МОДЕЛИРОВАНИЕ БОЛЕЗНИ ПАРКИНСОНА С ПОМОЩЬЮ ЭКЗОГЕННЫХ НЕЙРОТОКСИНОВ (ОБЗОР ЛИТЕРАТУРЫ)

In recent years, there has been an increase in the prevalence of neurodegenerative diseases including Parkinson’s disease (PD). It is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to disability of patients and large financial costs of the treatment and rehabilitation. In this regard, the understanding of the environmental factors causing this disease, the development of adequate experimental models for studying its pathogenesis, and the search for strategies to prevent its development, as well as possible neuroprotective drugs, have fundamental scientific value. Although some researchers believe that genetic mutations and aging of the population are the main factors for the development of PD, a lot of studies have shown that PD may be caused by exposure to a number of toxins which enter the body from the environment. This review discusses the main toxic substances that cause the development of PD and, therefore, are used to model this disease in animals and cell cultures, as well as the mechanisms of action of neurotoxins, and the advantages and disadvantages of specific models.В последние годы наблюдается увеличение распространенности нейродегенеративных заболеваний, одним из которых является болезнь Паркинсона (БП), характеризующаяся прогрессирующей дегенерацией дофаминергических нейронов в компактной части черной субстанции головного мозга и приводящая к инвалидизации больных и большим финансовым затратам на их лечение и реабилитацию. В связи с этим понимание экологических факторов, вызывающих данное заболевание, разработка адекватных экспериментальных моделей для изучения патогенеза и поиска стратегий предотвращения его развития, а также возможных нейропротекторных препаратов имеет фундаментальную научную значимость. Хотя некоторые исследователи считают, что основными факторами развития БП являются генетические мутации и старение популяции, множество исследований доказывает, что БП может быть вызвана воздействием ряда токсических веществ, попадающих в организм из окружающей среды. В данном обзоре будут рассмотрены основные экзогенные нейротоксины, вызывающие развитие БП и в связи с этим использующиеся для моделирования данного заболевания на животных и клеточных культурах, а также механизмы их действия, преимущества и недостатки конкретных моделей

The protective effect of (S)-trolox–carnosine on a human neuroblastoma SH-SY5Y cell culture under the impact of heavy metals

Evaluation of the dose-dependent effects of heavy metals on the viability of a human neuroblastoma SH-SY5Y cell culture showed that 50% cell death was observed in the presence of 5 × 10–4 М lead, 5 × 10–6 М cadmium, 5 × 10–5 М cobalt, and 10–5 М molybdenum. The presence of these metals led to an increase in the level of reactive oxygen species (ROS) (from 39% to 74% in the cases of lead and cobalt, respectively). We revealed a cytoprotective effect against toxic heavy metals (HMs) of a new synthetic compound, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-β-alanyl-L-hystidine. This compound is a combination of carnosine with a water-soluble vitamin E analog, trolox (S-trolox–carnosine, S-TC). S-TC efficiently increased the cell viability in the presence of any of the studied metals, which correlated with a decrease in the proportion of necrotic cells and with efficient inhibition of ROS formation. Trolox also had a large cytoprotective effect under toxic conditions caused by lead, cadmium, and cobalt. The protective activity of carnosine under these conditions was significantly lower than the effects of trolox or trolox–carnosine. In general, these results revealed the greater cytoprotective effect of S-trolox–carnosine in the presence of heavy metals as compared to its precursors, trolox and carnosine. © 2016, Pleiades Publishing, Ltd

The protective effect of (S)-trolox–carnosine on a human neuroblastoma SH-SY5Y cell culture under the impact of heavy metals

Evaluation of the dose-dependent effects of heavy metals on the viability of a human neuroblastoma SH-SY5Y cell culture showed that 50% cell death was observed in the presence of 5 × 10–4 М lead, 5 × 10–6 М cadmium, 5 × 10–5 М cobalt, and 10–5 М molybdenum. The presence of these metals led to an increase in the level of reactive oxygen species (ROS) (from 39% to 74% in the cases of lead and cobalt, respectively). We revealed a cytoprotective effect against toxic heavy metals (HMs) of a new synthetic compound, (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonyl-β-alanyl-L-hystidine. This compound is a combination of carnosine with a water-soluble vitamin E analog, trolox (S-trolox–carnosine, S-TC). S-TC efficiently increased the cell viability in the presence of any of the studied metals, which correlated with a decrease in the proportion of necrotic cells and with efficient inhibition of ROS formation. Trolox also had a large cytoprotective effect under toxic conditions caused by lead, cadmium, and cobalt. The protective activity of carnosine under these conditions was significantly lower than the effects of trolox or trolox–carnosine. In general, these results revealed the greater cytoprotective effect of S-trolox–carnosine in the presence of heavy metals as compared to its precursors, trolox and carnosine. © 2016, Pleiades Publishing, Ltd

Экзогенные факторы риска возникновения болезни Паркинсона

Parkinson disease (PD) is a chronic progressive neurodegenerative multifactorial disease characterized by selective loss of dopaminergic neurons in substantia nigra pars compacta. Potential risk factors include exposure to environmental toxic substances, aging processes and genetic mutations. 5-15% of all the cases are genetically determined PD. In this regard, the role of environmental factors in the development of the PD neurodegenerative process becomes particularly important. However, in most cases, the interaction of environmental and genetic factors (gene-environment interaction), apparently, appears to be the cause of PD development. At the cellular level, the pathogenetic mechanisms of the disease are associated with a violation of alpha-synuclein conformation and the formation of Lewy bodies, the development of oxidative stress, neuroinflammation, mitochondrial and protease dysfunction. This review examines the molecular mechanisms of toxic effects of various environmental pollutants that can lead neurodegenerative process and PD development: pesticides, metals, solvents, polychlorinated biphenyls and nanoparticles. The study of complex pathophysiological interactions between potential neurotoxins determining the risk of dopaminergic neurons damage and preventive neuroprotectors is one of the most perspective areas in development of PD treatment.Болезнь Паркинсона (БП) - хроническое прогрессирующее нейродегенеративное мультифакториальное заболевание, характеризующееся селективной потерей дофаминергических нейронов в компактной части черной субстанции. Потенциальными факторами риска возникновения болезни являются воздействие токсичных веществ из окружающей среды, процессы старения и генетические мутации. При этом на долю генетически детерминированного паркинсонизма приходится 5-15 % случаев. В связи с этим оценка роли средовых факторов в развитии нейродегенеративного процесса при БП приобретает особую значимость. Однако в большинстве случаев причиной развития БП, по-видимому, является взаимодействие факторов окружающей среды и генетических факторов (генно-средовое взаимодействие). На клеточном уровне патогенетические механизмы заболевания связаны с нарушением конформации белка альфа-синуклеина и образованием телец Леви, развитием окислительного стресса, нейровоспаления, митохондриальной и протеазной дисфункции. В данном обзоре рассмотрены молекулярные механизмы токсичного действия различных загрязнителей окружающей среды, которые могут приводить к развитию нейродегенеративного процесса и БП: пестицидов, металлов, растворителей, полихлорированных бифенилов и наноразмерных частиц. Изучение сложных патофизиологических взаимодействий потенциальных нейротоксинов, определяющих риск повреждения дофаминергических нейронов и предотвращающих эти события нейропротекторов, является в настоящее время одним из наиболее перспективных направлений в разработке новых методов лечения БП

Exogenous factors of Parkinson’s disease development

Parkinson disease (PD) is a chronic progressive neurodegenerative multifactorial disease characterized by selective loss of dopaminergic neurons in substantia nigra pars compacta. Potential risk factors include exposure to environmental toxic substances, aging processes and genetic mutations. 5-15% of all the cases are genetically determined PD. In this regard, the role of environmental factors in the development of the PD neurodegenerative process becomes particularly important. However, in most cases, the interaction of environmental and genetic factors (gene-environment interaction), apparently, appears to be the cause of PD development. At the cellular level, the pathogenetic mechanisms of the disease are associated with a violation of alpha-synuclein conformation and the formation of Lewy bodies, the development of oxidative stress, neuroinflammation, mitochondrial and protease dysfunction. This review examines the molecular mechanisms of toxic effects of various environmental pollutants that can lead neurodegenerative process and PD development: pesticides, metals, solvents, polychlorinated biphenyls and nanoparticles. The study of complex pathophysiological interactions between potential neurotoxins determining the risk of dopaminergic neurons damage and preventive neuroprotectors is one of the most perspective areas in development of PD treatment. © 2019, Northern State Medical University. All rights reserved

Carnosine prevents the development of oxidative stress under the conditions of toxic action of cadmium

Protective effect of the natural dipeptide carnosine on the antioxidant system of rats under conditions of oxidative stress caused by chronic cadmium administration was investigated. Oxidative status of experimental animals were evaluated based on a number of informative parameters of iron-induced chemiluminescence. It was shown that the introduction of cadmium for 7 days reduces the duration of the latent period of chemiluminescence in the brain, liver, and blood plasma suggesting the depletion of endogenous antioxidant defense. Coexposure to carnosine and cadmium led to significant increase in the level of antioxidant protection in plasma, liver, and brain of animals. Carnosine also prevented the increase of lipid hydroperoxides in the brain and prevented the development of lipid peroxidation content in liver and plasma of animals. Mechanism of the protective effect of carnosine under conditions of oxidative stress induced by cadmium administration was shown on human neuroblastoma SH-SY5Y cell culture. Addition of the cadmium to the incubation medium to a final concentration of 5 μM reduced cell viability of a culture, as was determined by MTT assay; simultaneous addition of carnosine (0.25 mM final concentration) with cadmium resulted in increased cell viability during 24 hours of incubation. Thus, carnosine in a final concentration of 1 mM effectively prevented the development of necrotic lesions of neuroblastoma cells, inhibiting the formation of reactive oxygen species as measured by flow cytometry. The results indicate the ability of carnosine to prevent the development of oxidative stress under the toxic action of cadmium. © 2016, Allerton Press, Inc

Effects of antioxidants on the viability of the human neuroblastoma SH-SY5Y cell culture under the conditions of heavy-metal toxicity

Protective action of antioxidants (mexidol, carnosine, N-acetyl cysteine) and the metal chelator Ca, Na2-EDTA was studied in the culture of human neuroblastoma SH-SY5Y cells after the addition of salts of heavy metals-lead, cadmium, cobalt, and molybdenum-to the culture medium. Cells were incubated with heavy metals and protectors for 24 h, and cell viability and cell death were evaluated. All the metals lowered cell viability in a concentration-related manner. Different protective agents were studied based on this model. The most pronounced capability of increasing the cell viability in conditions of heavy-metal toxicity was demonstrated by N-acetyl cysteine (the protective effect was demonstrated at the concentrations 0.5-1.0 mM and higher). Protective potential of carnosine was somewhat lower and that of mexidol was minimal. © 2016 Kulikova et al

Carnosine prevents the development of oxidative stress under the conditions of toxic action of cadmium

Protective effect of the natural dipeptide carnosine on the antioxidant system of rats under conditions of oxidative stress caused by chronic cadmium administration was investigated. Oxidative status of experimental animals were evaluated based on a number of informative parameters of iron-induced chemiluminescence. It was shown that the introduction of cadmium for 7 days reduces the duration of the latent period of chemiluminescence in the brain, liver, and blood plasma suggesting the depletion of endogenous antioxidant defense. Coexposure to carnosine and cadmium led to significant increase in the level of antioxidant protection in plasma, liver, and brain of animals. Carnosine also prevented the increase of lipid hydroperoxides in the brain and prevented the development of lipid peroxidation content in liver and plasma of animals. Mechanism of the protective effect of carnosine under conditions of oxidative stress induced by cadmium administration was shown on human neuroblastoma SH-SY5Y cell culture. Addition of the cadmium to the incubation medium to a final concentration of 5 μM reduced cell viability of a culture, as was determined by MTT assay; simultaneous addition of carnosine (0.25 mM final concentration) with cadmium resulted in increased cell viability during 24 hours of incubation. Thus, carnosine in a final concentration of 1 mM effectively prevented the development of necrotic lesions of neuroblastoma cells, inhibiting the formation of reactive oxygen species as measured by flow cytometry. The results indicate the ability of carnosine to prevent the development of oxidative stress under the toxic action of cadmium. © 2016, Allerton Press, Inc