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.

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.

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.

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.

Relief of bileduct obstruction by the percutaneous transhepatic insertion of an endoprosthesis.

Benign and malignant biliary strictures can be treated by the percutaneous transhepatic insertion of an endoprosthesis. We report the use of this technique in 44 patients, with a detailed description of the procedure. Insertion was successful in 41, three of whom later had elective surgery, and one, emergency laparotomy for biliary peritonitis.

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).

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.

Brain damage in mice from voluntary ingestion of glutamate and aspartate.

Previous studies have shown that the putative excitatory neurotransmitters and neurotoxins, glutamate (Glu) and aspartate (Asp), destroy neurons in the brains of various animal species when administered orally by feeding tube. It has been argued, however that Glu and Asp are safe for human use as food additives since tube feeding is not a natural means of oral intake and efforts to demonstrate the brain damage in animals from voluntary ingestion of Glu or Asp have yielded negative results thus far. Here we demonstrate that weanling mice will voluntarily ingest large enough volumes of aqueous solutions containing Glu or Asp (or both) to sustain conspicuous hypothalamic damage.

Non-surgical treatment of biliary obstruction.

Bileduct catheterisation percutaneously through the liver can be used in patients with obstructive jaundice as an adjunct or as an alternative to surgery. Preoperative drainage allows adequate treatment of severe cholangitis and reduces jaundice. Palliative drainage, whether internal or external, can be used instead of surgery.

Acute dendrotoxic changes in the hippocampus of kainate treated rats.

Kainic acid (KA), a potent neuroexcitatory and neurotoxic analog of glutamate (Glu), induces a widespread pattern of brain damage when administered subcutaneously to adult rats. The hippocampus is among the brain regions most consistently and severely damaged. Here we describe acute swelling of certain spines and branchlets of dendrites as the first detectable sign of KA neurotoxic changes in the hippocampus.

Minimal tissue concentrations of glutamate required to produce necrosis of hypothalamic neurons in newborn mice.

Groups of 4-day-old Cox Swiss albino mice were injected once subcutaneously with monosodium glutamate at several doses between 0.2 and 0.5 mg/g body weight.