Changes of cholinesterase activities in the plasma and some tissues following administration of L-carnitine and galanthamine to rats.

Changes of acetylcholinesterase (AChE) activities in the hypophysis and brain (frontal cortex, hippocampus, medial septum and basal ganglia), and butyrylcholinesterase in plasma and liver following galanthamine (GAL) administration were studied in rats pretreated with L-carnitine (CAR). Following only GAL administration (10 mg/kg, i.m.), both cholinesterases (without clinical symptoms of GAL overdosage) were significantly inhibited. Pretreatment with CAR (3 consecutive days, 250 mg/kg, p.o.) followed by GAL administration showed higher AChE inhibition in comparison with single GAL administration. However, a statistically significant difference was observed for AChE in the hippocampus only. The activity of peripheral cholinesterases was not influenced by CAR pretreatment. Thus, pretreatment with CAR enhanced AChE inhibition in some brain parts of the rat following GAL administration.

Effect of galantamine on acetylcholinesterase and butyrylcholinesterase activities in the presence of L-carnitine in rat selected brain and peripheral tissues.

OBJECTIVES: The alkaloid galantamine (GAL), which exhibits a combined anticholinesterase and direct parasympathomimetic mechanism of action, is employed in conjunction with therapeutic interventions in the stimulation of central cholinergic transfer in cognitive diseases. We attempted to achieve pharmacologically-induced enhancement of the parasympathomimetic activity of GAL in the key areas of rat brain, using an interactive combination of the alkaloid with the transmembrane enhancer L-carnitine (CAR). METHODS: We investigated activities of acetylcholinesterase (AChE) in brain areas (frontal cortex, basal ganglia, septum and hippocampus) and the hypophysis, and that of butyrylcholinesterase (BuChE) in plasma and liver. RESULTS: Following administration of the highest of the GAL doses used (2.5; 5; 10 mg/kg i.m.), AChE activity decreased mainly in the frontal cortex, hippocampus and hypophysis. In the interaction of GAL and CAR, AChE inhibition was stronger but without any statistical significance. The peripheral inhibition of BuChE was found to be dose-dependent. Premedication by CAR led to a slight change in the values of the activities monitored. CONCLUSIONS: CAR in terms of positive modulation of GAL targeting to the central nervous system had no statistically significant effect.

Galantamine antiacetylcholinesterase activity in rat brain influenced by L-carnitine.

Galantamine (GAL) is a selective, competitive and reversible acetylcholinesterase (AChE) inhibitor, which increases the activity of the cholinergic system and hence gives rise to an improvement of cognitive functions in patients suffering from dementia of Alzheimer type. L-Carnitine (CAR) is a natural component of the mammalian tissue and is known to increase penetration of some chemical compounds/groups across biological membranes. The aim of this study was to evaluate the influence of pretreatment with CAR on AChE inhibition caused by GAL in selected brain parts in rat (basal ganglia, septum, frontal cortex, hippocampus) and in hypophysis, which does not lay beyond the blood-brain-barrier. During the first stage of the study, GAL was administered i.m. in different doses ranging from 2.5 to 10 mg/kg. The highest degree of AChE dose dependent inhibition was observed in hypophysis, while that in CNS was lower and became apparent in frontal cortex and hippocampus only after the administration of the dose of 10 mg/kg i.m. In the second stage, CAR was administered daily during 3 consecutive days at a dose of 250 mg/kg p.o. prior to the administration of GAL (10 mg/kg i.m.). Pretreatment with CAR enhanced trend of AChE inhibition in all selected brain parts comparing with single GAL administration, however, significant difference was not observed. Comparing these results with control group, statistical significance was found in frontal cortex, hippocampus and hypophysis.

Intestinal single-pass in situ perfusion technique in rat: the influence of L-carnitine on absorption of 7-methoxytacrine.

7-Methoxytacrine (7-MEOTA) is an acetylcholine-esterase inhibitor that is potentially useful in the therapy of some neurodegenerative disorders. L-carnitine (CRT) is a naturally occuring compound that is known to increase penetration of some compounds through biological barriers. Aim of this study was how CRT influenced transintestinal absorption transport 7-MEOTA in rat using single-pass intestinal in situ perfusion method. The rate of absorption of 7-MEOTA during luminal perfusion with single 7-MEOTA was compared with rate of absorption during simultaneous perfusion with 7-MEOTA and CRT and with absorption rate after the premedication with CRT for period of three days before beginning of perfusion. The methodical system was the perfusion of mesenterial bed (from arteria mesenterica superior to vena portae) and intestinal luminal perfusion (from duodenum to ileum). The lower transintestinal absorption in the course of simultaneously administration of CRT than just in case of perfusion with single 7-MEOTA has been found. On the contrary a significantly higher absorption of 7-MEOTA has been noted in group of rats premedicated with CRT for three consecutive days. The interpretation suggested that molecules of CRT incorporated into the metabolism of intestinal cells facilitated transport of 7-MEOTA (as a representative substance which is at least partly transferred by carrier mechanism). In case of simultaneous luminal perfusion with CRT and 7-MEOTA competitive over-saturation of carrier systems is probably.

Biochemical and behavioral effects of soman vapors in low concentrations.

Soman belongs to the most dangerous nerve agents because of the low effectiveness of the presently available antidotes. Soman acts by inhibiting acetylcholinesterase (AChE) both peripherally and centrally, with a subsequent accumulation of neuromediator acetylcholine and other metabolic changes. From the data published in literature it can be concluded that exposure to nerve agents leading to acute effects or chronic exposure to nerve agents may lead to delayed and persistent adverse effects. The aim of this study was to demonstrate changes in AChE and butyrylcholinesterase (BuChE) activities, stressogenic markers (i.e., tyrosine aminotransferase [TAT] activity, and plasma corticosterone level), and neuroexcitability and behavior 24 h and 4 wk following a single soman inhalation exposure at low level. AChE activity in erythrocytes and BuChE activity in plasma was decreased (dependent on the dose of soman) 24 h and 4 wk after the exposure. A similar decrease in AChE activity in different brain parts was observed. One of the stressogenic parameters, TAT, was changed 24 h after exposure only. Behavior of experimental animals was changed 24 h after the exposure, and 4 behavioral parameters persisted 4 wk after the exposure. Neuroexcitability was increased at 24 h after the exposure and had become about normal 4 wk after the exposure. Summarizing, long-term effects (4 wk) were observed after inhalation exposure of guinea pigs to sublethal concentrations of soman.

The influence of sarin on various physiological functions in rats following single or repeated low-level inhalation exposure.

Long-term effects of low doses of highly toxic organophosphorus agent sarin on various hematological and biochemical markers and physiological functions were studied in rats exposed to sarin by inhalation. The results indicate that low-level sarin-exposed rats show long-term increase in studied markers of stress and decrease in synthesis of DNA de novo without the disturbance of the functions of cholinergic nervous system. Moreover, sarin at low doses is able to induce some neurotoxic effects including an increase in the excitability of central nervous system in rats at 3 mo following inhalation exposure. Relatively long-term spatial discrimination impairments in rats exposed to low-level sarin was demonstrated too. Therefore, nerve agents such as sarin seem to be harmful not only at high, clinically symptomatic doses but also at low doses without acute clinical manifestation of overstimulation of cholinergic nervous system because of long-term manifestation of alteration of neurophysiological and neurobehavioral functions in sarin-exposed rats.

Cyclosporine A inhibits acetylcholinesterase activity in selected parts of the rat brain.

Cyclosporine A (CsA) is the major immunosuppressive drug used for organ and neural transplantation and the therapy of selected autoimmune diseases. We investigated the effect of CsA on the activity of acetylcholinesterase (AChE) in the frontal cortex, hippocampus, septum, and basal ganglia. AChE was determined spectrophotometrically with acetylthiocholine as substrate and 5,5-bis-2-nitrobenzoic acid as chromogen. CsA was administered in single doses of 20 or 45 mg/kg perorally; in the case of the higher dose we also performed a repeated administration of CsA in three consecutive doses separated by 24 h intervals. Both lower and higher doses of CsA decreased AChE activity in the frontal cortex and hippocampus to practically the same extent. On the contrary, AChE activity was more diminished in the case of the higher dose of CsA used in the septum and basal ganglia. Repeated administration of the higher dose of CsA did not lead, with the exception of the hippocampus, to a further decrease in AChE activity in the brain structures observed. These findings contribute to rare evidence concerning the interaction of CsA and the cholinergic system in the brain.

Antiacetylcholinesterase activity of cyclosporine--a comparison of single and repeated administration and effect of 7-methoxytacrine.

The aim of this work is a comparison of single and repeated peroral administration of cyclosporine (CsA) and the interaction of repeated administration of CsA and 7-methoxytacrine (MEOTA) on the activity of acetylcholinesterase (AChE) in the frontal cortex, hippocampus, septum, and basal ganglia in rats. Both single and repeated administration of CsA diminished the activity of AChE in the frontal cortex, septum and basal ganglia, while the enzyme activity in the hippocampus was diminished only in the case of repeated CsA, as well as repeated CsA + MEOTA administration. Repeated administration of CsA led to a further augmentation of anticholinesterase activity only in the frontal cortex and--in a lesser extent--in the basal ganglia. No augmentation of AChE activity was observed in the hippocampus and septum.