Zbigniew S. Herman

The effects of noradrenaline on rat's behaviour

SummaryThe behavioural effects of NA injected without narcosis into the lateral brain ventricle of the rats were studied with two different techniques. Rats were classified according their normal level of exploratory activity into three groups: high, medium and low. It was shown that NA in a dose of 10 μg increased locomotor activity only in animals of low activity; a dose of 50 μg increased locomotor activity in all the animals; and a dose of 200 μg induced a complete abolition of locomotor activity and a stuporose syndrome lasting 2 hours. The evidence that NA in some experimental conditions increases locomotor activity of rats supports the hypothesis that NA regulates processes in the central nervous system which stimulate behaviour.

Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates.

Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)α activators (fibrates) proved to be effective in the primary and secondary prevention of cardiovascular diseases. The benefits of hypolipemic therapy in cardiovascular diseases cannot be explained only by the lipid-lowering potential of these agents. The aim of this study was to clarify the effect of hypolipemic agents on proinflammatory cytokine release from human monocytes in relationship with their action on plasma levels of sensitive systemic marker of low-grade vascular inflammation. Plasma lipid and high-sensitivity C-reactive protein (hsCRP) levels, and the release of tumor necrosis factor-α (TNFα) and interleukin-1β from monocytes were assessed at baseline and 30 and 90 days following randomization of IIa dyslipidemic patients into fluvastatin or simvastatin groups and randomization of type IIb dyslipidemic patients to the micronized form of either ciprofibrate or fenofibrate. Lipopolysaccharide-stimulated monocytes from dyslipidemic patients released significantly more TNFα (types IIa and IIb dyslipidemias) and interleukin-1β (type IIa dyslipidemia) in comparison with monocytes in 59 age-, sex-, and weight-matched control subjects. Their baseline hsCRP levels were also higher. Both statins and fibrates reduced the release of TNFα and interleukin-1β, and lowered plasma hsCRP levels. The effects of hypolipemic agents on cytokine release and plasma hsCRP were unrelated to their lipid-lowering action. Our results have demonstrated that type IIa and IIb dyslipidemic patients exhibit the abnormal pattern of TNFα and interleukin-1β production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARα activators normalize monocytic secretion of these cytokines, and this action may partially contribute to the systemic antiinflammatory effect of hypolipemic agents. The statin- and fibrate-induced suppression of proinflammatory cytokine release from monocytes seems to play a role in their beneficial effect on the incidence of cardiovascular events.

Influence of some psychotropic and adrenergic blocking agents upon amphetamine stereotyped behaviour in white rats

Summarydl-α-amphetamine sulphate in a dose of 10 mg/kg caused abnormal stereotyped behaviour in white rats. Major tranquillizers diminished or abolished this phenomenon; thymeretics increased its duration; minor tranquillizers did not influence it. Adrenergic blocking agents acted in various ways on the ASB phenomenon. The possible mechanism of amphetamine stereotyped behaviour is briefly discussed.

The influence of prolonged amphetamine treatment and amphetamine withdrawal on brain biogenic amine content and behaviour in the rat

Male Wistar rats were treated orally with D-l-amphetamine sulphate in a dose of 3 mg/kg daily during 9 months. An increase of locomotor activity during the first 3 months was observed, while in the following 6 months locomotor activity was similar to the control group. The estimations of noradrenaline and 5-hydroxytryptamine levels in 9 discrete areas of brain, after 9 months of amphetamine treatment showed no changes in 5-HT level, but a significant decrease of the noradrenaline level in the pons. Withdrawal of amphetamine from rats treated for 9 months with this drug caused an inhibition of locomotor activity and a decrease of noradrenaline and 5-hydroxytryptamine level in the cerebellum.

Effect of monthly atorvastatin and fenofibrate treatment on monocyte chemoattractant protein-1 release in patients with primary mixed dyslipidemia.

The aim of this study was to compare the effect of 30-day treatment with atorvastatin and fenofibrate on monocyte release and plasma levels of monocyte chemoattractant protein-1 (MCP-1). We studied 52 atherosclerotic patients with primary mixed dyslipidemia and 16 age-, sex-, and weight-matched control subjects with asymptomatic atherosclerosis. Dyslipidemic patients enrolled into the study were randomly divided into three groups, simultaneously treated with atorvastatin (20 mg/d, n = 18), fenofibrate (267 mg/d, n = 16), or placebo (n = 18). Plasma lipid-profile and content of MCP-1, and monocyte release of this chemokine were measured at baseline and after 30 days of therapy. Compared with the control subjects, dyslipidemic patients exhibited the increased plasma levels and monocyte MCP-1 release. Atorvastatin and fenofibrate not only improved lipid profile but also decreased monocyte secretion of this chemokine. Moreover, hypolipemic agents slightly reduced its plasma levels. MCP-1-lowering effect of atorvastatin and fenofibrate did not correlate with the lipid-lowering potential of these agents. Our results suggest that atorvastatin and fenofibrate produce their antiinflammatory effect partially via inhibiting monocyte release of MCP-1. The treatment-induced reduction in its secretion may contribute to the clinical effectiveness of statins and fibrates in the therapy for atherosclerosis and other chronic fibroproliferative diseases.

Central cholinergic receptor supersensitivity after long-term atropine administration.

Rats were treated with a single dose of atropine (AT) at 5 mg/kg, or every day for 14 or 31 days with the same dose of AT, 3 h after the single dose and 24 h after the last dose of chronically administered AT, 10 μg of ACh was injected intracerebroventricularly, and two tests were used to examine the behavior of the animals. The tremorigenic effect of oxotremorine was also measured in mice treated with 10 mg/kg of AT for 1 month. It was shown that a single dose of AT antagonized ACh-induced behavior. The long-term treatment with AT enhanced the depressive behavior of ACh in rats and the tremorigenic effect of oxotremorine in mice. The results suggest that long-term blockade of central cholinergic receptors induces their hypersensitivity.

To the problem of biologically active conformation of enkephalin

SummaryA semi-rigid structural analog of [Leu5] enkephalin, possessing the azo-bridge between Tyr1 and Phe4 residues, was synthesized, along with two other linear enkephalin analogs: [4′-amino Phe4] enkephalin and [4′hydroxyphenyl/-azo Phe4] enkephalin. The results of the determination of the analgesic activity of the synthesized compounds suggest that the biologically active conformation of the enkephalin molecule should be such that both aromatic rings, Tyr1 and Phe4, are situated in close proximity.

Mediation of central prostaglandin effects by serotoninergic neurons

Ten days after administration of 5,6-dihydroxytryptamine, which causes degeneration of central serotoninergic neurons, the depressive behavioral effects of PGF2α and PGE2 were evidently inhibited. Central chemical serotoninectomy abolished the hyperthermic and hypertensive effects of PGF2α, but only slightly affected those of PGE2. It is concluded that serotoninergic neurons mediate the depressive behavioral action of both PGF2α and PGE2. They also mediate the hyperthermic and hypertensive action of PGF2α but not of PGE2. This suggests that these prostaglandins have different central modes of action.

Behaviour of rats and biogenic amine level in brain after 6-hydroxy-dopamine

Male, Wistar rats were injected into the right lateral ventricle of the brain with 250 μg of 6-hydroxy-dopamine (6-OHDA). The behaviour of animals and the level of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) were measured after different periods of time. During the first hour after 6-OHDA injection the behaviour of rats was similar to that observed after reserpine or a benzoquinolizine derivative; 6 h after the drug injection signs of sedation occurred. 24 and 48 h after 6-OHDA treatment locomotor activity of rats was similar to the activity of untreated animals. 68 h after 6-OHDA application a decrease of exploratory activity was noted. 7 h after 6-OHDA treatment a decrease of NA level was observed in the cortex, mesencephalon, thalamus and hypothalamus but an increase of NA content in the striatum. 3 days after 6-OHDA injection a decrease of the NA content in the cortex, thalamus and hypothalamus was seen. The DA level increased in most of the examined areas 7 h after 6-OHDA application; 3 days after the drug injection the DA level decreased in hypothalamus, thalamus and striatum and did not change in other brain areas. The 5-HT level increased in the pons and medulla oblongata and decreased in the mesencephalon 7 h after 6-OHDA injection and was unchanged in all examined structures 3 days after 6-OHDA application. These biochemical changes in the brain were not correlated with the behavioural changes of rats.

Hypolipidemic drugs affect monocyte IL-1beta gene expression and release in patients with IIa and IIb dyslipidemia.

Because atherosclerosis has been proven to be an inflammatory disease, it became obvious that the proper treatment of dyslipidemic patients should not only correct lipid parameters but also inhibit the inflammatory state. One of the crucial proinflammatory and procoagulant cytokines participating in the pathogenesis of atherosclerosis is interleukin-1β (IL-1β). Therefore, the aim of the study was to asses the effect of statin and fibrate therapy (for dyslipidemia IIa and IIb, respectively) on IL-1β gene expression and monocyte release evaluated in each patient. Additionally, the effect of hypolipidemic therapy on fibrinolysis was evaluated. The study was carried out in 37 patients: 12 with biochemically confirmed type IIa dyslipidemia (treated with atorvastatin), 12 with type IIb dyslipidemia (treated with fenofibrate), and 13 age- and sex-matched normolipidemic persons (control). IL-1β concentrations in cultured monocytes and PAI-1 (Plasminogen Activator Inhibitor) plasma levels were measured using the ELISA method. To evaluate the expression of IL-1β gene in monocytes, a semiquantitive RT-PCR procedure was performed. The results were normalized with the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a housekeeping gene. Although IL-1β monocyte release was markedly elevated in patients with atherogenic dyslipidemias, IL-1β gene expression was only slightly and nonsignificantly higher in the studied groups versus control. We have observed significant reduction of IL-1β mRNA expression after 30-day treatment with the examined drugs (atorvastatin, 2.10 ± 0.50 versus 1.05 ± 0.15; P < 0.001, fenofibrate; 2.27 ± 0.48 versus 1.23 ± 0.27; P < 0.01). There was no significant difference between statin and fibrate effect on IL-1β mRNA expression. Similarly, we have noticed significant reduction of IL-1β release by cultured monocytes after 30-day statin therapy (133.0 ± 5.7 pg/mL versus 77.0 ± 3.6 pg/mL; P < 0.01) and fibrate therapy (143.9 ± 6.5 pg/mL versus 86.2 ± 5.9 pg/mL; P < 0.01). Besides this antiinflammatory effect, we have observed a 30% reduction of PAI-1 plasma levels in both treated groups. In conclusion, effective 1-month hypolipidemic therapy with atorvastatin or fenofibrate diminished plasma levels of proinflammatory and procoagulatory state markers.