[The role of mercury and arsenic in the etiology and pathogenesis of Parkinson's and Alzheimer's diseases]. / Rol' rtuti i mysh'yaka v etiologii i patogeneze boleznei Parkinsona i Al'tsgeimera.

A critical review of literature data on the toxic effects of mercury and arsenic on the human brain and their relationship with the etiology and pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases is presented. In the first case, the toxic effect of mercury and arsenic on the brain stimulates oxidative stress, which leads to the formation of free oxygen species and a decrease in the antioxidant defense of neurons. In the second case, the harmful effect of mercury changes the structure and properties of ß-amyloid, and the toxic effect of arsenic contributes to its accumulation. In the pathogenesis of the diseases under consideration, particular importance is attached to the reaction of astrocytes that initiate neuroinflammation, which is also characteristic of mercury and arsenic intoxication. Considering that the symptoms recorded during intoxication with mercury and arsenic are in many respects similar to those of Parkinson's and Alzheimer's diseases, and their pathogenetic mechanisms (oxidative stress and neuroinflammation) coincide, then the toxic effects of mercury and arsenic in neurodegenerative diseases analyzed in this review can be characterized as the influence of the most significant risk factors.

[Morphochemical study of alpha-synuclein, iron and iron-containing proteins in the substantia nigra of the brain in Parkinson's disease]. / Morfokhimicheskoe issledovanie al'fa-sinukleina, zheleza i zhelezosoderzhashchikh belkov v chernom veshchestve golovnogo mozga pri bolezni Parkinsona.

OBJECTIVE: To study, using a complex morphochemical approach, the localization of alpha-synuclein, iron compounds and iron-containing proteins in the structures of the substantia nigra of the brain in Parkinson's disease (PD). MATERIAL AND METHODS: Histochemistry and immunohistochemistry methods have been used to study the localization of pathological alpha-synuclein (α-Syn-p129), iron compounds and iron-containing proteins - transferrin receptor and ferritin in neurons and neuroglia in the substantia nigra of the brain of deceased PD patients and persons with no neurological symptoms detected during life (control). RESULTS: In the substantia nigra of PD patients, in comparison with the control, a stable accumulation of pathological alpha-synuclein (α-Syn-p129) in the bodies and processes of neurons was found, and in the neuroglia and neuropil - the accumulation of iron (II) and ferritin heavy chain, the reaction of microglia to protein CD68 was moderately elevated. The transmembrane protein CD71 was detected equally in the brains of PD patients and in controls. CONCLUSION: Synaptic protein alpha-synuclein in PD turns into a pathological metabolite that accumulates in the structures of substantia nigra, and probably disrupts the conduction of nervous excitation. Excessive accumulation of the ferritin heavy chain in neuroglia can increase the concentration of reactive forms of iron and increase neurotoxicity. The uniform distribution of the transmembrane glycoprotein CD71 in the of substantia nigra structures both in the control and in PD patients indicates the preservation of non-heme iron transport during the neurodegenerative process.

Immunomorphological Changes in Neuronal and Non-Neuronal Structures in the Rat Intestine in a Toxin-Induced Model of Parkinsonism.

The damage to the enteric nervous system structures and the localization of total and phosphorylated α-synuclein, the main pathomorphological marker of parkinsonism, were studied by immunomorphological methods on small intestine wholemounts from rats with parkinsonism induced by systemic administration of paraquat. Reduced density of neurons in the myenteric ganglia and degenerative changes with accumulation of phosphorylated α-synuclein in sympathetic afferents to the small intestine were revealed. Phosphorylated α-synuclein was also found in non-neuronal cells located outside the ganglia. The revealed changes presumably reflect the initial stage of spreading of the pathological process during the development of Parkinson's disease.

[The role of aluminum and lead in the development of Alzheimer's and Parkinson's diseases]. / Rol' alyuminiya i svintsa v razvitii boleznei Al'tsgeimera i Parkinsona.

The article summarizes the data available in the literature on the toxic effects of aluminum and lead on the human brain and assesses the relationship of these effects to the etiopathogenesis of the most common neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. The accumulation of ions of these metals in the brain structures leads to chronic intoxication that is manifested by the morphological signs that are typical for Alzheimer's disease, such as deposits of ß-amyloid and τ-protein mainly in the frontal and temporal regions of the cortex, and for Parkinson's disease, such as degeneration of dopamine neurons in the substantia nigra and their accumulation of α-synuclein. The most likely forms of participation of aluminum and lead ions in the mechanisms of neurodegeneration are the replacement of bivalent metal ions necessary for brain functioning, oxidative stress initiation, epigenetic modifications of histones, and increased expression of noncoding ribonucleic acids.

[Clinical and morphological analysis of a caseof Parkinson's disease]. / Kliniko-morfologicheskii analiz sluchaia bolezni Parkinsona.

Parkinson's disease (PD) is a neurodegenerative disease that belongs to a group of cerebral proteinopathies. The main pathomorphological signs of PD are neuronal degeneration in the midbrain substantia nigra and detection of pathological forms of the synaptic protein α-synuclein in the nigral neurons. At the same time, the pathological forms of α-synuclein in this disease have been recently shown to accumulate in the cells of not only the central, but also peripheral autonomic nervous system. The paper provides a clinical and morphological description of a PD case in a 70-year-old patient, which demonstrates that there are typical α-synuclein-positive inclusions in the brain regions (substantia nigra, caudate nucleus, and frontal cortex), salivary glands and colon. The systemic nature of α-synucleinopathy in PD is important in both clarifying the pathogenesis of the disease and elaborating new approaches to its diagnosis and, in the future, to targeted therapy.

[Morphochemical changes in human striatum during aging.]

Age-related neurodegenerative diseases, including Parkinson's disease, are characterized by a number of pathomorphological signs, such as neuron loss in certain brain structures, gliosis, iron accumulation. However, the literature indicates that these signs can also be observed during normal (physiological) aging. The aim of our work was to evaluate qualitative and quantitative morphochemical changes in neurons and neuroglia, and also to localize iron (II) compounds in the human striatum during physiological aging. In the old age group, compared with the mature one, the size of the neuron bodies was significantly smaller, the neuronal distribution density did not differ, but the distribution density of both the overall glia and astrocytes was significantly higher. In the old age group, the accumulation of iron (II) compounds were seen along the walls of the vessels, as well as inside the cytoplasm of neurons and glial cells. We conclude that the results obtained may serve as a basis for the comparative study of the neurodegenerative process and for the earlier and more accurate diagnosis of neurodegenerative diseases associated with aging, including Parkinson's disease.

Immunohistochemical Assessment of the Compensatory Responses in Rat Olfactory Bulbs after 6-Hydroxydopamine-Induced Lesion of the Substantia Nigra.

We assessed changes of olfactory bulbs in rata with 6-hydroxydopamine destruction of the substantia nigra. The expression of marker proteins of immature and differentiated neurons and glia (vimentin, PSA-NCAM, tyrosine hydroxylase, and S100) was analyzed by immunohistochemical and morphometric methods. The number of periglomerular dopamine neurons and astroglia in the olfactory bulbs increased on the side of toxin injection and expression of PSA-NCAM and vimentin increased in the rostral migratory stream. Destruction of the substantia nigra shifted differentiation of neuronal progenitors towards the dopaminergic phenotype and increased their survival in the olfactory bulbs, which can be explained by increased expression of PSA-NCAM.

[Lewy bodies in Parkinson's disease: histological, immunohistochemical, and interferometric examinations]. / Tel'tsa Levi pri bolezni Parkinsona (gistologicheskoe, immunogistokhimicheskoe i interferometricheskoe issledovanie).

OBJECTIVE: To quantify the morphochemical characteristics of Lewy bodies detected in the substantia nigra in patients with Parkinson's disease (PD). MATERIAL AND METHODS: The investigators studied the localization of alpha-synuclein (α-Syn) and the distribution of neurofilament protein and synaptophysin by immunohistochemical assas and compared with the results of interferometry and computer-assisted morphometry of Lewy bodies in the autopsy specimens of the substantia nigra from PD patients. RESULTS: Three groups of synuclein-positive aggregates differing in shape were identified. Mature Lewy bodies had a rounded shape, a concentric structure, a poorly stained core, and, as compared with neuropil, a high phase difference value. Comparison of the localization of α-Syn, neurofilaments, and synaptophysin showed that immunostaining of neurofilaments in the peripheral layer of Lewy bodies was shifted closer to the nucleus and the localization of synaptophysin and α-Syn coincided. CONCLUSION: Synuclein-positive protein aggregates showed heterogeneity in structure, shape, and protein composition in PD. The localization of neurofilament protein and synaptophysin in Lewy bodies attests that the cytoskeleton and neuronal synaptic vesicle trafficking in the substantia nigra are impaired in BP.

[Neurochemical and morphological changes of microstructures of the compact part of the substantia nigra of human brain in aging and Parkinson's disease (literature review).]

For investigation of pathogenetic patterns of Parkinson's disease, it is important to adequately assess the mechanisms of age-related involution and morphological changes that are formed in the brain during this process. Clinical symptoms, detected in Parkinson's disease (rigidity, hypokinesia, tremor), indicate the involvement in the pathological process of nigrostriate brain formations due to the death of dopamine neurons in the compact part of the substantia nigra. At the same time, the loss of these neurons, as well as the change in the number of neuroglia cells in the substantia nigra of the brain, are detected not only in Parkinson's disease, but also in physiological aging. This review presents and compares data on the morphological changes in the compact part of the substantia nigra of the human brain in physiological aging and Parkinson's disease.

Immunomorphological Changes in the Olfactory Bulbs of Rats after Intranasal Administration of Rotenone.

Changes in the structure of the olfactory bulbs after long-term intranasal administration of pesticide rotenone, a classical inductor of parkinsonism, to rats were studied by the methods of immunomorphology. In rats intranasally receiving rotenone in a dose of 2.5 mg/kg every other day over 2 weeks, a decrease in the density of dopaminergic neurons and the area of astrocyte processes in the olfactory bulbs, activation of microglia in the glomerular layer, and enhanced α-synuclein phosphorylation and its accumulation in the bodies of mitral layer neurons were observed. The observed changes agree with the hypothesis on pathological α-synuclein transport via the olfactory route in Parkinson's disease and confirm relevance of the rotenone model of Parkinson's disease for studies of the pathological accumulation of α-synuclein.

[Morphochemical changes in the substantia nigra cellular structures in Parkinson's disease]. / Morfokhimicheskie izmeneniia kletochnykh struktur chernogo veshchestva golovnogo mozga pri bolezni Parkinsona.

AIM: to clarify the features of morphochemical changes in the substantia nigra cellular structures in Parkinson's disease. MATERIAL AND METHODS: The structural characteristics of the substantia nigra were studied microscopically and quantified using computer morphometric methods at brain autopsies of individuals with Parkinson's disease who had died from intercurrent diseases and those who had no evidence of neurological disorders in their history (a control group). RESULTS: This investigation could clarify the features of morphochemical changes in both the neural network structures and the glial populations of the substantia nigra in Parkinson's disease. The number of neurons containing tyrosine hydroxylase (a marker of dopamine neurons) in the compact part of the substantia nigra (a ventral region) was smaller and the density distribution of Lewy bodies was higher in the patients with Parkinson's disease than in the control group. The accumulation of iron (II) compounds in the cellular elements and neuropile and the increased expression of glial fibrillary acidic protein in Parkinson's disease were more pronounced than those in the controls. CONCLUSION: Postmortem diagnosis in Parkinson's disease should be based on a full description of a set of neuronal and glial morphochemical and structural changes in the substantia nigra rather than on the identification of cellular markers for the neurodegenerative process.

Quantitative Evaluation of Changes in the Striatal Astrocyte Axons in Simulated Parkinsonism.

Three parkinsonism models using neurotoxin 6-OHDA and pesticides rotenone and paraquat were reproduced in Wistar rats and parameters of astrocyte processes in the striatum (axon number and length, area occupied by them, and axon branching pattern) detected by immunohistochemical reaction for acid glial fibrillary protein were studied by computer morphometry. By these parameters, three morphological types of astrocytes were distinguished. Two variants of changes were found in the used parkinsonism models: 1) more intense branching and even elongation of all axons and 2) reduction of small and elongation of the main remaining stems, which manifested in polarization of glial cell. Type 1 reaction was obviously associated with compensatory increase in astrocyte interaction with neurons, while type 2 reflected astrocyte response to injury and impaired glioneuronal interactions.

[Morphological parameters of the heterogeneity of the substantia nigra in elderly men and women].

OBJECTIVE: to define the quantitative characteristics of cell structures in the substantia nigra pars compacta of neurologically healthy elderly people (men and women). MATERIAL AND METHODS: Autopsy brain materials from neurologically healthy men and women who had died from intercurrent diseases at the age of 72 to 87 years were examined for quantitative characteristics of the substantia nigra pars compacta, by applying computed morphometric methods. RESULTS: In the elderly people (men and women), the compactness of arrangement of neurons, including those containing tyrosine hydroxylase (a marker of dopamine neurons), was much higher and the glial index was lower in the ventral area of the substantia nigra pars compacta than in the dorsal area. Comparing the structures in the substantia nigra pars compacta showed that the neurons were larger in the dorsal area and the variability of the compactness of their arrangement and the glial index were higher in the women than in the men. CONCLUSION: In the elderly people, the cell structures in the substantia nigra pars compacta are typified by high morphometric heterogeneity.

Effects of activated protein C on the size of modeled ischemic focus and morphometric parameters of neurons and neuroglia in its perifocal zone.

The effects of activated protein C (APC) on the quantitative parameters of neurons and neuroglia in the perifocal zone of infarction induced in the left hemispheric cortex were studied in two groups of rats. Group 1 animals served as control (control infarction). Group 2 rats were injected with APC (50 µg/kg) in the right lateral cerebral ventricle 3 h after infarction was induced, and after 72 h the infarction size was evaluated and the neurons and neuroglia in the perifocal zone were counted. APC reduced the infarction size 2.5 times in comparison with the control and reduced by 16% the neuronal death in the perifocal zone layer V, causing no appreciable changes in layer III, and did not change the size of neuronal bodies but increased (by 11%) the size of neuronal nuclei in layer III. The protein maintained the sharply increased count of gliocytes in the perifocal zone of infarction and promoted their growth. Hence, APC protected the neurons from death in the ischemic focus by increasing the gliocyte count and stimulating the compensatory reparative processes.

[Morphological changes of neurons and neuroglial cells in the brain of senescence-accelerated prone 1 (SAMP1) mice].

Computerized morphometry was used to examine the sizes of neuronal bodies and the compactness of arrangement of neurons and neuroglial cells in layers III and V of the sensorimotor cortex in senescence-accelerated prone 1 (SAMP1) mice (an experimental group) and senescence-accelerated-resistant strain 1 (SAMR1) ones (a control group). In the SAMP1 mice as compared to the SAMR1 ones, the neuronal body sizes were significantly unchanged; the compactness of their arrangement decreased by 17 and 20% in layers III and V, respectively; that of neuroglial cells significantly increased by 14% in layer III only. In the SAMP1 mice versus the SAMR1 ones, the glial index rose by 36% in layer III and by 24% in layer V. During simulation of physiological aging, the sizes of neuronal bodies were shown to be virtually unchanged in the cerebral cortex; the compactness of their arrangement (cell counts) moderately reduced and that of neuroglial cells increased, which caused a rise in the glioneuronal index that was indicative of the enhanced supporting function of neuroglial cells during the physiological aging of brain structures.

Quantitative morphochemical characterization of the neurons in substantia nigra of rat brain and its volume reconstruction.

Three cell compartments differing by size and proportion of neurons were identified by 3D reconstruction of the substantia nigra pars compacta of the rat brain based on immunohistochemical localization of tyrosine hydroxylase, a marker of dopamine neurons. Dopaminepositive neurons prevailed over dopamine-free neurons (1.45:1) in the most voluminous (75%) dorsal part, and in smaller lateral and ventral parts, inverse cell ratios were observed: 0.54:1 and 0.78:1, respectively. Morphometry characterized the substantia nigra pars compacta as a structure consisting not only of several parts, but of horizons and showed differences between the neurons both in several parts and in several layers within the part. The revealed morphochemical heterogeneity of the substantia nigra pars compacta provides better understanding of the selective damage to its structures in Parkinson's disease.

[Changes in neuroglial interactions in the cerebral nigrostriatal structures in a model of dopamine system dysfunction].

Hypofunction of the dopamine system was induced by haloperidol or reserpine in Wistar rats. Reserpine increased a number of glial fibrillary acidic protein (GFAP) containing astrocytes by 49% and reduced glutamine synthase astrocytes and monoamine oxidase activity by 23% and 1/3, respectively. Haloperidol had no effect on morpho-chemical characteristics of astrocytes but increased a number of oligodendrocytes. It has been supposed that the activation of astroglia by reserpine in a dopamine hypofunction model is caused by the dysfunction of the corticostriatal glutamatergic system as a result of inhibition of the dopaminergic transmission in the basal nuclei. The changes in the neuroglial interactions in the striatum that lead to the disbalance of neuromediator systems in the basal nuclei may underlie the dysfunction of the basal nuclei in some diseases including Parkinson's disease.

Immunohistochemical and morphological changes in neurons and neuroglia in the cerebral nigrostriatal structures under conditions of experimental nigral neurodegeneration.

The count of dopamine-containing neurons decreased by 77%, the area of the remaining cells shrank by 75%, and the neuroglia doubled 4 weeks after injection of toxin (6-hydroxydopamine) into the compact part of the substantia nigra of the right cerebral hemisphere of rats, while no changes in the substantia nigra of the left hemisphere were observed. Neurons of the caudate nucleus were virtually unchanged in comparison with the intact control, while the neuroglia was activated: its total volume in the right hemisphere increased by 33% (50% increase in astrocyte count and a 25% increase of the rest neuroglia), while in the left hemisphere only astrocyte count increased by 20%. Astrocyte nuclei in the caudate nuclei of both hemispheres were enlarged by 22-23%. Hence, unilateral destruction of the nigral dopamine-containing neurons stimulated the neuroglia (particularly astroglia) in the caudate nuclei, especially on the side of damage.

[Age-related dynamics of structure changes in the 17th cortical area of children with perinatal affection of the nervous system].

Brain autopsy of children standing afterperinatal affection of the nervous system and healthy children without any neurological disorders (a control group) has been studied by computers morphometric methods. The age-related dynamics of structure parameters in the 17th cortical area was investigated. Correlation between increasing of cortical lamina's diameters and age of children with perinatal affection of the brain wasn't revealed. The width of IVand V cortical layers, size of neurons and their density in the cortex of children with perinatal pathology were significantly fewer than in the control group. However the density of glia including GFAP-positive astroglia in the children with prenatal pathology was higher to compare with the control group. We suggest that detected disorders are signs of nonspecific structure-functional changes in the visual cortex and follows destructive and compensatory restorative reactions.

[Glial satellites as the source of additional energy supply to the neurons during the increased frequency of firing activity].

Using surviving slices of guinea pig somatosensory cortex, it was shown that functionally different regulation of spontaneous firing activity in different neurons corresponded to irregular distribution of glial satellites. Maximal increase of spike activity induced by acetylcholine (up to 36 spikes per second) was detected in "silent" neurons which account for 37.2% of nerve cells in layer V. According to the morphometric analysis, the same relative number of neurons (38.6%) were surrounded with glial satellites. In spontaneously active neurons only a small elevation of firing activity (5-22 spikes per second) above the basal level was recorded. The results allow to suggest that M-cholinergic reaction, controlling the spontaneous activity level, requires the additional energy supply for its maximal expression in inactive neurons. This is achieved by contacts of neurons with the surrounding glial satellites.