Disturbed Ion Homeostasis Research Articles

Batrachochytrium dendrobatidis zoospore secretions rapidly disturb intercellular junctions in frog skin

Global amphibian declines are in part driven by the chytrid fungus Batrachochytrium dendrobatidis, causing superficial dermatomycosis with epidermal hyperplasia and hyperkeratosis in infected amphibians. The susceptibility to chytridiomycosis and the severity of epidermal lesions in amphibians with chytridiomycosis are not consistent across species or even among individuals. Severe infections cause death of the animal most likely through disturbance of ion homeostasis. The mechanism by which this superficial skin infection results in epidermal lesions has so far eluded precise definition. It was the aim of this study to unravel how B. dendrobatidis causes alterations that affect skin integrity. Exposure of Xenopus laevis skin to B. dendrobatidis zoospore supernatant using skin explants and Ussing chambers caused rapid disruption of intercellular junctions, demonstrated using histology and transmission electron microscopy. The loss of intercellular junctions led to detachment-induced cell apoptosis, or anoikis. The zoospore supernatant induced neither apoptosis nor necrosis in isolated primary keratinocytes of X. laevis. This supports the idea that the loss of cell contacts triggered apoptosis in the skin explants. Mass spectrometric analysis of the protein composition of the supernatant revealed a complex mixture, including several new virulence associated proteins, such as proteases, biofilm-associated proteins and a carotenoid ester lipase. Protease and lipase activity of the supernatant was confirmed with a protease and lipase assay.In conclusion, B. dendrobatidis zoospores produce a complex mixture of proteins that quickly disturbs epidermal intercellular junctions leading to anoikis in the anuran skin. The role of the identified proteins in this process remains to be determined.

Effect of ionic stress on apoptosis and the expression of TRPM2 in human olfactory neuroepithelial-derived progenitors

Objectives. Disturbed ion homeostasis and apoptosis have been implicated in the pathophysiology of bipolar disorder (BD). TRPM2, a nonselective cation channel, is involved in apoptosis and is possibly linked with BD. In this study, monensin, a sodium ionophore, was used to model the increase [Na+]in and [Ca2+]in seen in BD patients. Methods. Human olfactory neuroepithelial-derived progenitors (ONP), which possess neuronal markers, were utilized to investigate the effects of monensin on apoptosis and the response of TRPM2, and the effects of lithium on the cellular response to monensin. Monensin treatment for 6 h activated caspase-3, -7 and poly(ADP-ribose) polymerase (PARP), inducing apoptosis. Results. [Na+]in increased to twice the basal level and reached steady state after 2 h of 10−6 M monensin treatment, while [Ca2+]in rose after 6 h of the treatment. Monensin treatment for 24 h decreased expression of the long form of TRPM2, and increased expression of the short form. Lithium (1 mM) pretreatment reduced the [Na+]in and [Ca2+]in elevation caused by monensin, down-regulated the leveles of caspase-3, -7 and PARP, and reduced expression of TRPM2. Conclusions. Our findings suggest that the elevation of [Na+]in and [Ca2+]in induced ONP apoptosis and altered the expression of TRPM2. Lithium pretreatment attenuated the apoptosis induced by ionic stress.

Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine

Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. In a group of genotyped FHM patients (five FHM-1, four FHM-2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception-specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). FHM patients had a more pronounced habituation during VEP (P=0.025) and nsBR recordings (P=0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned.

Impaired tissue clearance of verapamil in rat cardiac hypertrophy results in transcriptional repression of ion channels

Heart hypertrophy is a common cardiac complication of sustained arterial hypertension and is accompanied by an increased incidence of supraventricular tachyarrhythmia, such as atrial fibrillation and atrial flutter. Verapamil, a phenyalkylamine, belongs to the group of calcium channel antagonists (class IV antiarrhythmic drugs) and is frequently used for the management of supraventricular tachycardia and for ventricular rate control in atrial fibrillation and atrial flutter.Verapamil heart tissue and plasma levels after intraperitoneal dosing of spontaneously hypertensive and normotensive rats were investigated. Transcript expression of various ion channels, ion transporters, calcium handling, and cytoskeletal proteins by reverse transcriptase-polymerase chain reaction (RT-PCR) were further investigated. There was no difference in plasma pharmacokinetics when hypertensive and normotensive animals were compared. Strikingly, the tissue clearance of verapamil was highly significantly impaired in heart tissue of hypertensive animals. Gene expression analysis showed the repression of many cardiac-specific genes in spontaneously hypertensive but not in normotensive rats, therefore providing evidence for different modes of action in healthy and hypertrophic hearts.Verapamil heart tissue levels differed dramatically between normotensive and hypertensive rats and resulted in repression of many cardiac ion channels, ion transporters, and calcium handling proteins. A disturbed ion homeostasis induced by critical tissue levels of verapamil is therefore proposed as a molecular rational for its pro-arrhythmogenic activity. The observed changes can be a significant determinant of spatial electrophysiological heterogeneity, thereby contributing to increased conductance disturbance as observed with some patients.

Ultrastructural pathology of human hydrocephalic cerebral cortex

The ultrastructural pathology of cerebral cortex in human hydrocephalus is described. Cortical biopsies of 17 patients of ages ranging from 10 days to 21 years old examined in our laboratory are described. Nerve cells show moderate and severe swelling characterized by dilation of endoplasmic reticulum canaliculi and perinuclear cistern, edema and degenerative changes of Golgi apparatus, variable degrees of mitochondrial swelling, and fragmentation of plasma membrane. The neighboring neuropil exhibits notable enlargement of extracellular space and signs of synaptic plasticity and degeneration. The astrocytes display edematous changes and phagocytic activity. Glycogen rich- and glycogen-depleted astrocytes are observed. Oligodendroglial cells appear normal in certain cases and in others show moderate hydropic changes. Numerous myelin figures are observed in some unidentified nerve cell processes. The capillary wall shows evident signs of blood-brain barrier dysfunction featured by increased endothelial vesicular and vacuolar transport, closed and open interendothelial junctions, and in severely edematous areas thinning and breakdown of capillary basement membrane. The role of ischemia, oxidative stress, increased calcium concentration, activation of N-methyl-d-aspartate (NMDA) receptors, and disturbance of ion homeostasis are discussed in relationship with the fine structural alterations of hydrocephalic brain parenchyma.

Mechanism of action of the new anti-ischemia drug ranolazine.

Myocardial ischemia is associated with reduced ATP fluxes and decreased energy supply resulting in disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent years, increased persistent (late) sodium current was suggested to contribute to disturbed ion homeostasis by elevating intracellular sodium concentration with subsequent elevation of intracellular calcium. The new anti-ischemia drug ranolazine, a specific inhibitor of late sodium current, reduces sodium overload and hence ameliorates disturbed ion homeostasis. This is associated with symptomatic improvement of angina in patients. Moreover, ranolazine was shown to exhibit anti-arrhythmic effects. In the present article, we review the relevant pathophysiological concepts for the role of late sodium inhibition and summarize the most recent data from basic as well as clinical studies.

Dynamics of cadmium accumulation and effects in common carp (Cyprinus carpio) during simultaneous exposure to water and food (Tubifex tubifex)

In this study, the influence of exposure time and concentration on the accumulation of cadmium and the occurrence of adverse effects was investigated when carp were simultaneously exposed through contaminated water and food. As exposure concentrations increased (9, 105, and 480 microg/L through water and 9.5, 122, and 141 microg/g dry weight through food) the accumulation pattern of cadmium changed, with progressively more cadmium being accumulated in the liver and especially the kidney and less in the gills and the intestine. A strong concentration- and time-dependent effect of cadmium exposure on plasma calcium concentrations was observed, leading to a decrease, with approximately 16% in the mid group and up to 50% in the group exposed to the highest cadmium concentration. Also at the highest exposure concentrations, sodium and chloride levels as well as plasma osmolality were significantly reduced, indicating a disturbed ion homeostasis. Furthermore, an increase in plasma alanine transaminase activity indicated liver damage caused by the cadmium accumulation in this organ. At the end of the experiment, general stress responses such as decreased hematocrit, growth, and mortality (17%) also were observed. All together, these results suggest that plasma hypocalcemia as an ion-disruptive phenomenon is the most sensitive effect during cadmium exposure, although the occurrence and magnitude both depend on exposure time and concentration.

Chilling-injury and disturbance of ion homeostasis in the coxal muscle of the tropical cockroach ( Nauphoeta cinerea)

Adults of warm- and cold-acclimated tropical cockroaches, Nauphoeta cinerea were exposed to low temperatures of 0 or 5 °C for various time intervals (hours to days). Development of chilling-injury (defects in crawling and uncoordinated movements) and mortality during the exposure were assessed and correlated with the changes in concentrations of metal ions (Na +, K + and Mg 2+) in the haemolymph and coxal muscle tissue. Warm-acclimated insects entered chill-coma at both low temperatures. In their haemolymph, the [Na +] and [Mg 2+] linearly decreased and [K +] increased with the increasing time of exposure. The rate of concentration changes was higher at 0 than at 5 °C. The concentration changes resulted in gradually dissipating equilibrium potentials across the muscle cell membranes. For instance, E K decreased from − 49.8 to − 20.7 mV during 7 days at 5 °C. Such a disturbance of ion homeostasis was paralleled by the gradual development of chilling-injury and mortality. Most of the cockroaches showed chilling-injury when the molar ratio of [Na +]/[K +] in their haemolymph decreased from an initial of 4.4 to 2.1–2.5. In contrast, the cold-acclimated cockroaches did not enter chill-coma. They maintained constant concentrations of ions in their haemolymph, constant equilibrium potentials across muscle cell membranes and the development of chilling-injury was significantly suppressed at 5 °C for 7 days.

Nifedipine represses ion channels, transporters and Ca2+-binding proteins in hearts of spontaneously hypertensive rats

The Ca(2+) antagonists nifedipine has been used for more than three decades to treat hypertension, but its effects on the transcriptional regulation of cardiac genes are basically unknown. We therefore studied expression of genes coding for ion channels, ion transporters and associated partners as well as Ca(2+)-binding proteins in ventricular tissue of normotensive and spontaneously hypertensive (SH) rats after repeated intraperitoneally (i.p.) dosing of nifedipine. Notably, we observed significant (P < 0.05) repression in transcript levels of most of the genes investigated, including cardiac Na(+), K(+), Ca(2+)-channels (L-type Ca(2+)-channel, K(ir)3.4, K(ir)6.1, Na(v)1.5), ATP-driven ion exchangers (Na(+)-K(+)-ATPase, NCX-1, PMCA 2 and 4, SERCA 2a and 2b) and their associated partners (phospholamban, RyR-2) as well as cytoskeletal proteins (alpha and beta-MHC, alpha cardiac and alpha skeletal actin, troponin T and I). Repression in transcript levels was, however, only seen in ventricular tissue of hypertensive animals. This points to fundamental differences in the mode of action of nifedipine in diseased and healthy animals. Indeed, this preponderance of repressed genes will promote disturbed ion homeostasis to result in contractile dysfunction. It is of considerable importance that repressed gene expression was also seen in end-stage human heart failure. We propose repression of cardiac-specific gene expression as a hallmark of nifedipine treatment in hypertrophic hearts.

Ischemic neuronal cell death and organellae damage

The brain is an organ that consumes much energy. This is partially due to the character of neurons; they possess excitable plasma membrane and a large amount of ATP is indispensable for maintaining ion gradient. Once neurons experience energy failure, calcium accumulates in the intracellular space as a result of disturbed ion homeostasis. This, in turn, activates many cellular processes, which culminate in cell death. In this cellular catastrophic cascade, many organelles play important roles. In addition to the plasma membrane, cytosol is the 'organelle' that first becomes exposed to the increased level of calcium. Many proteases, kinases and lipases are localized here, and are activated directly or indirectly by the ischemic insult. Some enzymes are pro-apoptotic ones, while others are anti-apoptotic. It was reported that neurons that would die later showed activated pro-apoptotic enzymes, but ones that would survive possessed activated anti-apoptotic molecules. Mitochondria is the organelle that plays the central role for intrinsic pathways of apoptosis. The release of cytochrome c from this organelle is the key step in apoptotic cascade in the ischemic neurons. However, the exact molecular mechanism of cytochrome c release remains uncertain. In addition, expression of genes essential for mitochondrial function changes in neurons after ischemia, which further indicates the crucial role of this organelle in cell death. Endoplasmic reticulum (ER) not only mediates proteins processing, but also regulates intracellular calcium homeostasis and cell death signal activation. Recent reports indicate that dysfunction of this organelle occurs at an early stage after ischemia and might be the initial step of apoptotic cascades in neurons. Golgi apparatus and lysosomes are organelles that are involved in apoptotic cell death in some situations. There have been no reports that demonstrated active role of these organelles in ischemic neuronal cell death. Further investigation would be desired about this issue. Nucleus is the organelle that contains genomic DNA. Many studies demonstrated DNA breakage in the neurons that would die later, but whether this is the cause or merely the result of the insult remains uncertain. If the more precise role of each organelle in neuronal cell death are disclosed, we should be able to think about new means of therapy for ischemic stroke.

Administration of aggregated beta-amyloid peptide (25-35) induces changes in long-term potentiation in the hippocampus in vivo.

Intracereroventricular administration of aggregated beta-amyloid protein fragment (25-35) (7.5 nmol/ventricle) was followed one month later by significant changes in the dynamics of long-term potentiation in the hippocampus in vivo, expressed as powerful and stable increases in the amplitude of evoked potentials. This phenomenon may be associated with oxidative stress in the hippocampus, which has previously been demonstrated in this model, and, thus, with disturbances in ion homeostasis.

Energy metabolism in the hypertrophied heart.

In response to a prolonged pressure- or volume-overload, alterations occur in myocardial fatty acid, glucose, and glycogen metabolism. Oxidation of long chain fatty acids has been found to be reduced in hypertrophied hearts compared to non-hypertrophied hearts. However, this observation depends upon the degree of cardiac hypertrophy, the severity of carnitine deficiency, the concentration of fatty acid in blood or perfusate, and the myocardial workload. Glycolysis of exogenous glucose is accelerated in hypertrophied hearts. Despite the acceleration of glycolysis, glucose oxidation is not correspondingly increased leading to lower coupling between glycolysis and glucose oxidation and greater H(+) production than in non-hypertrophied hearts. Although glycogen metabolism does not differ in the absence of ischemia, synthesis and degradation of glycogen are accelerated in severely ischemic hypertrophied hearts. These alterations in carbohydrate metabolism may contribute to the increased susceptibility of hypertrophied hearts to injury during ischemia and reperfusion by causing disturbances in ion homeostasis that reduce contractile function and efficiency to a greater extent than normal. As in non-hypertrophied hearts, pharmacologic enhancement of coupling between glycolysis and glucose oxidation (e.g., by directly stimulating glucose oxidation) improves recovery of function of hypertrophied hearts after ischemia. This observation provides strong support for the concept that modulation of energy metabolism in the hypertrophied heart is a useful approach to improve function of the hypertrophied heart during ischemia and reperfusion. Future investigations are necessary to determine if alternative approaches, such as glucose-insulin-potassium infusion and inhibitors of fatty acid oxidation (e.g., ranolazine, trimetazidine), also produce beneficial effects in ischemic and reperfused hypertrophied hearts.

Glucose and lactate metabolism after severe human head injury: influence of excitatory neurotransmitters and injury type.

The survival of traumatized brain tissue depends on energy substrate delivery and consumption. Excitatory amino acids produce a disturbance of ion homeostasis and thus, increase energy demand. In head-injured patients, massive release of glutamate has been reported, especially in patients with focal contusions. Therefore, we studied the interrelationship between glutamate, glucose and lactate in relation to the type of injury. We investigated 37 severely head-injured patients in which a microdialysis probe was placed next to a focal contusion (n = 14) or together with a ventricular catheter in diffusely injured tissue (n = 23). Within-subject Spearman-rank correlation revealed an overall strong relationship between glutamate and lactate (p < 0.001) and glutamate and glucose (p < 0.01), but not between glucose and lactate (n.s.). The interrelationship was more pronounced in diffusely injured brain (normal CT appearance) compared to the contused tissue. The results demonstrate that glutamate clearly influences the release of lactate following injury, supporting the hypothesis that glutamate "drives" glycolysis in astrocytes. The strong positive correlation between glutamate and glucose might indicate an effect of glutamate upon glucose uptake by cells which differs according to the type of injury.

Regional cerebral blood flow in peritumoral brain edema during dexamethasone treatment: a xenon-enhanced computed tomographic study.

Regional cerebral flood flow (rCBF) in peritumoral brain edema is assumed to be decreased because of increased interstitial pressure. Impaired blood flow might lead to local hypoxia, altered metabolism, and disturbed ion homeostasis, thus causing neurological sequelae. Steroid treatment is thought to positively influence the sequelae of brain edema. We aimed to determine the rCBF in peritumoral edema in humans receiving dexamethasone treatment and the relationship of rCBF to global CBF. We measured rCBF in 11 patients with untreated anaplastic gliomas or glioblastomas that were World Health Organization Grade III or IV restricted to one hemisphere with significant peritumoral edema who were receiving a standard dose of dexamethasone. rCBF was determined using stable xenon-enhanced computed tomography in a stereotactic frame. Edema was defined both by means of actual histology (stereotactic biopsies) and by imaging criteria. rCBF in peritumoral edema was decreased by 32% as compared with contralateral normal white matter. In each patient, this reduction was linearly related to blood flow in nonaffected white matter and cortex. The flow ratio in the different compartments was 1 (edema):1.5 (contralateral white matter):2.7 (contralateral cortex). Absolute perfusion values in contralateral cortex (means +/- standard deviations) (29.9+/-7.1 ml/100 g/min) and contralateral white matter (16.1+/-3.7 ml/100 g/min) were significantly decreased as well. Our study demonstrated that rCBF in peritumoral brain edema during steroid treatment is still decreased and is in a range in which it may cause neurological sequelae. Also, global CBF was decreased in all patients.

Ion transport in human skeletal muscle cells: disturbances in myotonic dystrophy and Brody's disease.

After excitation of skeletal muscle, the disturbed ion homeostasis is restored by Na+, K+ ATPase of the sarcolemma and Ca2+ ATPase of the sarcoplasmic reticulum (SR). Contrary to Na+, K+ ATPase, the concentration and isoenzyme distribution of SR Ca2+ ATPase in human skeletal muscle depend on fibre type and age. In cultured human muscle cells the concentration and activity of Na+, K+ ATPase and SR Ca2+ ATPase increase with maturation. In skeletal muscle and cultured muscle cells of patients suffering from myotonic dystrophy (MyD), the activity and the concentration of both Na+, K+ ATPase and SR Ca2+ ATPase are decreased by about 40%. In addition, we measured in cultured MyD muscle cells at rest an increased cytosolic Ca2+ concentration ([Ca2+]i) caused by active voltage-operated Ca2+ channels, which are inactive in resting control cells. However, the restoration of a stimulus-induced Ca2+ transient is unaffected. A differentiation-related disturbance of membranes or a modulation defect of membrane proteins may play a role in MyD. In skeletal muscle and cultured muscle cells of patients suffering from Brody's disease, which is characterized by impaired muscle relaxation, the SR Ca2+ ATPase activity is reduced by about 50%, but the concentrations of total SR Ca2+ ATPase and the predominant SERCA1 isoform are normal. Diseased muscle cells show a delayed restoration of [Ca2+]i after stimulation, which might be explained by structural modifications of SERCA1. Reduction of the Ca2+ release by drugs balances the excitation-relaxation cycle of the pathological cells.

Daunomycin-induced cardiomyopathy in rats and its possible therapy with peptide preparation isolated from the heart

A well-known consequence of treating malignant diseases with anthracycline antibiotics (AA), and the first to be noted by clinicians, is their cardiotropy, result ing in cardiomyopathy, in some cases with progressive heart failure and even a lethal ou tcome. Due to the high affinity of AA to membranes and their ability to intercalate between D N A bases, the immedia te and delayed effects of anthracycline therapy are manifested in inhibition of nucleic acid and protein synthesis, reduced activity of the mitochondrial respiratory enzymes, and disturbances of ion homeostasis . This results in an energy deficit, an overload with metabol ica l ly inactive calcium, and LPO activation in the cells, as well as impaired contractile funct ion, and enhanced diastolic rigidity of the myoca rd ium [5,7]. Bearing in mind that there are no effective means for protect ing the myoca rd ium under condi t ions of anthracycline cardiomyopathy, we proposed a peptide preparat ion f rom the heart (HP) which is known to s t imula te c a r d i o m y o c y t e repai r af ter damage caused by industrial toxins [2] and to possess an antiischemic effect [6]. In the present study we tested the possibility of correcting daunomycin-induced cardiomyopathy with the heart-derived peptide preparation.

Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats.

Brain trauma is associated with acute functional impairment and neuronal injury. At present, it is unclear to what extent disturbances in ion homeostasis are involved in these changes. We used ion-selective microelectrodes to register interstitial potassium ([K+]e) and calcium ([Ca2+]e) concentrations in the brain cortex following cerebral compression contusion in the rat. The trauma was produced by dropping a 21 g weight from a height of 35 cm onto a piston that compressed the cortex 1.5 mm. Ion measurements were made in two different locations of the contused region: in the perimeter, i.e., the shear stress zone (region A), and in the center (region B). The trauma resulted in an immediate increase in [K+]e from a control level of 3 mM to a level > 60 mM in both regions, and a concomitant negative shift in DC potential. In both regions, there was a simultaneous, dramatic decrease in [Ca2+]e from a baseline of 1.1 mM to 0.3-0.1 mM. Interstitial [K+] and the DC potential normalized within 3 min after trauma. In region B, [Ca2+]e recovered to near control levels within 5 min after ictus. In region A, however, recovery of [Ca2+]e was significantly slower, with a return to near baseline values within 50 min after trauma. The prolonged lowering of [Ca2+]e in region A was associated with an inability to propagate cortical spreading depression, suggesting a profound functional disturbance. Histologic evaluation 72 h after trauma revealed that neuronal injury was confined exclusively to region A. The results indicate that compression contusion trauma produces a transient membrane depolarization associated with a pronounced cellular release of K+ and a massive Ca2+ entry into the intracellular compartment. We suggest that the acute functional impairment and the subsequent neuronal injury in region A is caused by the prolonged disturbance of cellular calcium homeostasis mediated by leaky membranes exposed to shear stress.

Effects of R 56865 and phenytoin on mechanical, biochemical, and morphologic changes during ouabain intoxication in isolated perfused rabbit heart.

The Na+/Ca2+ overload inhibitor R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl)-N-methyl-2- benzothiazolamine) has been reported to prevent or attenuate ischemia- as well as ouabain-induced cellular sodium and calcium load. We investigated the potency of this compound in preventing mechanical, biochemical, and ultrastructural consequences of ouabain (OUA) intoxication in isolated rabbit heart. The protective effect of the digitalis antidote phenytoin (PHT) on the consequences of ouabain intoxication was examined for comparison. In isolated perfused rabbit heart, OUA (0.4 microM) caused an increase in left ventricular end-diastolic pressure (LVEDP) that was accompanied by depletion of high-energy phosphates (80% less than in control), accumulation of tissue lactate (12-fold) and damage of contractile elements and mitochondria. Accumulation of lactate was associated with a decrease in oxygen consumption by the isolated perfused heart. R 56865 (1.0 microM) and phenytoin (60 microM) prevented increase in LVEDP, breakdown of the energy-rich phosphates creatine phosphate (CrP) and ATP, accumulation of lactate, and morphologic changes induced by OUA. The above-mentioned toxic effects of OUA are interpreted as consequences of mitochondrial failure finally leading to breakdown of the oxidative phosphorylation. Thus, we conclude that the protective action of both compounds, R56865 and PHT, may be attributed to prevention or attenuation of mitochondrial failure due to OUA-induced disturbance of ion homeostasis.

Cloning of the genes for excitatory amino acid receptors.

Glutamate is the major excitatory neurotransmitter in the mammalian brain, with receptors on every neuron in the central nervous system; it has major roles in fast synaptic transmission and in the establishment of certain forms of memory. More than 20 years ago Olney and his colleagues described the 'Excitotoxic Hypothesis' which postulates that, in addition to its normal function in the healthy brain, glutamate can kill neurons by prolonged, receptor-mediated depolarization resulting in irreversible disturbances in ion homeostasis. Therefore, glutamate is a two-edged sword; in certain undefined, adverse conditions it undergoes a transition from neurotransmitter to neurotoxin. Its toxicity has been implicated in the death of neurons in ischemia, epilepsy, and the neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's disease. Recent advances in the molecular cloning of the genes for the glutamate family of receptors has revealed a plethora of receptor subtypes and an unexpected level of complexity in the mechanisms of receptor expression and function.

Effects of nimodipine on the responses to cerebral ischemia in the Mongolian gerbil.

Brain ischemia has significant implications to the development of damage in patients undergoing stroke condition. In order to understand the mechanisms involved, a few animal models have been adopted. The Mongolian gerbil, having an incomplete circle of Willis, is widely used as a model for partial or complete ischemia (Levy and Brierley, 1974. Berry et al, 1975. Kobayashi et al, 1977. Mayevsky, 1978. Mies and Hossmann, 1983. Mayevsky et al, 1985). The disturbances of ion homeostasis in the brain under ischemia were recorded by a few groups using an extracellular K+ electrode and more recently, Ca+ electrode (Branston et al, 1977. Hansen and Zeuthen, 1981. Harris et al, 1981. Choki et al, 1984. Mayevsky et al, 1985. Mayevsky and Zarchin, 1987).