Teruhisa Noguchi

Colchicine lesions in the rat hippocampus mimic the alterations of several markers in Alzheimer's disease

An infusion of colchicine into the hippocampi of rats resulted in destruction of hippocampal cells. Twelve days after infusion, preoperative trained colchicine-treated rats showed a significant decrease in choice accuracy in a T-maze learning task. There was also local reduction in choline acetyltransferase (ChAT) activity and significant losses of 55-kDa protein in the soluble fraction and of 50-kDa protein in myelin and synaptosomal fractions in the hippocampi of colchicine-lesioned rats. There was a marked increase in [3H]glutamate binding in the hippocampus and cortex. In contrast, [3H]quinuclidinyl benzilate binding in the hippocampus was slightly reduced, whereas [3H]dihydroalprenolol binding was not affected by the colchicine treatment. Scatchard analysis revealed that the increase in glutamate binding is due to an increase in the number of glutamate receptors without significant change in their affinity. Some of the changes caused by hippocampal infusion of colchicine resemble those seen in Alzheimers disease suggesting the use of such rats as one model for the disease.

Mutagenic, cytogenetic and teratogenic studies on thiophanate-methyl

Abstract Graded single doses of thiophanate-methyl (8–500 mg/kg) were injected ip into male mice, which were then mated with untreated females over a subsequent 8-week period. Thiophanate-methyl administered to male mice acutely produced no mutagenic effect in the dominant lethal assay, as measured directly by increased early fetal deaths or indirectly by increased preimplantation losses. In rats injected with this chemical there was no direct relation between dosage levels and percentage of spermatogonial and bone marrow cells showing chromosomal breaks. Thiophanate-methyl was given po (1000, 500 200 and 40 mg/kg/day) to pregnant mice from day 1 to day 15 of gestation. The highest dosage level effected a small difference in the number of living fetuses from the control group but the other groups dosed with 500 mg/kg/day or less presented no differences in implantation sites, number of living fetuses, body weight of living fetuses and number of dead fetuses from the control group. Investigation of cleared skeletons showed no significant difference in the incidence of malformations in all treated groups as compared to the control group. It is concluded that thiophanate-methyl did not exert significant mutagenic, cytogenic and teratogenic effects under the present experimental conditions.

Acute toxicity on dimethyl 4,4′-o-phenylene bis(3-thioallophanate), thiophanate-methyl fungicide

Abstract A new thiophanate-methyl fungicide, dimethyl 4,4′- o -phenylene bis(3-thioallophanate), was studied in a variety of species of animals. The toxicologic examination of the compound showed the acute toxicity of thiophanate-methyl to be low, and the species or sex variation in sensitivity also to be low. Thiophanate-methyl did not exhibit significant activity in any of the toxicologic tests utilized, including inhalation, subchronic dermal, cutaneous sensitization, contact phototoxicity and photosensitivity and acute toxicity to fish.

(6R)-5,6,7,8-Tetrahydro-l-biopterin modulates nitric oxide-associated soluble guanylate cyclase activity in the rat cerebellum

(6R)-5,6,7,8-Tetrahydro-L-biopterin (R-THBP) is a cofactor not only for aromatic amino acid hydroxylases in mammalian tissues but also for nitric oxide synthase (NOS) induced by endotoxins or cytokines in some kinds of cells. Recently it has been reported that nitric oxide (NO) has biological activity in endothelium and in brain as well. NO activates soluble guanylate cyclase (sGC). Superoxide reacts with NO easily and shortens the half-life of NO actions. We found, in a study using rat cerebellar cytosol fraction, that R-THBP itself did not directly activate sGC, but activated sGC at concentrations ranging from 0.1 to 10 microM only under NO generating conditions of activated NOS and in the presence of sodium nitroprusside. In addition, R-THBP (1 microM) did not alter the NOS activity, which was determined by L-citrulline formation. These results suggest that R-THBP may regulate sGC activity associated with NO formation in the central nervous system.

Some pharmacologic properties of a new fungicide thiophanate-methyl.

Abstract Thiophanate-methyl exhibited few general pharmacologic actions in various species of animals below the toxic dose, except for a weak sympathomimetic action, and a minute effect on the central and peripheral nervous system and various peripheral organs. Thiophanate-methyl also exhibited a slight hemolytic and anticoagulant activity. A decrease of about 20% in white cell count of rabbits treated with 1000 mg/kg of thiophanate-methyl was observed. No inhibition of cholinesterase activity was found.