Search PubMed⌕ Search

Biomedical subjects

J W Olney

Publications and source records attributed to J W Olney.

At least 127 records · Page 7Linked to original sources
PubMed1986

The anti-excitotoxic effects of certain anesthetics, analgesics and sedative-hypnotics.

Various agents were tested for their ability to antagonize the acute excitotoxic action of N-methyl-DL-aspartate (NMA) and kainic acid (KA) on neurons in the in vitro chick embryo retina. The following compounds (in order of descending potencies) were effective in completely blocking the neurotoxic activity of NMA: phencyclidine, ketamine, (+/-)-SKF 10,047, pentazocine, D-aminophosphonovalerate, D-amino-phosphonoheptanoate, D-alpha-aminoadipate, OH-quinoxaline carboxylate, kynurenate, (+/-)-cis-2,3-piperidine dicarboxylate, secobarbital, amobarbital and pentobarbital. The latter 6 agents also protected against KA toxicity but complete protection was observed only from relatively high concentrations. At 20 mM, Mg2+ blocked NMA toxicity but at concentrations up to 30 mM did not block KA toxicity. Compounds that failed to block either NMA or KA toxicity include D- and L-aminophosphonobutyrate, L-glutamic acid diethyl ester, xanthurenate, GABA and taurine. The chick embryo retina is a useful preparation for identifying agents that have either excitotoxic or anti-excitotoxic activity.

Analgesics↗
PubMed1986

Components of hypothalamic obesity: bipiperidyl-mustard lesions add hyperphagia to monosodium glutamate-induced hyperinsulinemia.

Rats with bilateral electrolytic lesions in the general region of the ventromedial hypothalamic (VMH) nucleus develop hyperinsulinemia, excessive food intake and obesity. Monosodium glutamate (MSG) destroys neurons of the arcuate hypothalamic (AH) nucleus and produces hyperinsulinemic but hypophagic obesity. Bipiperidyl mustard (BPM) primarily destroys VMH neurons, but has produced only a slight obesity even when rats were maintained on high-fat diets. In the present study, rats treated with MSG (AH lesion) were hyperinsulinemic, moderately obese and hypophagic; BPM rats (primarily VMH lesion) were not different from controls when fed standard chow diets. However, MSG/BPM rats (AH + VMH lesion) were hyperinsulinemic, massively obese and hyperphagic. Thus, two components of the electrolytic lesion syndrome previously attributed to VMH damage (hyperinsulinemia and obesity) were reproduced simply by MSG treatment alone. The third component (hyperphagia) occurred only when both AH and VMH were lesioned, suggesting that neurons in both nuclei may perform a satiety function and may be able to substitute for one another in this respect. Since MSG treatment is required for all components of both obesity syndromes described here, this underscores the importance of MSG-sensitive neurons in mechanisms of obesity. The combined treatment approach also represents the first rat model of hyperinsulinemic, hyperphagic obesity that can be entirely produced by systemic administration of neurotoxins.

Animals↗
PubMed1986

The role of specific ions in glutamate neurotoxicity.

When the chick embryo retina is incubated in balanced salt solution containing glutamate (Glu) in 1 mM concentration, a neurodegenerative reaction occurs within 30 min. Here we report that the neurotoxic action of Glu on retinal neurons is dependent on the presence of Na+ and Cl-, but not Ca2+, in the incubation medium. Also, we report that depolarizing concentrations of K+ can induce a severe cytotoxic reaction in chick retina which, like the depolarization-linked neurotoxicity of Glu, is a Cl- dependent phenomenon.

Animals↗
PubMed1986

N-methylaspartate: an effective tool for lesioning basal forebrain cholinergic neurons of the rat.

The ability of the excitotoxin, N-methyl-D,L-aspartic acid (NMA), to destroy basal forebrain cholinergic (BFC) neurons was evaluated. NMA (100 nmol) was directly injected into the peripallidum, a region containing a proportionately large number of cortically-projecting BFC neurons. Cholineacetyltransferase (ChAT) activity 10 days later was markedly and significantly reduced (up to 62%) in the cortex ipsilateral to the lesion. NMA induced a focal lesion affecting BFC neurons without damaging axons of passage or causing lesions distant from the site of injection. ChAT immunohistochemistry (IHC) was used to directly demonstrate loss of ChAT-positive neurons from the lesion site. This loss persisted at all survival times examined, from 2 days to 7.5 months post-injection.

Animals↗
PubMed1986

Increase in hypothalamic cholecystokinin following acute and chronic morphine.

Recent evidence supports an antagonistic interaction between cholecystokinin (CCK) and opiate peptides. The present study determined the effects of various levels of morphine treatment on hypothalamic levels of CCK as determined by radioimmunoassay. Acute treatment with morphine sulfate (10 mg/kg) or implantation of one morphine pellet (75 mg free base) increased levels of CCK in whole hypothalamus. Increased exposure to morphine by either chronic injections or implantation of two pellets did not result in a further change in whole hypothalamic CCK levels. In samples dissected into hypothalamic subregions, the effect of morphine on CCK levels was localized to medial but not lateral or posterior regions. These experiments extend earlier in vitro findings and suggest that some of the physiological and behavioral effects of opiate peptides may result from modulation of endogenous CCK.

Animals↗
PubMed1986

Glutamate and the pathophysiology of hypoxic--ischemic brain damage.

Information obtained over the past 25 years indicates that the amino acid glutamate functions as a fast excitatory transmitter in the mammalian brain. Studies completed during the last 15 years have also demonstrated that glutamate is a powerful neurotoxin, capable of killing neurons in the central nervous system when its extracellular concentration is sufficiently high. Recent experiments in a variety of preparations have shown that either blockade of synaptic transmission or the specific antagonism of postsynaptic glutamate receptors greatly diminishes the sensitivity of central neurons to hypoxia and ischemia. These experiments suggest that glutamate plays a key role in ischemic brain damage, and that drugs which decrease the accumulation of glutamate or block its postsynaptic effects may be a rational therapy for stroke.

Animals↗
PubMed1986

Inciting excitotoxic cytocide among central neurons.

Here I have reviewed evidence from electron microscopic studies showing that each of several sustained limbic seizure syndromes is associated with a type of acute brain damage which is ultrastructurally indistinguishable from the brain damage induced by Glu and other excitotoxins. In addition, I have presented evidence that persistent stimulation of specific axonal tracts that use Glu as transmitter results in Glu-like excitotoxic degeneration of postsynaptic neurons innervated by such tracts. Phencyclidine and ketamine, which powerfully block the neurotoxicity of the Glu analog NMA, protect against seizure-related brain damage. This may be explained by either an anticonvulsant or antiexcitotoxic mechanism, or both. Recent evidence suggests that an excitotoxic mechanism (excessive activation of Glu/Asp receptors) may underlie both seizure-mediated and anoxic brain damage. The acute fulminating type of neuronal degeneration induced by Glu is a Na+ and Cl- but not Ca2+ dependent phenomenon. According to a recent study, however, Glu may induce neuronal necrosis not only by an acute Ca2+ independent process but by a more slowly evolving Ca2+ dependent process. If, as these data suggest, an excitotoxic mechanism underlies brain damage associated with anoxia and epilepsy, a better understanding of excitotoxic mechanisms may lead eventually to prophylactic approaches for preventing such forms of brain damage.

Action Potentials↗
PubMed1986

Further characterization of the extra-arcuate alpha-melanocyte stimulating hormone-like material in hypothalamus: biochemical and anatomical studies.

Previous studies had shown the existence of an extra-arcuate cell group in lateral hypothalamus which contains alpha-melanocyte stimulating hormone (a-MSH)-like immunoreactivity, but no other pro-opiomelanocortin (POMC) immunoreactivity. The question we have attempted to address in this series of studies is whether the material is indeed a-MSH or a cross-reacting material. Chromatographic studies failed to detect any material which is different from a-MSH or des-acetyl-a-MSH, suggesting that either the material is authentic a-MSH/des-acetyl-a-MSH, or that it is not detected by our RIAs. A series of manipulations including dissections of arcuate vs. extra-arcuate hypothalamic areas, treatment with colchicine, lesions with monosodium glutamate and knife cuts were aimed at isolating the extra-arcuate region and showing that it contains an excess of a-MSH over beta-endorphin (B-END), presumably deriving from the extra-arcuate group. However, all studies showed parallel changes in a-MSH and B-END, suggesting that we were not detecting a non-POMC derived a-MSH in these studies. This led to the tentative conclusion that the material was not a-MSH and was not being detected by our RIA's. This hypothesis was tested by further characterizing the material immunohistochemically. These studies led to the conclusion that the extra-arcuate material had a carboxy-terminal homology with a-MSH but differed from it in the midregion, since antisera directed at the 4-10 region of a-MSH failed to stain this non-POMC cell group. Finally, the anatomy of this extra-arcuate group is described, particularly the projections to the striatum, hippocampus, neocortex and olfactory bulb.

Animals↗
PubMed1986

Excitotoxic mechanisms of epileptic brain damage.

It is well established that the putative excitatory neurotransmitters, glutamate (Glu) and aspartate (Asp), are neurotoxins that have the potential of destroying central neurons by an excitatory mechanism. Kainic acid (KA), a rigid structural analog of Glu, powerfully reproduces the excitatory neurotoxic (excitotoxic) action of Glu on central neurons and, in addition, causes sustained limbic seizures and a pattern of seizure-linked brain damage in rats that closely resembles that observed in human epilepsy. In the course of studying the seizure-related brain damage syndrome induced by KA, we observed that a similar type of brain damage occurs as a consequence of sustained seizure activity induced by any of a variety of methods. These included intraamygdaloid or supradural administration of known convulsants such as bicuculline, picrotoxin and folic acid, or systemic administration of lithium and cholinergic agonists or cholinesterase inhibitors that have not commonly been viewed as convulsants. We have further observed that this type of brain damage can be reproduced in the hippocampus by persistent electrical stimulation of the perforant path, a major excitatory input to the hippocampus that is thought to use Glu as transmitter. It is a common feature of all such neurotoxic processes that the acute cytopathology resembles the excitotoxic type of damage induced by Glu or Asp, which is acute swelling of dendrites and vacuolar degeneration of neuronal soma, without acute changes in axons or axon terminals. We have found that the seizure-brain damage syndrome induced by cholinergic agents can be prevented by pretreatment with atropine and that the syndrome induced by any of the above methods, cholinergic or noncholinergic, can be either prevented or aborted respectively by either pre-or posttreatment with diazepam. Our findings in experimental animals may be summarized in terms of their potential relevance to human epilepsy as follows. Sustained complex partial seizure activity consistently results in cellular damage if allowed to continue for longer than 1 hr. Hippocampal, or Ammon's horn, sclerosis is the primary pathological result. It may be a priority goal, therefore, in the management of human epilepsy to control such seizure activity within very narrow limits. This proposal is discussed in terms of three major transmitter systems that may be involved; cholinergic, GABAergic, and glutamergic/aspartergic. The cholinergic system may play a role in generating or maintaining this type of seizure activity, and anticholinergics may protect against it provided they are given prior to commencement of behavioral seizures.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Topical↗
PubMed1985

Calcium influx accompanies but does not cause excitotoxin-induced neuronal necrosis in retina.

Several authors have recently proposed that excessive calcium (Ca++) influx into postsynaptic cells may be the mechanism by which excitotoxins such as glutamate (Glu), N-methylaspartate (NMA) and kainic acid (KA) cause neuronal necrosis. Here we have undertaken both in vivo and in vitro studies to explore this hypothesis. Our findings indicate that Ca++ does accumulate selectively in neural elements undergoing degeneration in the in vivo mouse hypothalamus following subcutaneous administration of NMA. However, pretreatment with the putative Ca++ channel blocker nimodipine resulted in augmentation rather than suppression of the toxic action of NMA and Glu on the mouse hypothalamus and eliminating Ca++ from the incubation medium did not interfere with the toxic action of Glu, NMA or KA on the chick embryo retina in vitro. We conclude, therefore, that Ca++ influx is an unlikely explanation for excitotoxin-induced degeneration of retinal or hypothalamic neurons.

Animals↗
PubMed1984

Morphine analgesia potentiated but tolerance not affected by active immunization against cholecystokinin.

Administration of cholecystokinin was recently found to attenuate opiate analgesia. In the present study, the role of endogenous cholecystokinin in opiate analgesia was examined. Endogenously released cholecystokinin was sequestered by antibodies to cholecystokinin developed in response to an active immunization procedure. Morphine analgesia was potentiated and prolonged in rats immunized against cholecystokinin. The rate of development of morphine tolerance, however, was not affected by the antibodies. Endogenous cholecystokinin appears to function as a short-term modulator of opiate action.

Animals↗
PubMed1984

Uptake of exogenous aspartate into circumventricular organs but not other regions of adult mouse brain.

Adult mice were treated intraperitoneally with aspartate (Asp) at one of several doses (0.47-3.75 mmol/kg) and 30 min later given a subcutaneous Asp injection at the same dose. This treatment regimen resulted in steady state blood Asp elevations, a given dose producing the same degree of elevation at both 30 and 60 min. The lowest and highest doses, respectively, produced four-fold and 55-fold elevations of serum Asp. In selected circumventricular organ (CVO) regions of brain which lack blood brain barriers, tissue Asp levels rose 1.5 and 3 times above control values following the lowest and highest doses, respectively, whereas tissue Asp remained unchanged in non-CVO brain regions. Thus, even very moderate Asp dosing causes marked increases in CVO Asp. In order to analyze the pattern of Asp uptake into CVO, Asp was assayed in numerous subdivisions of each CVO, and maps were constructed which reflected microregional concentration differences. The pattern of Asp distribution suggests that Asp enters brain via fenestrated capillaries serving certain portions of CVO and then spreads into adjacent brain tissue. In separate experiments, we administered a single high dose of Asp (15 mmol/kg) to both adult and infant mice and measured Asp in serum and select brain regions 60 min later. Asp concentrations in serum and CVO (but not other brain regions) rose markedly at both ages but the increases were greater in serum and therefore also in CVO of infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1983

Neuroactive amino acids influence gonadotrophin output by a suprapituitary mechanism in either rodents or primates.

Systemic administration of excitatory amino acids (Glu or NMA) rapidly enhances LH release (rodents or primates) and GABA blocks this action (rodents). In the present study rodent and primate pituitaries were incubated with NMA, Glu and/or GABA, with or without added LH-RH. Only LH-RH affected LH release. Therefore the probable site of NMA, Glu or GABA action on LH release in both rodents and primates is suprapituitary.

Amino Acids↗
PubMed1983

Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats.

Administration of pilocarpine or physostigmine to rats treated with lithium chloride produced sustained limbic seizures, widespread brain damage, and increased concentrations of D-myo-inositol-1-phosphate (a metabolite of the phosphoinositides, lipids involved in membrane receptor function) in the brain. The syndrome was preventable with atropine. The physostigmine doses and concentrations of blood lithium that caused the syndrome are similar to those considered appropriate for psychiatric chemotherapy.

Animals↗
PubMed1983

Seizure-related brain damage induced by cholinergic agents.

Distinctive acute brain damage involving limbic and related brain regions develops in adult rats following sustained limbic seizures induced by systemic administration of kainic acid or dipiperidinoethane (DPE) or by intra-amygdaloid injection of kainic acid or folic acid. This seizure-brain damage (S-BD) syndrome is of particular interest because it tends to parallel the type of seizures and brain damage seen in human temporal lobe epilepsy. We have observed that DPE induces the S-BD syndrome by systemic but not intra-mygdaloid injection, whereas an oxidized DPE derivative which structurally resembles the cholinergic agonist oxotremorine is effective when injected into the amygdala. Prompted by this finding, we injected known acetylcholine (ACh) agonists and cholinesterase (ChE) inhibitors into the rat amygdala and found that either class of agent reproduces this type of S-BD syndrome. These and related findings suggest that ACh mechanisms might have a more important role in human epilepsy and epileptic brain damage than has generally been appreciated.

Acetylcholine↗
PubMed1983

"Epileptic" brain damage in rats induced by sustained electrical stimulation of the perforant path. II. Ultrastructural analysis of acute hippocampal pathology.

Sustained electrical stimulation of the perforant path evokes granule cell population spikes and epileptiform discharges, abolishes recurrent inhibition in the granule cell layer and induces a reproducible pattern of hippocampal damage (see preceding paper, this volume, for electrophysiological and light microscopic findings). Electron microscopic findings described here reveal that the hippocampal damage is identical in pattern and cytopathological detail to that associated with sustained limbic seizures induced by chemical convulsants such as kainic acid, folic acid and dipiperidinoethane. Acutely swollen dendritic segments distributed in a laminar pattern corresponding closely with the termination of putative glutamate or aspartate-containing fibers, including those of the perforant path, were a conspicuous finding. Cell bodies of CA1 and CA3 pyramidal neurons and various interneurons in the hilus and elsewhere displayed degenerative changes ranging from mild to severe. Both the dendritic and somal degenerative changes closely resemble the "excitotoxic" type of damage that the putative transmitters glutamate and aspartate are known to cause. It is proposed, therefore, that sustained electrical stimulation of the perforant path results in excessive synaptic release and accumulation of glutamate (or aspartate) at numerous dendrosomal receptors in the hippocampus with consequent degeneration of the dendrosomal structures housing these receptors. Early excitotoxic effects on interneurons that mediate recurrent inhibition may play an important role in the observed loss of recurrent inhibition and in the evolution of subsequent excitotoxic degeneration in the hippocampus.

Afferent Pathways↗