Search

A computational model of long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus is presented. The model assumes the existence of retrograde signals, is in good agreement with several experimental data on LTP, LTD, and their pharmacological manipulations, and shows how a simple kinetic scheme can capture the essential characteristics of the processes involved in LTP and LTD. We propose that LTP and LTD could be two different but conceptually similar processes, induced by the same class of retrograde signals, and maintained by two distinct mechanisms. An interpretation of a number of experiments in terms of the molecular processes involved in LTP and LTD induction and maintenance, and the roles of a retrograde signal are presented and discussed.

Ellagic acid (1) and its two derivatives, 4-O-methylellagic acid (2) and 4-(α-rhamnopyranosyl)ellagic acid (3) were isolated as inhibitors of aldose reductase (AR) from Myrciaria dubia (H. B. & K.) McVaugh. Compound 2 was the first isolated from the nature. Compound 3 showed the strongest inhibition against human recombinant AR (HRAR) and rat lens AR (RLAR). Inhibitory activity of compound 3 against HRAR (IC50 value=4.1×10−8 M) was 60 times more than that of quercetin (2.5×10−6 M). The type of inhibition against HRAR was uncompetitive.

To test the hypothesis that diabetes can selectively affect the intracellular and extracellular components of the noradrenergic vascular response in rats, we studied changes in blood pressure, in vitro vascular contraction and (45) Ca(2+) uptake in experimental diabetes induced by injection of 60 mg/kg of streptozotocin (STZ). One week after induction of diabetes mean blood pressure decreased significantly from 106 +/- 3 mmHg to 89 +/- 2 mmHg. After incubation in Ca(2+) =1.6 mM, contraction of STZ aortic rings to 10(- 7) M of norepinephrine was preserved in its intracellular component (Control: 231 +/- 28, STZ: 274 +/- 22 mgForce/mgTissue, NS) but depressed in its extracellular component (Control: 277 +/- 24, STZ: 133 +/- 33 mgForce/mgTissue, P0.05). Uptake of (45) Ca(2+) in the same rings was depressed in both components. Norepinephrine contractions due to extracellular Ca(2+) (prior depletion of norepinephrine-sensitive Ca(2+) stores) unexpectedly exhibited a initial component whose magnitude in control rings was similar to the response due to intracellular Ca(2+) (extra: 503 +/- 65 mg, intra: 411 +/- 30 mgForce/mgTissue), and was not depressed in STZ preparations (399 +/- 62 mgForce/mgTissue). The sustained contraction to norepinephrine in extracellular Ca(2+) was significantly reduced in STZ aortas (1163 +/- 92 vs. 528 +/- 95 mgForce/mgTissue). We conclude that: 1) Short-term streptozotocin-induced diabetes features reduced blood pressure along with deficient aortic (45) Ca uptake and contraction to norepinephrine, and 2) Only the sustained phase of the norepinephrine contraction, dependent on extracellular Ca(2+), was depressed in the diabetic rats and could possibly be associated with the observed fall in blood pressure.

The mechanisms of arsine (AsH3) toxicity are not completely understood. Studies were undertaken to determine AsH3 and arsenite [As(III)] toxicity in a renal tubular epithelial cell line to model kidney dysfunction caused by AsH3 exposure. The hypothesis was that As(III) is the toxic metabolite responsible for the renal toxicity of AsH3. There was a concentration- and time-dependent toxic response after As(III) incubation. As(III) produced significant LDH leakage as early as 1 h and intracellular potassium loss at 5 h. AsH3 produced no changes in these parameters. AsH3 affected neither potassium nor LDH levels over 24 h and up to 1 mM AsH3 concentration. In this system, As(III) induced LDH leakage before K+ loss. Oxidative stress-like toxicity effects were also studied by determining levels of glutathione (GSH), glutathione disulfide (GSSG), and heat-shock protein 32 (Hsp32) levels. GSH levels were not markedly affected by any arsenical over a 6-h period or up to 100 microM concentration of the arsenical. However, 100 microM AsH3 significantly increased GSSG levels as early as 30 min and reached a maximum at 2.5 h. Incubation with 10 microM AsH3 was sufficient to significantly increase GSSG levels. As(III) had no marked effect on GSSG. Both arsenicals (50 microM) produced a slight increase (about threefold) in Hsp32 levels after 4-h incubation. These results showed that unchanged AsH3 produced oxidative stress-like toxic effects without producing cell death. However, similar As(III) concentrations induced the stress response and were toxic to the cells. These data indicated that AsH3 is not directly toxic to LLC-PK1 cells.

With the development of a rapid assay for arsenite methyltransferase (Zakharyan et al., 1995), the specific activity of this critical enzyme for arsenite biotransformation was determined by incubating liver, testis, kidney, or lung cytosol of male B6C3F1 mice with sodium arsenite and S-[methyl-3H]adenosyl-L-methionine and measuring the formation of [methyl-3H]monomethylarsonate. The mean arsenite methyltransferase specific activities (U/mg +/- SEM) measured in these organs were liver, 0.40 +/- 0.06; testis, 1.45 +/- 0.08; kidney, 0.70 +/- 0.06; and lung, 0.22 +/- 0.01. Heretofore, the enzymatic methylation of arsenite has been regarded primarily as a hepatic function. The arsenite methyltransferase specific activity of the testis was 3.6 times greater than that of the liver (p0.01) and the specific activity of the kidney was 1.8 times greater than that of the liver (p0.05). Additionally, when mice were given arsenate in drinking water for 32 or 91 days at concentrations of 25 or 2500 micrograms As/L, the arsenite methyltransferase activities of liver, testis, kidney, and lung cytosol were not significantly increased in animals receiving either dose of arsenic for either 32 or 91 days compared to controls. No evidence for the induction of arsenite methyltransferase was found under these experimental conditions.

Application of a 126 V, 3 Ampers electrical current produces brain death in dogs assessed by irreversible installation of an isoelectric electroencephalogram. Cerebral death was immediate or preceded by a paroxistic activity of short duration (25 +/- 12 Seconds; Mean +/- SD). Besides the isoelectric electroencephalogram, there were immediate respiratory arrest and cardiac fibrillations followed by heart stopping. Reflexes were absent and no response to painful stimuli was observed. An appropriate utilization of the experimental method described in this study may contribute to improve the knowledge about the pathophysiology of cerebral death in humans.

Various substances have been used as sleep inductors, but their use has declined, due to their undesirable side effects, and they have been replaced mainly by benzodiazepines. There currently exists a great variety of benzodiazepines with an increasing, clinical use, although they also present certain disadvantages. The effect on sleep of the intraperitoneal administration (0.9 mg/kg) of 7-(p-cl-phenyl)-8-phenoxy-4,5-benzo-3-aza-2-none, was analysed in chronically implanted wistar rats. Results indicate that this substance decreases wakefulness and increases significantly slow-wave and paradoxical sleep. Latency of the first phase of paradoxical sleep show a tendency to increase. It is concluded that this substance has hypnogenic effects.

The object of this investigation was to study the effect of a benzodiazepine upon the cycle wakefulness-sleep. Wistar rats received 0.9 mg/kg of the chlorate derivative of beta lactam 1.5 benzodiazepine intraperitoneally and the action was analyzed by means of continuous polygraphic registers for ten hours long. Results indicate that this substance decreases wakefulness and slightly increases slow wave sleep. Paradoxical sleep increases significantly (p less than 0.05). Latency of the first phase of paradoxical sleep decreases considerably. These effects suggest that this compound favors sleep under present experimental conditions.

GABA released either iontophoretically or synaptically near pyramidal neurons in the CA1 region of the rat hippocampal slice could produce a biphasic response: a hyperpolarization followed by a depolarization. The depolarizing component elicited by either method was accompanied by an increased membrane conductance, and a reduction in neuronal discharge. The depolarization was reversed at a potential which was less negative than the resting membrane potential; it was blocked by antagonists of GABA action such as picrotoxin; it was sensitive to manipulation of extracellular chloride concentration; and it persisted in the presence of concentrations of cobalt or manganese which were sufficient to block evoked synaptic activity. Iontophoresis of GABA near the apical dendrites elicited an initial depolarization rather than an initial hyperpolarization, suggesting a dendritic origin for the depolarizing component. Together, these results suggest that GABA can produce, in the same neuron, both hyperpolarizing and depolarizing responses which depend at least in part upon changes in chloride conductances.

— The effect of topical application of diethyl-α-fluoroglutarate on the primary response of cat cerebral cortex to thalamic stimulation was investigated, and samples of the involved tissue and of homologous contralateral control tissue were removed at appropriate times for biochemical analyses. Changes in electrocortical response were first noted 30–40 min after topical application of 10 μ1 (52.7 μmol) of the drug to the pericruciate gyrus. A rapid reduction in amplitude of the surface negative component of the primary response was observed initially, followed by amplitude reduction and rapid disappearance of the primary response throughout the cortical field within a few minutes after the change first observed at the surface. The effects were interpreted either as a direct action of the drug on the somadendritic membrane or an inhibition of the excitatory synaptic impingement. Analyses of the tissues removed at the time of maximum electrocortical response indicated profound metabolic changes, including depletion of energy reserves and several Krebs cycle intermediates. Large increases in tissue levels of glucose, glucose 6-phosphate, and pyruvate were found. Changes in amino acids comprised depletion of glutamate with increased tissue levels of aspartate, GABA, NH3, threonine, serine and alanine. Tissues were also removed at 10 min after topical application of the drug but before the advent of electrocortical changes. Decreased levels of glutamate were associated with a rise in tissue aspartate. Tissue levels of the other amino acids were unchanged. Glucose, glucose 6-phosphate and pyruvate levels were increased, lactate and ATP levels were unchanged, and P-creatine, α-KG and malate levels were reduced. We believe that the observed pattern of changes represents responses of the cerebral cortex to either a block in the synthesis of glutamate or in oxidation of pyruvate, with consequent interference with oxidative and energy metabolism and eventual depression of cortical electrical activity.

Blood pressure changes due to the progressive closing of each of the carotid and each of the vertebral arteries were studied at various arterial levels, including femoral and one lingual, both linguals, and lingual and branch of the middle cerebral artery. The changes in lingual artery pressure were closely related to changes in systemic pressure, especially with regard to the degree of recovery which followed the initial drop in pressure caused by clamping one or more of the main arteries to the brain. The anastomotic nature of the circle of Willis was demonstrated in animals in which the posterior communicating artery or the basilar artery had been clipped. Under these experimental conditions, clipping of the basilar artery removed all functional connections between the carotid and vertebral circulations. Qualitatively, the lingual artery pressure appeared to be a good reflection of pressure in an arterial branch in the cerebral cortex. Quantitatively, the cortical pressure remained significantly higher than the lingual pressure until the last main artery to the brain was closed.

Penicillin enhances the excitatory postsynaptic potential of the squid stellate ganglion. This effect suggests the hypothesis that the epileptic focus created by the topical application of penicillin to the mammalian cerebral cortex is produced by the facilitation of excitatory synaptic coupling within the preexisting positive recurrent feedback system.

During paradoxical sleep, large amplitude phasic activity is found in different areas of the nervous system. This activity can also be pharmacologically induced by either reserpine or p -chlorophenylalanine (PCPA). Recently, this phenomenon has been reported at the level of the auditory pathway during paradoxical sleep and after the administration of reserpine. Thus, it was considered likely that this activity was qualitatively similar to that recorded in other brain structures and that it might be induced by PCPA as well. It was found that PCPA induced the appearance of phasic activity in structures of the auditory pathway that were recorded (cochlear nucleus and auditory cortex), as well as in those of the visual pathway (lateral geniculate body and visual cortex). Furthermore, total insomnia was produced between 48 and 72 hr after the injection of the drug, being most intense after the administration of a double dose (2 × 300 mg/kg). It is suggested that this phasic activity forms part of a common system together with that which has been recorded in other regions under similar physiological conditions.

The effectsof phenytoin (35 μg/ml) on membrane properties and inhibitory postsynaptic potentials (IPSPs) in CA1 and CA3 pyramidal neurons of the in vitro rat hippocampus were examined. No significant change was observed on input resistance or resting membrane potential. Action potential amplitude, overshoot, rate of rise and rate of decay were decreased. IPSP conductance increase and reversal potential, evoked in CA3 cells through mossy fiber stimulation and in CA1 cells through recurrent and Schaffer's collateral stimulation, were unaffected.

To analyze the possible correlation between steroidogenic activity of the Leydig cells and their morphology and ultrastructure in the boar testes at different ages, testes from six Yorkshire boars were obtained by orchidectomy at 8,14,28,40,70,78,86,94 and 100 days of age. Using representative sections of testicular parenchyma, light as well as transmission electron microscopic studies were performed. Homogenized, albuginea-free tissue was further used for quantitative estimation of total proteins and metabolic pools of androstenedione (A), testosterone (T) and 5 alpha-dihydrotestosterone (DHT). Under light microscopy, abundant hyperplastic Leydig cells were observed from 14 to 40 days, thereafter was a decrease in their size and number. Spermatogenesis remained in the spermatogonia stage while the tubules increased in diameter until age 80 days; from 90 days on, pachytene primary spermatocytes could be found. A well developed smooth endoplasmic reticulum was observed in Leydig cells from the 8th postnatal day. Metabolic pools from age 8 to 28 days showed a decrease for T and A from 4.33 to 1.78 and 2.51 to 0.48 microgram/mg protein respectively, maintaining thereafter the same levels throughout the age-span studied. However, DHT was found at low levels from the beginning of neonatal period (from 0.07 to 0.38 microgram/mg protein).

The cellular phenomena underlying focal epilepsy are currently understood in the context of contemporary concepts of cellular and synaptic function. Interictal discharges appear to be due to a combination of synaptic events and intrinsic currents, the exact proportion of which in any given neuron may vary according to the anatomic and functional substrate involved in the epileptic discharge and the epileptogenic agent used in a given model. The transition to seizure appears to be due to simultaneous increments in excitatory influences and decrements in inhibitory processes--both related to frequency-dependent neuronal events. A variety of specific hypotheses have been proposed to account for the increased excitability that occurs during epileptiform activity. Although each of the proposed mechanisms is likely to contribute significantly to the epileptic process, no single hypothesis provides an exclusive unifying framework within which all kinds of focal epilepsy can be understood. The spread of epileptic activity throughout the brain, the development of primary generalized epilepsy, the existence of "gating" mechanisms in specific anatomic locations, and the extrapolation of hypotheses derived from simple models of focal epilepsy to explain more complex forms of human epilepsy, all are not yet fully understood.