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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Local anaesthetics are responsible for 5 to 10% of all reported adverse reactions to anaesthetic drugs. Adverse effects may be classified as: (a) those associated directly with blocking ion channels in cell membranes, such as cardiovascular and CNS toxicity; (b) those due to other effects of drug or vehicle (mainly peripheral nerve complications); (c) allergic reactions (often a mistaken diagnosis); and (d) mechanical or other effects of technique, such as needle trauma or introduction of infection. Signs and symptoms of CNS toxicity include convulsions, followed by coma and respiratory depression. Convulsions are due to disinhibition of nervous conduction, probably by an action at the gamma-aminobutyric acid (GABA) receptor complex, while depressant effects, which predominate at higher doses, are due to blockade of sodium channels. CNS toxicity is potentiated by hypoxia and hypercapnia, so acute management must minimise these. Cardiovascular toxicity also involves sodium channel blockade, reducing contractility and interfering with conduction. Bupivacaine differs from lidocaine (lignocaine) in the sudden occurrence of dangerous ventricular arrhythmias including fibrillation at subconvulsant doses. Ropivacaine is a newer amide local anaesthetic with toxicity intermediate between these but potency similar to bupivacaine. Neurotoxic complications leading to prolonged deficit after intraspinal administration are uncommon. Causes are multifactorial, and include pH of and additives to preparations. Allergic reactions account for only 1% of untoward reactions, but anaphylactoid collapse can be lifeth-reatening and requires rapid and effective management.
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PMID:Adverse effects of local anaesthetics. 150 66

Correlations were made among ATP synthesis, transmembrane K+ gradients, and leakage of three amino acid neurotransmitters, gamma-aminobutyric acid (GABA), aspartate, and glutamate, in rat brain synaptosomes incubated under normoxic and respiration-limited conditions. Even under normoxic conditions, a substantial proportion of total ATP synthesis (8%) was provided by glycolysis. Limitation of respiration by approximately 30% through addition of amobarbital (Amytal) caused a twofold decrease in the creatine phosphate/creatine ([CrP]/[Cr]) ratio, and consequently the [ATP]/[ADP] ratio, and a threefold increase in lactate production. There was a detectable decrease in intracellular [K+] and small rises in external GABA, aspartate, and glutamate concentrations. More severe limitations in ATP synthesis caused larger declines in the [CrP]/[Cr] ratio and progressive leakage of K+ and neurotransmitter amino acids. A comparison of delta GATP and delta GNa, K showed the former to be larger by 6 kcal, which indicates that the plasma membrane Na+/K+ pump operates at far from equilibrium. Under respiration-limited conditions, even when total ATP synthesis decreased by approximately 80% and [ATP] declined to less than 0.4 mM, delta GATP was still larger than delta GNa,K. It is suggested that during hypoxia and ischemia, the activity of the plasma membrane Na+/K+ pump in brain becomes limited by [ATP], which falls below the Km value for the low-affinity regulatory site on the enzyme. This failure of the pump and consequent collapse of the ion gradients may contribute to the leakage of neurotransmitter amino acids that occurs in these pathological states.
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PMID:Relationships among ATP synthesis, K+ gradients, and neurotransmitter amino acid levels in isolated rat brain synaptosomes. 244 8

Gamma-aminobutyric acid A (GABAA) receptors are the principal mediators of synaptic inhibition, and yet when intensely activated, dendritic GABAA receptors excite rather than inhibit neurons. The membrane depolarization mediated by GABAA receptors is a result of the differential, activity-dependent collapse of the opposing concentration gradients of chloride and bicarbonate, the anions that permeate the GABAA ionophore. Because this depolarization diminishes the voltage-dependent block of the N-methyl-D-aspartate (NMDA) receptor by magnesium, the activity-dependent depolarization mediated by GABA is sufficient to account for frequency modulation of synaptic NMDA receptor activation. Anionic gradient shifts may represent a mechanism whereby the rate and coherence of synaptic activity determine whether dendritic GABAA receptor activation is excitatory or inhibitory.
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PMID:Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. 763 14

In this study, we determined whether the retina cell death observed in response to an ischemic-like insult is related to an overactivation of the ionotropic glutamate receptors and/or to a collapse of the energy levels. Cultured chick retina cells were submitted to 'chemical ischemia' by metabolic inhibition with sodium cyanide and iodoacetic acid, which block oxidative phosphorylation and glycolysis, respectively. The assessment of neuronal injury was made spectrophotometrically by quantification of cellularly reduced MTT, which gives information about mitochondrial function, or by staining with fluorescein diacetate (FDA), which correlates with changes in the plasma membrane permeability. 'Chemical ischemia' induced both an acute and a delayed time-dependent degeneration of chick retina cells. We observed that 2 min after the ischemic insult, the levels of ATP were reduced to a minimum. On the other hand, the metabolic inhibition induced the release of aspartate, glutamate and gamma-aminobutyric acid, and the activation of AMPA/kainate receptors during the period of metabolic arrest was partially responsible for the loss of mitochondrial function. However, the NMDA and non-NMDA receptor antagonists (MK-801 and CNQX) did not prevent the plasma membrane damage caused by sodium cyanide and iodoacetic acid. The results show that the collapse of the energy levels, rather than the increase in excitatory amino acids, appears to underlie the observed cell injury, suggesting an important relationship between ischemia-induced depletion of high-energy metabolites and retina cell degeneration.
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PMID:'Chemical ischemia' in cultured retina cells: the role of excitatory amino acid receptors and of energy levels on cell death. 936 12

Edge enhancement in the retina is thought to be mediated by classical center-surround antagonism, first encountered as the interactions between horizontal cells and cones. But in the salamander retina these interactions do little to enhance edges. Instead, a robust dynamic interaction between amacrine and bipolar cells appears to be responsible for a sharp edge enhancement. To demonstrate this we recorded extracellularly from a single ganglion cell and moved a flashed square, 300 micro(m) on a side, over a 1.5 x 1.0 mm2 grid at 25-micro(m) increments. Playing back all of these recordings simultaneously simulated the pattern of responses that would have been measured from an array of ganglion cells. The emerging pattern of ganglion cell activity first faithfully represented the flashed square, but after approximately 60 ms the center of the representation collapsed, leaving a representation of only the edges. We inferred that the feedback synapse from amacrine to bipolar cells at gamma-aminobutyric acid-C (GABAC) receptors mediated this effect: bicuculline and strychnine were ineffective in altering the response pattern, but in picrotoxin the center of the representation did not collapse. The GABAergic amacrine cells thought to mediate this effect have quite narrow spread of processes, so the existence of this edge-enhancing effect suggests a mechanism quite different from classical lateral inhibition, namely the delayed inhibition of a spatially expanding input pattern.
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PMID:Spatiotemporal patterns at the retinal output. 965 62

The gamma-aminobutyric acid (GABA) is one of the most important inhibitory transmitter in the CNS. When GABA is released in the synaptic cleft, it can act on two types of receptors, type A (GABAA-R) and type B. The GABAA-R is an ionotropic receptor whose subunits form a chloride channel. It contains specific binding sites at least for GABA, benzodiazepines, picrotoxin, barbiturates, anesthetic steroids, divalent cations such as Zn2+ and other compounds. Neurotransmitters and neuropeptides that regulate intracellular second messengers may modulate the responses of GABAA-R in the post-synaptic membrane and thus affect the synaptic plasticity. While consensus sites for several kinases are present on many subunit-subtypes, the functional consequences of these phosphorylations are unclear. However, the maintenance of normal GABA currents required the activity of a unique kinase specific for the GABAA-R. This intracellular regulation site might be involved in synaptic plasticity and considered as a site of vulnerability for epileptogenesis. The generation of epileptic discharge, synchronized burst firing and interictal spikes, can be subsequent to the alteration of GABAA-R function. A consequence of GABAergic disinhibition is the formation of new polysynaptic pathways leading to a network of neurons that were previously not connected. Cell loss and plasticity are currently observed in most patients with temporal lobe epilepsy. CA1 pyramidal cells are missing and mossy fibers of dentate granule cells project back through the granule cell layer to form recurrent terminals on granule cell dendrites. This mossy fiber sprouting leads to the destruction of most dentate hilar somatostatine interneurons. Nevertheless, local circuit neurons containing glutamic acid decarboxylase survive in this layer and in all regions of the sclerotic hippocampus. A decrease of the GABA release has been proposed as a basis for disinhibition temporal-lobe epilepsy is partially characterized by a loss of glutamate-stimulated GABA release that is secondary to a reduction in the number of GABA transporters. A molecular reorganization of GABAA-R subunits has been suggested in the kindling model of temporal lobe epilepsy because the zinc released from abberantly sprouted mossy fiber terminals is responsible for a collapse of augmented inhibition by GABA. These results support the concept of a loss of inhibition in chronic epilepsy models and probably in human epilepsies.
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PMID:[Intervention of GABAergic neurotransmission in partial epilepsies]. 968 48

In examining the role of Class 3 secreted semaphorins in the prenatal and postnatal development of the septohippocampal pathway, we found that embryonic (E14-E16) septal axons were repelled by the cingulate cortex and the striatum. We also found that the hippocampus exerts chemorepulsion on dorsolateral septal fibers, but not on fibers arising in the medial septum/diagonal band complex, which is the source of septohippocampal axons. These data indicate that endogenous chemorepellents prevent the growth of septal axons in nonappropriate brain areas and direct septohippocampal fibers to the target hippocampus. The embryonic septum expressed np-1 and np-2 mRNAs, and the striatum and cerebral cortex expressed sema 3A and sema 3F. Experiments with recombinant semaphorins showed that Sema 3A and 3F, but not Sema 3C or 3E, induce chemorepulsion of septal axons. Sema 3A and 3F also induce growth cone collapse of septal axons. This indicates that these factors are endogenous cues for the early guidance of septohippocampal fibers, including cholinergic and gamma-aminobutyric acid (GABA)ergic axons, during the embryonic stages. During postnatal stages, when target cell selection and synaptogenesis take place, np-1 and np-2 were expressed by septohippocampal neurons at all ages tested. In the target hippocampus, pyramidal and granule cells expressed sema 3E and sema 3A, whereas most interneurons expressed sema 3C, but few expressed sema 3E or 3A. Combined tracing and expression studies showed that GABAergic septohippocampal fibers terminated preferentially onto sema 3C-positive interneurons. In contrast, cholinergic septohippocampal fibers terminated onto sema 3E and sema 3A-expressing pyramidal and granule cells. The data suggest that Class 3 secreted semaphorins are involved in postnatal development. Moreover, because GABAergic and cholinergic axons terminate onto neurons expressing distinct, but overlapping, patterns of semaphorin expression, semaphorin functions may be regulated by different signaling mechanisms at postnatal stages.
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PMID:Role of class 3 semaphorins in the development and maturation of the septohippocampal pathway. 1538 96

We used western blotting to measure the quantity of glutamate and gamma-aminobutyric acid (GABA) transporters proteins within hippocampal tissue obtained from rats who had undergone epileptogenesis. Chronic seizures were induced by amygdalar injection of FeCl(3). We found that the glial glutamate transporters GLAST and GLT-1 were down-regulated at 60 days after initiation of chronic and recurrent seizures. However, the neuronal glutamate transporter EAAC-1 and the GABA transporter GAT-3 were increased. We performed in vivo microdialysis in freely moving animals to estimate in vivo redox state. We found that the hippocampal tissues were oxidized, resulting in even further impairment of glutamate transport. Our data show that epileptogenesis in rats resulting in chronic and recurrent seizures is associated with collapse of glutamate regulation caused by both the molecular down-regulation of glial glutamate transporters combined with the functional failure due to oxidation.
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PMID:Functional role for redox in the epileptogenesis: molecular regulation of glutamate in the hippocampus of FeCl3-induced limbic epilepsy model. 1748 25

The roles of endocannabinoid signaling during central nervous system development are unknown. We report that CB(1) cannabinoid receptors (CB(1)Rs) are enriched in the axonal growth cones of gamma-aminobutyric acid-containing (GABAergic) interneurons in the rodent cortex during late gestation. Endocannabinoids trigger CB(1)R internalization and elimination from filopodia and induce chemorepulsion and collapse of axonal growth cones of these GABAergic interneurons by activating RhoA. Similarly, endocannabinoids diminish the galvanotropism of Xenopus laevis spinal neurons. These findings, together with the impaired target selection of cortical GABAergic interneurons lacking CB(1)Rs, identify endocannabinoids as axon guidance cues and demonstrate that endocannabinoid signaling regulates synaptogenesis and target selection in vivo.
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PMID:Hardwiring the brain: endocannabinoids shape neuronal connectivity. 1752 44

The Na(+)-K(+)-Cl(-) cotransporter 1 and K(+)-Cl(-) cotransporter 2 regulate the levels of intracellular chloride in hippocampal cells. Impaired chloride transport by these proteins is thought to be involved in the pathophysiological mechanisms of mesial temporal lobe epilepsy. Imbalance in the relative expression of these two proteins can lead to a collapse of Cl(-) homeostasis, resulting in a loss of gamma-aminobutyric acid-ergic inhibition and even epileptiform discharges. In this study, we investigated the expression of Na(+)-K(+)-Cl(-) cotransporter 1 and K(+)-Cl(-) cotransporter 2 in the sclerosed hippocampus of patients with mesial temporal lobe epilepsy, using western blot analysis and immunohistochemistry. Compared with the histologically normal hippocampus, the sclerosed hippocampus showed increased Na(+)-K(+)-Cl(-) cotransporter 1 expression and decreased K(+)-Cl(-) cotransporter 2 expression, especially in CA2 and the dentate gyrus. The change was more prominent for the Na(+)-K(+)-Cl(-) cotransporter 1 than for the K(+)-Cl(-) cotransporter 2. These experimental findings indicate that the balance between intracellular and extracellular chloride may be disturbed in hippocampal sclerosis, contributing to the hyperexcitability underlying epileptic seizures. Changes in Na(+)-K(+)-Cl(-) cotransporter 1 expression seems to be the main contributor. Our study may shed new light on possible therapies for patients with mesial temporal lobe epilepsy with hippocampal sclerosis.
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PMID:Anomalous expression of chloride transporters in the sclerosed hippocampus of mesial temporal lobe epilepsy patients. 2520


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