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Biomedical subjects

J W Olney

Publications and source records attributed to J W Olney.

At least 145 records · Page 8Linked to original sources
PubMed1982

Focal cortical seizures cause distant thalamic lesions.

Topical application of convulsants to the rat sensorimotor cortex in concentrations sufficient to cause repetitive focal motor seizures resulted in acute neuropathology (dark cell neuronal degeneration and spongiform neurophil changes) involving both the cortical seizure focus and certain thalamic nuclei within seizure pathways. Changes in the cortex were localized primarily in layer IV and those in the thalamus in nuclei having reciprocal connections with the cortical focus. The spongiform neuropil changes consisted of massively dilated presynaptic axon terminals in the cortex and postsynaptic dendrites in the thalamus. The dendritic and dark cell changes resemble the excitotoxic damage caused by glutamate and aspartate. Since these putative transmitters may be released locally from recurrent collaterals and remotely from corticothalamic axons, excessive release of glutamate or aspartate may account for the changes in both sites. The abnormal axons in sensory cortex appear to be terminals of thalamocortical neurons. Swelling of these axons may be caused by excessive anti- and orthodromic firing in the course of focal motor seizures.

Animals↗
PubMed1982

Naloxone blocks morphine enhancement of kainic acid neurotoxicity.

Kainic acid (KA) is a potent convulsant which, when administered subcutaneously, induces sustained limbic seizures and a pattern of limbic brain damage that is thought to be seizure-mediated. Diazepam suppresses and morphine enhances both the seizures and brain damage induced by KA. Here we show that morphine enhancement of KA neurotoxicity is blocked in a dose-dependent manner by subcutaneous pretreatment with naloxone. Theses and related findings support the hypothesis that morphine enhances the seizure-linked neurotoxicity of KA by an opiate specific action at certain limbic receptor sites where opiates suppress GABAergic activity, thereby lowering the threshold for propagation of seizure activity in limbic circuits.

Animals↗
PubMed1982

The toxic effects of glutamate and related compounds in the retina and the brain.

This paper has reviewed information pertaining to an interesting group of amino acids--glutamate, aspartate, and certain of their structural analogs, some of which are neurotransmitter candidates, and all of which have both neuroexcitatory and neurotoxic activities. Evidence for the excitotoxic concept, which holds that an excitatory and possibly synapse-related mechanism underlies the neurotoxicity of these compounds, is presented. Unlike a number of environmental neurotoxicants which induce toxic changes primarily in axons, these agents attack the dendrosomal portions of the neuron, which has led to their use as "axon-sparing" lesioning agents. When administered either systemically or by direct microinjection into the CNS, they delete intrinsic neurons from infiltrated regions without disturbing axons that are passing through or terminating therein. They are potentially useful tools, therefore, for studying anatomical pathways and structure-function relations in the CNS. The basis for their use as systemic investigational tools--that they have access from blood to the retina and specialized regions of brain, the circumventricular organs--is also the basis for considering them potentially hazardous for use as food additives or drugs. Ways in which the consumer may be exposed to these agents are considered and relevant mechanisms of risk are discussed.

Animals↗
PubMed1981

D-aminophosphonovalerate is 100-fold more powerful than D-alpha-aminoadipate in blocking N-methylaspartate neurotoxicity.

Here we report that the D-isomers of 2-amino-5-phosphonovalerate (D-APV) and alpha-amino-adipate (D-alpha AA) protect arcuate hypothalamic neurons from the potent excitotoxic activity of N-methylaspartate (NMA). Consistent with evidence that APV is much more powerful than alpha AA in antagonizing the neuroexcitatory activity of NMA, we found D-APV nearly 100 times more powerful than D-alpha AA in preventing NMA from destroying arcuate neurons.

2-Amino-5-phosphonovalerate↗
PubMed1981

Intrastriatal folic acid mimics the distant but not local brain damaging properties of kainic acid.

Folic acid (pteroyl-L-glutamine acid, PGA), when injected into the rat striatum, has the kainic acid (KA) property of inducing sustained seizures and a disseminated pattern of distant brain damage, but lacks the KA property of destroying neurons locally at the injection site. This suggests the interesting possibility that one component of KA neurotoxicity (seizure-related distant damage) may involve interaction with a folate system. Folates are promising tools for exploring the neurotoxic properties of KA and, more importantly, for studying mechanisms of epilepsy and epileptic brain damage.

Animals↗
PubMed1981

Uptake of exogenous glutamate and aspartate by circumventricular organs but not other regions of brain.

Glutamate (Glu) and aspartate (Asp) concentrations in blood and selected regions of brain were measured at sequential intervals over a 3-h period following subcutaneous administration of Glu, Asp, or Glu plus Asp (2 mg/g body wt) to 4-day old mouse or rat pups. Marked serum elevations of the administered amino acids (peak values exceeding 200 times control levels) were detected within 1 h. In circumventricular organ (CVO) regions of brain, which are thought to have no blood-brain barriers, a sharp and steady increase times higher than control levels) occurred during a 15-120 min interval, whereas no appreciable increase were detected in other brain regions. When 2 mg/g Glu plus 2 mg/g Asp were administered, CVO tissue concentrations of each amino acid rose to approximately the same level obtained when the individual amino acids were given. It is concluded that blood-brain barriers preventing net entry of Glu or Asp into brain proper are relatively well established by the 4th postnatal day in rodents, but that CVO brain regions lack such barriers; selective access of blood-borne Glu or Asp to CVO neurons explains why these neurons are selectively destroyed by systemic administration of these neurotoxic amino acids.

Animals↗
PubMed1981

Only certain anticonvulsants protect against kainate neurotoxicity.

Kainic acid (KA), a heterocyclic structural analog of the putative excitatory neurotransmitter, glutamate (Glu), powerfully mimics many of the neuroexcitatory and neurotoxic properties of Glu. KA differs from Glu and its straight chain "excitotoxic" analogs, however, in inducing a limbic seizure-brain damage syndrome when administered subcutaneously (12 mg/kg) to adult rats. This syndrome consists of sustained seizures, resembling amygdaloid kindled seizures, and acute destruction of neural elements in limbic brain regions (amygdala, olfactory cortex, hippocampus, lateral septum and several thalamic nuclei). Early changes consist of massive edematous swelling of glia and neuronal dendrites and either swelling or dark cell changes in neuronal somata, with subsequent necrosis of many of the neurons involved. Elsewhere we demonstrated that pretreatment with morphine markedly enhances both the convulsant and brain damaging actions of KA. Here we report that pretreatment with 2 anticonvulsants (diazepam or phenobarbital) markedly reduces both athe seizure and brain damaging actions of KA, whereas, two other anticonvulsants (phenytoin or valproic acid) fail to suppress either phenomenon. Our findings suggest that a seizure mechanism underlies much of the limbic brain damage induced by systemic KA and that the toxic mechanism may have two mutually reinforcing components--a glutamergic excitatory component and a GABAergic disinhibitory component.

Animals↗
PubMed1980

Stereospecificity of the gliotoxic and anti-neurotoxic actions of alpha-aminoadipate.

The glutamate (Glu) analog, DL-alpha-aminoadipate (DL-alpha AA), and the separate D and L isomers of alpha AA, were administered subcutaneously to infant mice and histopathological effects on the arcuate hypothalamic (AH) nucleus were studied. L-alpha AA induced striking gliotoxic and neurotoxic changes; D-alpha AA and DL-alpha AA respectively induced mild and extreme gliotoxic but not neurotoxic changes. The neurotoxicity of L-alpha AA is of interest in view of its known neuroexcitatory potential. The non-neurotoxicity of DL-alpha AA implies effective antagonism by D-alpha AA of the neurotoxicity of L-alpha AA, which is of interest in that D-alpha AA is recognized as an effective antagonist of amino acid excitants and is thought to block specifically at the excitatory receptor.

2-Aminoadipic Acid↗