compared. In the case of all‐or‐none observations (such as symptoms), the diagram presents the overall rate of occurrence (Prevalence), the difference of the rates of occurrence in the two treatment groups (contrast), and the statistical significance of the result. The prevalence‐contrast (p‐c) diagram can also be applied to other variables (such as scores, temperature, blood pressure, etc.). Accumulation of p‐c diagrams from related studies adds clinical‐biological relevance to statistical s

ISSN:0272-4391    

DOI:10.1002/ddr.430150409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430150401

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1988

数据来源: WILEY