Biomedical subjects
Publications and source records attributed to I Jacobson.
For high sensitivity analysis of neuroactive amino acids, liquid chromatography employing precolumn derivatisation with o-phthalaldehyde (OPA) is suitable for several reasons. The OPA reagent is non-fluorescent per se, the reaction occurs rapidly in alkaline aqueous solutions and forms highly fluorescent derivatives with primary amines.
The effects of severe hypoglycemia on perforant path-evoked field potentials were examined in the rat hippocampus. Although a complete loss of this response was noted when blood glucose concentration fell below 1 mM, this occurred before cessation of electroencephalogram (EEG) activity. Both spontaneous and evoked responses recovered partially following glucose readministration. D-2-Amino-5-phosphonovalerate, an NMDA-sensitive acidic amino acid receptor antagonist, facilitated this recovery from the hypoglycemic challenge when administered via a dialysis probe.
Extracellular (EC) adenosine, hypoxanthine, xanthine, and inosine concentrations were monitored in vivo in the striatum during steady state, 15 min of complete brain ischemia, and 4 h of reflow and compared with purine and nucleotide levels in the tissue. Ischemia was induced by three-vessel occlusion combined with hypotension (50 mm Hg) in male Sprague-Dawley rats. EC purines were sampled by microdialysis, and tissue adenine nucleotides and purine catabolites were extracted from the in situ frozen brain at the end of the experiment. ATP, ADP, and AMP were analyzed with enzymatic fluorometric techniques, and adenosine, hypoxanthine, xanthine, and inosine with a modified HPLC system. Ischemia depleted tissue ATP, whereas AMP, adenosine, hypoxanthine, and inosine accumulated. In parallel, adenosine, hypoxanthine, and inosine levels increased in the EC compartment. Adenosine reached an EC concentration of 40 microM after 15 min of ischemia. Levels of tissue nucleotides and purines normalized on reflow. However, xanthine levels increased transiently (sevenfold). In the EC compartment, adenosine, inosine, and hypoxanthine contents normalized slowly on reflow, whereas the xanthine content increased. The high EC levels of adenosine during ischemia may turn off spontaneous neuronal firing, counteract excitotoxicity, and inhibit ischemic calcium uptake, thereby exerting neuroprotective effects.
The effects of excitatory amino acid antagonists on extracellular field potentials in the olfactory bulb produced by lateral olfactory tract stimulation were analyzed in vivo. The two compounds tested, D-2-amino-5-phosphonovalerate and kynurenic acid, were administered by brain dialysis. Only kynurenic acid was able to effectively suppress the monosynaptic excitation of the major class of interneurons, the granule cells. This pharmacological profile suggests the involvement of non-NMDA receptors.
The effect of ouabain on extracellular amino acid levels was investigated in the rabbit olfactory bulb using brain dialysis. Extracellular field potentials, elicited by stimulation of the lateral olfactory tract (LOT), were recorded simultaneously. Ouabain (100 microM) induced a rapid increase in extracellular aspartate, glutamate and gamma-aminobutyric acid. LOT-evoked potentials changed concomitantly, suggesting a neuronal depolarization.
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The effects of excitatory amino acid antagonists on extracellular field potentials in the olfactory bulb produced by lateral olfactory tract stimulation were analysed in vivo. The compounds tested D-2-amino-5-phosphonovalerate, L-(+)2-amino-4-phosphonobutyrate, gamma-D-glutamylglycine, L-glutamic acid diethylester and cis-2,3-piperidine dicarboxylic acid, were administered by brain dialysis. Of the compounds tested, only cis-2,3 piperidine-dicarboxylic acid and gamma-D-glutamylglycine were able to suppress the synaptic excitation of granule cells. This pharmacological profile suggests the involvement of non-N-methyl-D-aspartate receptors. However, the suppression was accompanied by a reduction in the amplitude of the presynaptic volley. A second finding was that D-2-amino-5-phosphono-valerate and gamma-D-glutamyl glycine attenuated granule cell mediated inhibition of mitral cells, suggesting the involvement of N-methyl-D-aspartate-sensitive receptors. The possibility that mitral cells and that either centrifugal fibres, or an intrinsic olfactory bulb feedback loop might use an excitatory amino acid as its neurotransmitter is therefore discussed.
Mongolian gerbils were exposed for 12 months to trichloroethylene (TCE) 50 or 150 ppm or perchloroethylene (PCE) 120 ppm. Vermis posterior of cerebellum and hippocampus were used for measurement of high-affinity uptake and release of 3H-gamma-aminobutyric acid (GABA) and 14C-glutamate, as well as for determination of total free tissue amino acids and glutathione. Glutathione was significantly elevated in the hippocampus of animals exposed to 150 ppm or TCE. Levels of amino acids were not appreciably affected. After PCE exposure, 120 ppm for 12 months, taurine significantly decreased in the hippocampus and even more in the posterior part of the cerebellar vermis. Glutamine was elevated in the hippocampus. No other significant changes in amino acids or glutathione were observed. After exposing the animals to TCE (50 and 150 ppm) for 12 months, the accumulation of glutamate by the posterior part of the cerebellar vermis increased in a dose-dependent manner, but no significant changes were observed in the hippocampus. The uptake of glutamate and GABA in cerebellum and hippocampus were unaffected after PCE exposure to 120 ppm for 12 months. The potassium-stimulated release of glutamate and GABA was unaffected in hippocampal tissue slices from gerbils exposed to 50 and 150 ppm TCE.
Extracellular amino acids were followed in the hippocampus during sustained seizures induced by systemic administration of kainic acid (KA) or bicuculline (BC). KA epilepsy was associated with marked increases in phosphoethanolamine (PEA) and taurine. Alanine and ethanolamine were moderately raised while other amino acids were unaffected. BC seizures encompassed a slightly different pattern of alterations. In contrast to KA seizures, BC epilepsy had no effect on taurine. Significant increments were observed for PEA and alanine while elevations of ethanolamine were subtle. In both types of seizures, glutamate and GABA remained unaffected extracellularly, probably due to efficient recapture mechanisms.
The effect of kainic acid (KA) on the extracellular content of amino acids in the rabbit olfactory bulb was investigated, both in vivo with the brain dialysis technique and in vitro with a superfused tissue slice preparation. Olfactory bulb EEG activity and lateral olfactory tract (LOT)-evoked field potentials were monitored simultaneously during dialysis experiments. KA induced a rapid (within 5 min) increase of extracellular aspartate, glutamate, GABA, phosphoethanolamine and taurine in vivo. LOT-evoked potentials were altered concomitantly in a concentration- and time-dependent manner. The antidromic invasion of mitral/tufted cells was depressed and the synaptic activation of granule cells was abolished in the presence of KA. Olfactory bulb EEG activity was also affected. Oscillatory bursts in olfactory bulb EEG were abolished by 10 mM in most experiments, whereas sustained oscillations were induced by 1 mM KA. The effects of KA may partly be due to a blockade of amino acid reuptake since dihydrokainate (DKA) perfusion was found to increase extracellular aspartate and glutamate. However, DKA had no significant effect on EEG or evoked potentials. In vitro, aspartate and glutamate were selectively increased during KA perfusion.
Brain ischemia was induced for 10 or 30 min by clamping the common carotid arteries in rabbits whose vertebral arteries had previously been electrocauterized. EEG and tissue content of high energy phosphates were used to verify the ischemic state and to evaluate the degree of postischemic recovery. Extracellular levels and total contents of amino acids were followed in the hippocampus during ischemia and 4 h of recirculation. At the end of a 30-min ischemic period, GABA had increased 250 times, glutamate 160 times, and aspartate and taurine 30 times in the extracellular phase. The levels returned to normal within 30 min of reflow. A delayed increase of extracellular phosphoethanolamine and ethanolamine peaked after 1-2 h of reflow. Ten minutes of ischemia elicited considerably smaller but similar effects. With respect to total amino acids in the hippocampus, glutamate and aspartate decreased to 30-50% of control while GABA appeared unaffected after 4 h of reflow. Alanine, valine, phenylalanine, leucine, and isoleucine increased severalfold. The importance of toxic extracellular levels of excitatory amino acids, as well as of high extracellular levels of inhibitory amino acids, are considered in relation to the pathophysiology of neuronal cell loss during cerebral ischemia.
We report the clinical presentation and management of 34 patients with a histologically proven chordoma, treated in the neurosurgical departments in Edinburgh and Dundee, over the past 50 years. Although these tumors are commonly regarded as being locally invasive with a variable, but generally slow growth rate, they can metastasize, and this may precede surgical intervention, as in one of our patients. Our cases are compared to those in previously published series, and a comprehensive review of the treatment modalities for tumors at various sites is presented. The optimal treatment to be recommended from our own experience, and that of others, is aggressive operation and radiotherapy. A combination of hyperthermia and chemotherapy has shown some promise, but remains untested, and highlights the need for a multicenter trial with long follow-up to allow the evaluation of new therapeutic approaches.
Free amino acids were studied in the olfactory bulb of the rabbit during basal conditions and veratridine-induced depolarization, in vitro with a tissue slice preparation and in vivo with a perfusion-dialysis technique. In vivo, basal extracellular concentrations of GABA, beta-alanine and aspartate were low, while glutamine showed the highest level. The basal steady-state concentration ratio between the total tissue pool of free amino acids and amino acids in the extracellular fluid was high for GABA, aspartate and glutamate, while low for glutamine and other 'non-transmitter' amino acids. Veratridine induced a marked TTX-sensitive release of GABA (40-50 times the control) both in vivo and in vitro. In vivo, the GABA release showed a peak during the first minutes of veratridine perfusion. The TTX-sensitive release of aspartate and glutamate, on the other hand, was approximately 5 times higher in vitro than in vivo. Furthermore, a prolonged response to veratridine was seen for glutamate and aspartate in vivo consisting of an early peak, followed by a sustained release. Taurine showed a time-delayed veratridine response, both in vivo and in vitro, whereas glutamine displayed a slow, TTX-sensitive decrease. No effect of veratridine was seen on beta-alanine or carnosine-threonine levels.
A case of medullary hemangioblastoma is described occurring in association with familial hyperparathyroidism. The possibility that this combination may represent a previously unreported variant of Lindau's disease is discussed.
All patients with chordomas that have been treated in the Dundee neurosurgical unit are reviewed. Five intracranial and two sacral chordomas have presented since the unit opened in 1966. Survival has ranged from one to fifteen years following treatment. The difficulties in diagnosis and in assessing treatment of these rare slow growing neoplasms are discussed.
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The chemically evoked efflux of endogenous amino acids from perfused rabbit superior colliculus (SC) slices was studied. Amino acids in the perfusates were determined fluorimetrically with a precolumn derivatisation method and subsequent separation on an HPLC column. Potassium-induced depolarisation caused a calcium-dependent release of beta-alanine, GABA, glutamate, and aspartate. Veratridine-evoked efflux was essentially similar in selectivity and could be blocked by tetrodotoxin (TTX). The results are indicative of a neurotransmitter role of beta-alanine, GABA, glutamate, and aspartate in the SC of the rabbit.