Cognitive impairment in old rats: a comparison of object displacement, object recognition and water maze.

The behavioral performance of young and aged rats was studied in a repeated-trials test. Young animals reacted to both spatial displacement and novelty, whereas most aged rats lost the ability to react to novelty although maintaining spatial memory. The cluster analysis procedure performed on all the tested subjects enabled the recognition of a consistent group of the aged sample (35%) with a mild degree of spatial and non-spatial memory impairment. Spatial memory impairment of some of the aged animals was also evaluated in the Morris water maze test. On the fifth day of the task, we observed a very low percentage of impaired aged animals, which partially corresponded to the impaired group identified by the object recognition test. In contrast, the subgroup of mildly impaired rats performed similarly to the young animals. We advance that the Morris water maze might represent a stressful experimental condition for aged rats, enhancing the motivational level of animals subjected to this procedure. This condition may alter the cognitive responses. As a consequence, the "mildly impaired" rats, which may be considered an interesting group for investigating memory-enhancing drugs, will infrequently be recognized with the Morris water maze test. Cognitive impairment in aged rats should be studied utilizing a sensitive test in which motivation does not substantially influence the results of the test.

Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT2A and alpha1 receptor binding affinity.

A series of triazolopyridine derivatives (compounds 2a-l) were synthesized in order to explore the effect of modifications of the alkylpiperazine moiety of trazodone (fragment A) on binding affinity for 5HT2A and alpha1 receptors. All of the synthesized compounds show a decrease of affinity for both 5HT2A and alpha1 receptors, as compared to trazodone, with the exception of compounds 2b,c which bear a methyl group in an alpha position to the aliphatic nitrogen atom N1. These compounds showed a decrease of affinity only for the alpha1 receptor. The stereochemical influence of the piperazine moiety of compound 2c was also evaluated. Enantiomer (S)-2c showed the most significant differences between 5HT2A and alpha1 receptor affinity (IC50 values) and among the corresponding functional properties (pA2 values). Since (S)-2c cannot generate the metabolite 4-(3-chlorophenyl)piperazine this product was selected for further pharmacological studies.

Effect of the subchronic treatment with the acetylcholinesterase inhibitor heptastigmine on central cholinergic transmission and memory impairment in aged rats.

The effect of subchronic administration of the acetylcholinesterase (AChE) inhibitor heptastigmine (HEP 0.6 mg/kg s.c. daily for 15 days) was investigated on cortical extracellular acetylcholine (ACh) levels and on memory function in aged male rats (26 months old at the beginning of the experiments) using microdialysis and behavioural techniques. Twenty-four hours after the last treatment, cortical ACh levels were significantly higher in rats subchronically treated with HEP than in rats treated with saline and AChE activity was still inhibited in cortex, hippocampus and striatum. The injection of a challenge dose of HEP (0.6 mg/kg s.c.) 24 h after the last treatment produced a faster and a more sustained increase of ACh in the cortex of subchronically treated rats compared to those repeatedly injected with saline. However, the maximum increase of ACh levels after injection of the challenge was comparable in both groups. In an object recognition test in which the pretest and test phase were spaced by 45 days, HEP prevented the deterioration of spatial memory occurring during this period, but had no effect on non-spatial memory. The present results suggest that moderate inhibition of brain AChE is able to maintain high levels of cortical extracellular ACh in aged rats and that this increase matches facilitatory effect of HEP on spatial memory.

Pivagabine: a novel psychoactive drug.

Pivagabine (4-[(2,2-dimethyl-1-oxopropyl)amino]butanoic acid, CAS 69542-93-4, Tonerg) is a metabolically stable compound with a modulatory effect on some biochemical parameters involved in stress conditions (corticotropin releasing factor, neurosteroids). The compound, tested in several animal models, prevents stress-correlated behavioural deficits. Moreover, pivagabine has a highly significant therapeutic potential in clinical conditions characterized by manifestations of psychological distress due to an inadequate management of stressful events.

Abnormal glycosylation of hemopexin in arthritic rats can be blocked by bindarit.

Induction of arthritis in rats with Freund's complete adjuvant was accompanied by a distinctive alteration of concanavalin A (Con-A) reactivity in their serum proteins in which the concentrations of selected Con-A reactive proteins were significantly higher when compared to healthy rats. To assess if the observed increase in Con-A reactivity of specific serum proteins reflects an increase in carbohydrate moieties in these proteins in addition to an increase in their protein concentrations, a heme binding serum glycoprotein, hemopexin, also an acute phase reactant, was selected as a marker protein. Hemopexin was purified to apparent homogeneity from pools of serum samples derived from rats with yeast induced inflammation, a monospecific polyclonal antibody was prepared and was used for immunoblot analysis. It was noted that the concentration of hemopexin increased in rats with adjuvant induced arthritis; however, its concentration fell to normal levels after administration with a newly synthesized drug, bindarit, (2-[(1-benzyl-indazol-3-yl)methoxy]-2-methyl propionic acid, C19H20N2O3. Hemopexin was micropurified individually from healthy rats, adjuvant induced arthritic rats, and adjuvant arthritic rats treated with bindarit, cleaved with a Glu-C endopeptidase, Staphylococcus aureus protease V8, and the resultant peptide fragments resolved by SDS-PAGE and examined by silver staining, Coomassie blue staining, and lectin blots using Con-A. It was subsequently noted that hemopexin isolated from adjuvant induced arthritic rats showed a significant increase in Con-A reactivity in selected peptide fragments and that such an increase in glycosylation could be reversed to a pattern similar to healthy rats following treatment with bindarit.(ABSTRACT TRUNCATED AT 250 WORDS)

A new protein antidenaturant agent, bindarit, reduces secondary phase of adjuvant arthritis in rats.

Bindarit (or 2-[(1-benzyl-indazol-3-yl)methoxy]-2-methyl propionic acid) reduces heat induced denaturation of bovine and rat serum albumin in vitro (EC50 = 8.5 and 65 micrograms/ml, respectively) and inhibits heat induced serum albumin denaturation after in vivo (12.5-25-50 mg/kg po) administration in rats. To assess the relationship between protein denaturation and the development of chronic inflammatory diseases, the drug (0.5 or 0.12% medicated diet) was studied in comparison with indomethacin (1 mg/kg po daily) in rats injected with complete Freund's adjuvant. Bindarit appeared different from aspirin-like drugs, antiinflammatory steroids and immunosuppressants because it does not reduce primary inflammation of arthritic rats and was shown to be completely inactive on cyclo and lipooxygenase activity in vitro and on immune reactions of mice in vivo. Nevertheless, the drug strongly reduced the development of the secondary phase of adjuvant induced arthritis. The most significant effect of bindarit in this phase was a strong inhibition of serum albumin denaturation in arthritic rats. Assessment of both electrophoretic and quantitative changes suggests that the reduction of albumin during inflammation is due, at least in part, to a denaturation of native albumin, which loses its electrophoretic mobility. The involvement of protein denaturation in the production of new antigenic determinants, their pathogenic relevance in the development of adjuvant arthritis and the possibility that protein stabilization by bindarit could be the mechanism of action of the drug are discussed.

Effects of benzydamine eye drops on the rabbit's eye reaction to surgical, physical, and chemical stimuli.

The effects of benzydamine eye drops on the ocular reaction to different irritating stimuli in rabbits are reported. Benzydamine at the concentration of 0.1% reduces inflammatory tissue changes induced by AgNO3 burning of the cornea and inhibits the blood-aqueous barrier breakdown due to peripheral iridectomy or laser irradiation of the iris. Benzydamine reduces the aqueous PGE2 concentration to a similar extent as a 0.5% commercially available eye drop formulation of piroxicam. This result is in contrast with previous in vitro results demonstrating that benzydamine is devoid of any effects on PG synthesis. The possibility that PGE2 reduction is an indirect effect due to other biochemical activities of benzydamine is discussed. In the normal eye benzydamine manifests a local anaesthetic effect which is not accompanied by irritative changes in the anterior segment of the eye, changes in the intraocular pressure or pupillary size. It is suggested that in the clinical use of benzydamine eye drops the local anaesthetic activity may contribute to reducing both the neurogenic component of ocular inflammation and acute pain following injuries to the eye.

Trypanosoma lewisi in liquid culture: findings and comparisons with different types of media. Culture medium for Trypanosoma lewisi.

The culture technique used proved to be more simple and economical than the different culture methods described in literature. This process permits the in vitro growth of parasites for a period long enough (10 days) to determine the possible activity of drugs. On the 10th day the cultures are infectious.