The glycine receptor: pharmacological studies and mathematical modeling of the allosteric interaction between the glycine- and strychnine-binding sites

The displacement by glycine of 3H-strychnine binding to rat spinal cord membranes cannot be explained by a simple competitive interaction. Indeed, protein-modifying reagents can completely abolish the inhibition of 3H-strychnine binding by glycine and other agonists, whereas the interaction of strychnine itself and other related compounds with the binding site is unimpaired. Moreover, glycine cannot inhibit completely saturable 3H-strychnine binding, the extent of its maximum inhibitory effect depending on the ionic composition of the medium. Hill coefficients less than 1 (whose magnitude also depends on the assay medium) were obtained from glycine displacement curves. These properties are consistent with a mathematical model of two different, but mutually interacting, binding sites for strychnine and glycine on the glycine receptor. The effect of ions and protein-modifying reagents might be explained in this model as modifications of the mechanisms that mediate the allosteric interaction, and/or the affinity of glycine for the receptor. The agonists beta-alanine and taurine and the new antagonists, THAZ, iso-THAZ, and 4,5-TAZA, also seem to interact with a site different from the strychnine-binding site, probably the glycine-binding site.     

Cyclophosphamide affects the dynamics of granuloma formation in experimental visceral leishmaniasis

We observed histopathological and ultrastructural hepatic changes following the intracardiac inoculation ofLeishmania donovani amastigotes into inbred LHC hamsters (group I). Since granuloma formation is known to be T-cell-dependent, we also examined infected hamsters under cyclophosphamide immunosuppressive treatment (group ICy) and evaluated the production of interleukin-2 (IL-2) by their cells. Group I showed more intense hepatocyte and endothelial cell clasmatosis as well as hepatocyte degeneration and necrosis, deposits of connective tissue fibers, granulomas with multinucleated giant cells (MGCs) of foreign-body and Langhans' types and reduced production of IL-2 by spleen cells. In contrast, group ICy hamsters exhibited larger eosinophil and lymphocyte populations within sinusoids and peri-sinusoidal areas but showed no MGCs in granulomas. A striking decline in IL-2 production was noted. These results suggest that cyclophosphamide induces a delay in the natural evolution ofL. donovani-induced granulomatous hepatic inflammation.     

Synthesis of poly[isobutyl (2S,3R)-3-benzyloxyaspartate]

A chiral poly(3-substituted isobutyl D -aspartate) 12 was synthesized by polymerization of the chiral β-lactam 11 derived from D -glyceraldehyde. The new polyamide was characterized by elemental analyses, and infrared, ¹H- and ¹³C nuclear magnetic resonance spectroscopies. The molecular weight was estimated as 543 000 and 230 000 on the basis of viscosimetric measurements and gel-permeation chromatography, respectively. Polyamide 12 is soluble in a variety of organic solvents including chloroform.     

Differential Stimulation of Noradrenaline Release by Reversal of the Na+/Ca2+ Exchanger and Depolarization in Chromaffin Cells

We compared the effectiveness of Ca²⁺ entering by Na⁺/Ca²⁺ exchange with that of Ca²⁺ entering by channels produced by membrane depolarization with K⁺ in inducing catecholamine release from bovine adrenal chromaffin cells. The Ca²⁺ influx through the Na⁺/Ca²⁺ exchanger was promoted by reversing the normal inward gradient of Na⁺ by preincubating the cells with ouabain to increase the intracellular Na⁺ and then removing Na⁺ from the external medium. In this way we were able to increase the cytosolic free Ca²⁺ concentration ([Ca²⁺]_c) by Na⁺/Ca²⁺ exchange to 325 ± 14 nM, which was similar to the rise in [Ca²⁺]_c observed upon depolarization with 35 mM K⁺ of cells not treated with ouabain. After incubating the cells with ouabain, K⁺ depolarization raised the [Ca²⁺]_c to 398 ± 31 nM, and the recovery of [Ca²⁺]_c to resting levels was significantly slower. Reversal of the Na⁺ gradient caused an −6-fold increase in the release of noradrenaline or adrenaline, whereas K⁺ depolarization induced a 12-fold increase in noradrenaline release but only a 9-fold increase in adrenaline release. The ratio of noradrenaline to adrenaline release was 1.24 ± 0.23 upon reversal of the Na⁺/Ca²⁺ exchange, whereas it was 1.83 ± 0.19 for K⁺ depolarization. Reversal of the Na⁺/Ca²⁺ exchange appeared to be as efficient as membrane depolarization in inducing adrenaline release, in that the relation of [Ca²⁺]_c to adrenaline release was the same in both cases. In contrast, we found that for the same average [Ca²⁺]_c, the Ca²⁺ influx through voltage-gated channels was much more efficient than the Ca²⁺ entering through the Na⁺/Ca²⁺ exchanger in inducing noradrenaline release from chromaffin ceils. This greater effectiveness of membrane depolarization in stimulating noradrenaline release suggests that there is a pool of noradrenaline vesicles which is more accessible to Ca²⁺ entering through voltage-gated Ca²⁺ channels than to Ca²⁺ entering through the Na⁺/Ca²⁺ exchanger, whereas the adrenaline vesicles do not distinguish between the source of Ca²⁺.     

Comparative studies on antidepressant action of alprazolam in different animal models

Alprazolam, a new benzodiazepine from triazolobenzodiazepine group, produced anxiolytic action in the conflict test with potency similar to that of diazepam. The myorelaxant activity of the drug was relatively weak. Unlike desipramine, alprazolam failed to reduce the immobility of rats in the forced swim test and was unable to prevent clonidine-induced hypothermia. Alprazolam, unlike desipramine, failed also to potentiate behavioral effect of noradrenaline injected into the hippocampus. Alprazolam after acute but not chronic administration antagonized the synchronizing effect of clonidine on EEG pattern. On the other hand, alprazolam similarly to tricyclic antidepressants, prevented the suppression of dominance behavior by clonidine in rats competing for food. The results indicate that alprazolam acts only weakly upon noradrenergic mechanisms related to depression and to antidepressant action of drugs.     

Periodic lateralized epileptiform discharges: etiology, clinical aspects, seizures, and evolution in 130 patients.

The purpose of this study was to analyze the clinical aspects in 130 patients presenting periodic lateralized epileptiform discharges (PLEDs) in their EEG and to compare these results with those found in the literature. Etiology, neurologic deficit, seizure occurrence, and evolution were studied in each patient by historical review. The recordings were obtained on 8- or 16-channel EEGs with electrode placement according to the International 10-20 System. Recordings containing PLEDs were selected. PLEDs were defined as repetitive periodic, focal, or hemispheric epileptiform discharges (spikes, spike and waves, polyspikes, sharp waves) usually recurring every 1 to 2 seconds. The statistical study was carried out via the chi(2) test using the computer program SPSS. The main etiology found in this group of patients was stroke (61 of 130 patients). Other processes found were brain infections, tumors, hematomas, and several other entities grouped together as miscellaneous (anoxic encephalopathy, subarachnoid hemorrhage, craniocerebral trauma, Creutzfeldt-Jacob disease, migraine, multiple sclerosis, and aminophylline intoxication). Half of these patients (65 of 130) developed seizures, mostly partial motor seizures. No significant relation between etiology and seizures was found (chi(2) = 2.81, P = 0.4222). Seizures recurred in 14 of 130 patients during a follow-up of 14.5 months. PLEDs were not recorded in any EEG at the time of seizure recurrence. PLEDs constitute a distinctive but uncommon EEG phenomenon of repetitive, periodic, and stereotyped lateralized complexes. In agreement with the literature, PLEDs were associated with an acute process and occurred early during the course of the illness in all patients studied and were usually associated with structural lesions, with stroke being the main etiology. Traditionally, seizures occur with PLEDs but it is also accepted that they can exist in patients who never develop epileptic activity, either clinically or electrically, as demonstrated in 50% of the patients studied. No significant association between seizures and any etiology could be found. It was not demonstrated that the occurrence of seizures may influence the outcome in any way.