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A study of the influence of newly synthesized acyclonucleosides and 1,2,3,4-tetrahydroisoquinoline derivatives on deoxythymidine and deoxycytidine kinase activities in human neurofibrosarcoma and ovarian cancer

100%

Modrzejewska H., Brzezinska E., Draminski M., Zgit-Wroblewska A., Krzykowska K., Rozponczyk E., Greger J.

Acta Biochimica Polonica

2003

tom 50

nr 4

The influence of nine newly synthesized uracil acyclonucleosides, and 36 derivatives of 1,2,3,4-tetrahydroisoquinoline on the activity of enzymes catalysing dTMP and dGMP synthesis, on the content of dTTP and dGTP in acid soluble fraction and on the incorporation of [14C]dThd and [14C ]dGuo into DNA in tumour homogenates was studied. The influence of the compounds was studied in the cytosol from intraoperatively excised human tumours — neurofibrosarcoma and ovarian cancer. It was shown that dTMP and dGMP synthesis is inhibited competitively by 34.1±4.0% in both types of tumours by 0.2 mM 1-N-(3'-hydroxypropyl)-6-methyluracil (1) and 0.2 mM 1-N-(3'-hydroxypropyl)- 5,6- tetramethyleneuracil (2). The mentioned acyclonucleosides reduced the content of dTTP and dGTP in the acid soluble fraction of tumours (59.7±3.1% of control). 1-(4-chlorophenyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline (3), 1-(2,3-dichlorophenyl)-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline (4) and 1-(3-methoxyphenyl)-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline (5) at 0.2 mM concentration caused a mixed type inhibition of the synthesis of dTMP and dGMP by, on average, 33.2±4.4%, and reduced the content of dTTP and dGTP in the acid soluble fraction (52.6±3.7% of control) but were active only in the cytosol of neurofibrosarcoma. While acyclonucleosides undergo phosphorylation in the cytosol by cellular kinases, with their triphosphates being active acyclonucleoside metabolites, active 1,3,4,5-tetrahydroisoquinoline derivatives (compounds not containing a deoxyribose moiety), cannot be phosphorylated. ACN and THI derivatives which inhibit dThd and dCyd kinase activities, inhibit also the incorporation of [14C]dThd and [14C]dGuo (ACN — 50.2±2.7%, THI — 53.4±3.9% of incorporation inhibition) into tumour DNA. The obtained results point to the mechanism of uracil acyclonucleosides and 1,2,3,4-tetrahydroisoquinoline biological activity consisting in inhibiting the synthesis of DNA components.

Antidepressant-like effect of 1,2,3,4-tetrahydroisoquinoline in reserpine model of depression in rat – changes in noradrenaline and serotonin levels

84%

Mozdzen E., Wasik A., Michaluk J., Romanska I., Antkiewicz-Michaluk I.

Acta Neurobiologiae Experimentalis

2013

tom 73

nr 1

It is well known that monoamine neurotransmitters: noradrenaline (NA) and serotonin (5-HT) play a key role in central nervous system (CNS) in pathophysiology of depression. The alterations in their metabolism in the brain seem to be related to the therapeutic action of antidepressants. Abnormalities with monoaminergic storage and neurotransmission are associated with a number of neurological disorders as: e.g. depression. Reserpine, used as an antihypertensive, antipsychotic drug in a low doses is a potent inhibitor of the vesicular monoamine transporter 2 (VMAT2) and acts by depleting cells of their monoamines stores. It is known that patients who took reserpine chronically began to display symptoms similar to that seen in depression. The reserpine model of depression in rat based on universally accepted monoamine hypothesis of depression and offers good predictive validity in terms of monoamine-based antidepressant activity. The aim: the present study aimed to investigate the potential antidepressant properties of an endogenous amine 1,2,3,4-tetrahydroisoquinoline (TIQ) and its possible mechanisms of action. In behavioral study, the forced swim test (FST) was used to evaluate the effects of TIQ in reserpine model of depression in rat. Additionally, the motor function of rat was checked in locomotor activity test after investigated drugs administration. Further, the content of NA, 5-HT and their metabolites, as well as the rate of metabolism in different rat brain structures were determined by HPLC methodology with ED. The reserpine model of depression was induced by chronic (14 consecutive days) administration of reserpine in a low dose (0.2 mg/kg i.p.). Results: The results from both behavioral and neurochemical studies have shown depressive-like effect of reserpine after its chronic administration. In the behavioral tests, reserpine decreased the locomotor activity (about 30% vs. control group, P<0.05) measured in actometers (Opto-Varimex activity monitors, Columbus Instruments, USA) linked on-line to a compatible IBM-PC. 14-days administration of reserpine induced also behavioral changes in FST: increase of immobility time with a simultaneous decrease of swimming activity (about 30% vs. control group). Depressive-like action of reserpine was also observed in neurochemical study by decline NA and 5-HT levels in the brain structures, mainly in the frontal cortex and striatum. TIQ (25 mg/kg i.p.) revealed antidepressant-like effect in FST and has the ability to reverse the pro-depressive effect of reserpine. In biochemical studies, TIQ completely antagonized reserpine-induced monoaminergic depression in rat brain structures. Conclusion: The obtained data indicate first, that chronically administered reserpine at a low dose leads to a good animal model of depression. Secondly, the antidepressant-like effect of TIQ based mainly on activation of monoaminergic system and antagonizing the effect of reserpine by inhibition of MAO-dependent oxidation of monoamines and increased their concentrations in the brain. Thus, in that light TIQ may be useful as a new safer and more effective compound in clinical practice for therapy of depression.

Ograniczanie wyników

1 Acta Biochimica Polonica

1 Acta Neurobiologiae Experimentalis

1 Antkiewicz-Michaluk I.

1 Brzezinska E.

1 Draminski M.

1 Greger J.

1 Krzykowska K.

1 Michaluk J.

1 Modrzejewska H.

1 Mozdzen E.

1 Romanska I.

1 Rozponczyk E.

1 Wasik A.

1 Zgit-Wroblewska A.

1 2013

1 2003

Wyniki wyszukiwania

A study of the influence of newly synthesized acyclonucleosides and 1,2,3,4-tetrahydroisoquinoline derivatives on deoxythymidine and deoxycytidine kinase activities in human neurofibrosarcoma and ovarian cancer

Antidepressant-like effect of 1,2,3,4-tetrahydroisoquinoline in reserpine model of depression in rat – changes in noradrenaline and serotonin levels