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1.
Stroke ; 22(7): 915-21, 1991 Jul.
Article in English | MEDLINE | ID: mdl-1906647

ABSTRACT

Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 mg/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 83.29 +/- 0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p less than 0.001) in the high-dose dimethylthiourea group, 53.7% (p less than 0.001) in the low-dose MK-801 group, and 66.4% (p less than 0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Amino Acids/physiology , Brain Edema/etiology , Brain Ischemia/complications , Neurotoxins/physiology , Oxygen/physiology , Animals , Brain/metabolism , Dizocilpine Maleate/pharmacology , Drug Interactions , Free Radicals , Male , Potassium/metabolism , Rats , Rats, Inbred Strains , Sodium/metabolism , Thiourea/analogs & derivatives , Thiourea/pharmacology
2.
Article in English | MEDLINE | ID: mdl-1982481

ABSTRACT

Using a rat model of subdural haematoma which is associated with ischaemic damage in the ipsilateral hemisphere, we have measured cerebral blood flow and release of excitatory amino acids after the haematoma. A more than sevenfold rise in glutamate and aspartate, persisting for forty minutes occurred in the severely ischaemic cortex (CBF less than 5 ml 100 gm-1 min-1) and a threefold, sustained rise was seen in hippocampus, although CBF was preserved (85 ml/100 g/-1 min-1). Excitotoxic mechanisms may, therefore, be involved in the ischaemic damage associated with subdural haematoma.


Subject(s)
Extracellular Space/metabolism , Glutamates/metabolism , Hematoma, Subdural/metabolism , Acute Disease , Amino Acids/metabolism , Animals , Cerebrovascular Circulation , Dialysis/methods , Glutamic Acid , Neurotoxins/physiology , Osmolar Concentration , Rats , Rats, Inbred Strains , Time Factors
3.
Eur Neurol ; 30 Suppl 1: 21-30, 1990.
Article in English | MEDLINE | ID: mdl-1968832

ABSTRACT

Studies of the changes in brain neurotransmitter and neurotoxin receptors in Parkinson's disease now provide information about the state of many receptors. The status of dopamine receptors in the striatum, the possibility that specific neurotoxin receptors exist and the likelihood that receptors in other brain regions, including pathologically involved substantia nigra and cerebral cortex, can provide meaningful information about brain function and the disease are reviewed. Increasing information about these receptors is also available from molecular biological studies of dopamine receptors, and of genes encoding several of the putative candidate sites for possible neurotoxin action. Such approaches are providing an increasingly important perspective on Parkinson's disease therapeutics and possible pathogenesis.


Subject(s)
Neurotoxins/physiology , Neurotransmitter Agents/physiology , Parkinson Disease/physiopathology , Receptors, Cholinergic/physiology , Receptors, Neurotransmitter/physiology , Humans , Neurotoxins/genetics , Receptors, Cholinergic/genetics , Receptors, Neurotransmitter/genetics
4.
J Membr Biol ; 110(3): 199-207, 1989 Sep.
Article in English | MEDLINE | ID: mdl-2553976

ABSTRACT

The effects of scorpion and sea anemone polypeptide toxins on partially purified veratridine (VER)-activated Na channels from rat brain were studied at the single-channel level in planar lipid bilayers. The probability of the VER-activated channel being open (Po) increased with depolarization; Po was 0.5 at -40 to -50 mV. Saxitoxin (STX) blocked VER-activated channels with an apparent dissociation constant of about 1 nM at -45 mV. The apparent single-channel conductance was approximately 9 pS, similar to that seen in VER-activated Na channels from skeletal muscle transverse tubules. Addition of sea anemone or scorpion polypeptide toxins to VER-activated Na channels resulted in a 19% increase in apparent single-channel conductance and a hyperpolarizing shift in the Po vs. Vm relation such that the channels were more likely to be open at potentials less than 40 mV. These effects of the polypeptide toxins on the single-channel properties of VER-activated Na channels may account for the previously described potentiation of VER action by polypeptide toxins.


Subject(s)
Ion Channel Gating/physiology , Lipid Bilayers/metabolism , Neurotoxins/physiology , Sodium Channels/physiology , Veratridine/pharmacology , Veratrine/analogs & derivatives , Animals , Brain Chemistry , Electric Conductivity/physiology , Ion Channel Gating/drug effects , Membrane Lipids/analysis , Membrane Lipids/metabolism , Membrane Lipids/physiology , Membrane Potentials/physiology , Neurotoxins/pharmacology , Rats , Scorpions , Sea Anemones , Sodium Channels/drug effects , Sodium Channels/metabolism
6.
Int Arch Allergy Appl Immunol ; 88(1-2): 59-62, 1989.
Article in English | MEDLINE | ID: mdl-2651320

ABSTRACT

The likely roles of the eosinophil leukocyte in human disease are reviewed. The eosinophil is richly endowed with toxic cationic proteins and is able to mount a respiratory burst. Thus, eosinophils have the capability to damage various targets, and evidence exists that they do so during helminth infections and during the course of many hypersensitivity diseases. Here we discuss the role of the eosinophil in human onchocerciasis with particular attention to the Mazzotti reaction. We also discuss other diseases where eosinophil degranulation is seen, especially cutaneous diseases. Finally, the possible role(s) of the granule major basic protein in human pregnancy is noted.


Subject(s)
Eosinophils/physiology , Onchocerciasis/immunology , Ribonucleases , Animals , Blood Proteins/physiology , Cytoplasmic Granules/physiology , Eosinophil Granule Proteins , Eosinophil Peroxidase , Exocytosis , Female , Humans , Inflammation/physiopathology , Neurotoxins/physiology , Onchocerca , Peroxidases/physiology , Pregnancy/immunology
10.
Neurology ; 35(4): 589-92, 1985 Apr.
Article in English | MEDLINE | ID: mdl-3982652

ABSTRACT

A 27-year-old man was bitten by a coral snake in Mexico. Within 24 hours he had ptosis, dysphonia, difficulty chewing, and limb weakness. His symptoms peaked at 72 hours with loss of ambulation. Neurologic examination was consistent with severe myasthenia. Repetitive stimulation of the median nerve showed a postsynaptic defect that was not corrected by edrophonium. He was monitored in an intensive care unit, but received no antivenom globulin or acetylcholinesterase inhibitors. The syndrome abated in 3 weeks.


Subject(s)
Nervous System Diseases/etiology , Snake Bites/complications , Adult , Humans , Male , Nervous System Diseases/metabolism , Neurotoxins/physiology , Snake Bites/metabolism , Snake Venoms/physiology
11.
Acta Neuropathol ; 67(3-4): 279-88, 1985.
Article in English | MEDLINE | ID: mdl-4050343

ABSTRACT

A detailed light- and electron-microscopic study of the damage to the rat dentate gyrus in hypoglycemia was undertaken, in view of the previously advanced hypothesis that hypoglycemic nerve cell injury is mediated by a released neurotoxin. The distribution of neuronal necrosis showed a relationship to the subarachnoid cisterns. Electron microscopy of the dentate granule cells and their apical dendrites revealed dendrosomal, axon-sparing neuronal pathology. Dentate granule cells were affected first in the dendrites in the outer layer of the stratum moleculare, sparing axons of passage and terminal boutons. Subsequently, the neuronal perikarya were affected, and Wallerian degeneration of axons followed. Cell membrane abnormalities preceded the appearance of mitochondrial flocculent densities and degradation of the cytoskeleton, and are suggested to be early lethal changes. The observed early dendrotoxic changes, and the dendrosomal, axon-sparing nature of the lesion implicate an excitotoxin-mediated neuronal necrosis in hypoglycemia.


Subject(s)
Hippocampus/pathology , Hypoglycemia/pathology , Neurons/pathology , Neurotoxins/physiology , Animals , Hippocampus/ultrastructure , Male , Microscopy, Electron , Necrosis , Neurons/ultrastructure , Rats , Rats, Inbred Strains
12.
J Immunol ; 133(4): 2180-5, 1984 Oct.
Article in English | MEDLINE | ID: mdl-6206154

ABSTRACT

Major basic protein (MBP), an arginine-rich basic polypeptide that constitutes the crystalloid core of the large specific eosinophil granule, has previously been shown to stimulate noncytolytic histamine release from human basophils and rat mast cells by an IgE-independent mechanism. Two additional basic polypeptides present in eosinophil granules, eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN), were examined for similar activity in the present study. Acid-solubilized eosinophil granules were fractionated by chromatography on a Sephadex G-50 column. Incubation of basophil-containing human mononuclear cells with the individual column fractions demonstrated that histamine release occurred only with the fractions that contained MBP. The selectivity of the basophil response for MBP was confirmed by using equimolar concentrations of purified MBP, ECP, and EDN. In contrast, both MBP and ECP, but not EDN, stimulated histamine release from purified rat peritoneal mast cells. Reduction and alkylation of the MBP molecule diminished the response of human basophils to MBP but enhanced the potency of the molecule with rat mast cells. The distinct potency of MBP as a stimulus for histamine secretion from human basophils suggests that eosinophil release of MBP may be a specific event in the augmentation of immediate hypersensitivity reactions and other disorders characterized by eosinophilia.


Subject(s)
Basophils/immunology , Blood Proteins/physiology , Histamine Release , Mast Cells/immunology , Ribonucleases , Animals , Chromatography, Gel , Cytoplasmic Granules/analysis , Eosinophil Granule Proteins , Eosinophils/analysis , Humans , Male , Neurotoxins/physiology , Rats , Rats, Inbred Strains
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