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1.
Neurotoxicology ; 25(3): 481-94, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15019311

ABSTRACT

The organophosphate cholinesterase (ChE) inhibitor paraoxon is the oxidized active metabolite of parathion, a pesticide whose use in agriculture has been matter of increasing concern. The present work was aimed at reproducing a prolonged exposure to low concentrations of paraoxon and assessing possible damage to the hippocampus during the period of most significant cholinergic development. Male Wistar rats were given, from P8 to P20, subcutaneous daily injections of paraoxon (0.1, 0.15 and 0.2mg/kg). The rate of body weight gain was reduced by all doses of paraoxon and brain ChE activity progressively decreased up to 60% by P21. Some deaths occurred in the beginning of the treatment, but the surviving animals showed neither convulsions nor overt signs of cholinergic hyperstimulation. Morphometric analysis of Lucifer Yellow-stained CA1 pyramidal neurons in coronal sections of the hippocampus showed that by P21 paraoxon caused a decrease in spine density on basal but not on secondary apical dendrites. The dendritic arborization and the pyramidal and granular cell body layers were not altered by paraoxon. ChE staining decreased in all hippocampal and dentate gyrus regions studied, whereas choline acetyltransferase (ChAT) and zinc-positive fibers remained as in control. In summary, chronic exposure to low paraoxon concentrations during the period of rapid brain development caused significant and selective decrease in basal dendritic spine density of the CA1 pyramidal neurons. Distinct modulation of the basal tree at the stratum oriens by the interplay of cholinergic afferent and GABAergic interneurons, as well as the remodeling process in response to a repetitive and rather mild paraoxon insult, may account for this selective susceptibility of basal dendritic spines. The hippocampal alterations described here occurred in the absence of toxic cholinergic signs and may affect brain development and cause functional deficits that could continue into adulthood.


Subject(s)
Dendrites/drug effects , Insecticides/administration & dosage , Paraoxon/administration & dosage , Pyramidal Cells/cytology , Pyramidal Cells/drug effects , Acetylcholinesterase/metabolism , Animals , Animals, Newborn , Cell Count/methods , Dendrites/physiology , Dose-Response Relationship, Drug , Environmental Exposure/adverse effects , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/enzymology , Male , Pyramidal Cells/enzymology , Rats , Rats, Wistar
2.
J Med Chem ; 46(7): 1144-52, 2003 Mar 27.
Article in English | MEDLINE | ID: mdl-12646025

ABSTRACT

A new family of tacrine (THA) analogues (7-9, 12), containing the azaheterocyclic pyrazolo[4,3-d]pyridine or pyrazolo[3,4-b][1,8]naphthyridine systems as isosteres of the quinoline ring of THA, has been synthesized. The compounds were tested in rat brain cholinesterases using Ellman's method, and all were fully efficacious in inhibiting the enzymes. Compounds 9 and 12b were the most potent against acetylcholinesterase (AChE), showing IC(50) of 6.0 and 6.4 microM, and were less active against rat brain butyrylcholinesterase, showing selectivity indexes of 5.3 and 20.9, respectively. Compounds 7-9 and 12 were also tested for their acute neurotoxicity in vitro, using cultured rat cortical cells. Compounds 7 and 8 were not significantly toxic; 9 was toxic at 500 microM, but not at 100 microM. The naphthyridine derivatives 12a and 12b showed a significant concentration-dependent neurotoxicity, being able to kill most cells at 500 microM. Molecular dynamic simulation using the X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new THA isosteres.


Subject(s)
Cholinesterase Inhibitors/chemical synthesis , Naphthyridines/chemical synthesis , Neuroprotective Agents/chemical synthesis , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Acetylcholinesterase/chemistry , Animals , Butyrylcholinesterase/chemistry , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/toxicity , Crystallography, X-Ray , Models, Molecular , Naphthyridines/chemistry , Naphthyridines/toxicity , Neuroprotective Agents/chemistry , Neuroprotective Agents/toxicity , Pyrazoles/chemistry , Pyrazoles/toxicity , Pyridines/chemistry , Pyridines/toxicity , Rats , Rats, Wistar , Structure-Activity Relationship , Torpedo
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