[Inhibitors of mitochondrial permeability transition pore prevent apoptosis of dopaminergic neurons in the mesencephalon].

In the study the role of apoptosis in development of dopaminergic neuronal cell death within substantia nigra (parts compacta) and ventral tegmental area induced by 6-OHDA was investigated. It was found that intermittent hypoxia and the water-soluble vitamine E (Trolox) and melatonin, as antioxidants and inhibitors of mitochondrial permeability transition pore protect dopaminergic cells from cytotoxic effect of 6-OHDA. It is supposed that mitochondrial permeability transition pore plays an important role in apoptosis of neurons in the brain.

[The nitric oxide system in a chronic deficiency of mesostriatal dopamine: the action of nitroglycerin]. / Systema oksydu azotu za umov khronichnoho defitsytu mezostriatnoho dofaminu: diia nitrohlitserynu.

Unilateral chronic deficiency in dopamine was induced by injection of the neurotoxin 6-hydroxydopamine into the mesostriatum of male Wistar rats (n = 15). The content of the nitric oxide metabolite--NO2- was three time less than in controls in the neostriatum on the operated side only, whereas, in the heart, aorta and plasma it was reduced by 1.9, 1.7 and 3.2 times, respectively. Four hours after subcutaneous injection of nitroglycerin (10 mg/kg, n = 4), a significant 6 fold increase in NO2- content in the neostriatum in the operated hemisphere and 2 fold increase on the in the intact side was observed. In heart, aorta and plasma NO2- content increased 2, 9, 3 times, respectively. The same dose of nitroglycerin given to intact rats (n = 4) had less effect on NO2- content: a 2 fold increase in heart, aorta and plasma only. Activity of NO-synthase (NOS) in animals with dopamine deficiency was reduced 2.7 fold in the neostriatum of the operated hemisphere and by 1.8 time on the intact side, in heart and aorta--by 1.8 and 3 time, respectively. Injection of nitroglycerin increased activity of NOS in the neostriatum of the operated hemisphere 2 fold and on the intact side 3 time; in heart (11 time) and aorta (1.3 time) after 4 hours. Similarly subcutaneous nitroglycerin injection restored the reduced endothelium-dependent vasodilator responses characteristic of the rats with mesostriatal dopamine deficiency. Thus the amplitude of acetylcholine-induced smooth muscles relaxation of the aorta increased by more than 70%. In these animals the injection of nitroglycerin also exerted a normalizing effect on the characteristic apomorphine-induced behaviour asymmetry (rotatory movements). On week after the injection of nitroglycerin the rotatory behaviour was reduced by 20.7% of control rotations. We show that nitroglycerin, a NO-donor, is a useful drug. It correct the abnormalities in the metabolic pathways on NO synthesis in a variety of tissues, endothelium-derived vascular responses and also the behaviour abnormalities induced by unilateral mesostriatal lesions. Our experimental animals are thought to be a model of human hemi-Parkinsonism. Thus nitroglycerin might be of use in Parkinson's disease.

[The nitrous oxide system under conditions of chronic cerebral dopamine deficiency and hypoxia]. / Systema oksydu azotu za umov khronichnoho defitsytu tserebral'noho dofaminu ta hipoksiï.

Acute experiments were conducted on adult Wistar rats two months after unilateral microinjection of the 6-hydroxydopamine into the medial forebrain bundle. This led to a greater than 90% decrease of dopamine, fell by 70% of the content of the stable metabolite of nitric oxide-nitrite anion and by up to 80% of nitric oxide synthase activity in the lesioned neostriatum. Nitric oxide synthase activity fell by 30% in the heart, by 60% in the aorta, while nitrite anion decreased in the heart and aorta, in blood plasma and erythrocytes by 45%, 40%, 70%, 30% compared with controls rats, respectively. Lesioned rats also showed changes in the pattern of responses of the smooth muscle of the aorta predominantly to endothelium-dependent (acetylcholine), rather than to endothelium-independent (nitroprusside) vasoreactivity. The amplitude of acetylcholine-induced relaxation of aortic smooth muscle decreased 4-fold, the rate of this response decreased 5-fold and the latent period increased 4-fold. Exposure of lesioned rats, controls rats to moderate hypoxia for 30 min resulted in a rise of nitrite anion content in all tissues; it increased 2-fold in erythrocytes of lesioned rats vs controls rats, in the lesioned and unlesioned neostriatum hypoxia restored the values to controls, while in the heart, aorta and plasma the levels were also increased but did not reach control values. Hypoxia also led to a rise of nitric oxide synthase activity in both lesioned rats and controls rats. However, compared to normoxia, the levels increased over 2 times in the lesioned neostriatum and in the heart, whereas in controls the increase was less that 2-fold. Hypoxia resulted in partial normalization of the functional deficit in endothelium-dependent dilatory responses of aortic smooth muscle. We conclude that the disturbances in nitric oxide system induced by mesostriatal dopaminergic lesions in animals may have relevance to Parkinson's disease. The improvement with ambient hypoxia in quantitative and functional aspects of the disturbances in nitric oxide system may also have relevance in the management of the disease.