Using analytical technologies it is possible now to measure the entire diversity of molecules even in a small amount of biological samples. Metabolomic technologies simultaneously analyze thousands of low-molecular substances in a single drop of blood. Such analytical performance opens new possibilities for clinical laboratory diagnostics, still relying on the measurement of only a limited number of clinically significant substances.
View Article and Find Full Text PDFIn terms of time, cost, and reproducibility of clinical laboratory tests, a mass spectrometric clinical blood metabogram (CBM) enables the investigation of the blood metabolome. Metabogram's components provide clinically relevant information by describing related groups of blood metabolites connected to humoral regulation, the metabolism of lipids, carbohydrates and amines, lipid intake into the organism, and liver function. For further development of the CBM approach, the ability of CBM to detect metabolic changes in the blood in the early stages of Parkinson's disease (PD) was studied in this work.
View Article and Find Full Text PDFThe hypothalamus is a key link in neuroendocrine regulations, which are provided by neuropeptides and dopamine. Until the late 1980 s, it was believed that, along with peptidergic neurons, hypothalamus contained dopaminergic neurons. Over time, it has been shown that besides dopaminergic neurons expressing the dopamine transporter and dopamine-synthesizing enzymes - tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) - the hypothalamus contains neurons expressing only TH, only AADC, both enzymes or only dopamine transporter.
View Article and Find Full Text PDFParkinson's disease (PD) is diagnosed by the onset of motor symptoms and treated long after its onset. Therefore, the development of the early diagnosis of PD is a priority for neurology. Advanced methodologies for this include (1) searching for patients at risk of developing prodromal PD based on premotor symptoms; (2) searching for changes in the body fluids in these patients as diagnostic biomarkers; (3) verifying the diagnosis of prodromal PD and diagnostic-value biomarkers using positron emission tomography (PET); (4) anticipating the development of motor symptoms.
View Article and Find Full Text PDFStudying the initial molecular mechanisms of the pathogenesis of Parkinson's disease (PD), primarily in the nigrostriatal dopaminergic system, is one of the priorities in neurology. Of particular interest is elucidating these mechanisms in the preclinical stage of PD, which lasts decades before diagnosis and is therefore not available for study in patients. Therefore, our main goal was to study the initial molecular mechanisms of the pathogenesis of PD in the striatum, the key center for dopamine regulation in motor function, in a mouse model of the earliest preclinical stage of PD, from 1 to 24 h after the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
View Article and Find Full Text PDFStudying the molecular mechanisms of the pathogenesis of Parkinson's disease (PD) is critical to improve PD treatment. We used OpenArray technology to assess gene expression in the substantia nigra (SN) cells of mice in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD and in controls. Among the 11 housekeeping genes tested, was taken as the reference gene due to its most stable expression in normal and experimental conditions.
View Article and Find Full Text PDFThe mammalian striatum is known to contain non-dopaminergic neurons that express dopamine (DA)-synthesizing enzymes and produce DA, responsible for the regulation of motor function. This study assessed the expression of DA-synthesizing enzymes in striatal neurons and their role in DA synthesis in transgenic mice expressing the green fluorescent protein (GFP) gene under the tyrosine hydroxylase (TH) gene promoter in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). We showed that, in Parkinsonian animals, the number of neurons expressing the TH gene increased by 1.
View Article and Find Full Text PDFGiven the limited access to clinical material for studying the pathogenesis of Parkinson's disease (PD), these studies should be carried out on experimental models. We have recently developed a subchronic model of the progressive development of PD with a gradual transition from the preclinical (asymptomatic) stage to the clinical (symptomatic) one. The aim of this study was to evaluate changes in the expression of a wide range of genes in the substantia nigra (SN), the central link in the regulation of motor function, in mice in our subchronic model of PD.
View Article and Find Full Text PDFParkinson's disease (PD) is diagnosed many years after its onset, under a significant degradation of the nigrostriatal dopaminergic system, responsible for the regulation of motor function. This explains the low effectiveness of the treatment of patients. Therefore, one of the highest priorities in neurology is the development of the early (preclinical) diagnosis of PD.
View Article and Find Full Text PDFThe low effectiveness of symptomatic pharmacotherapy for Parkinson's disease (PD), which compensates for dopamine (DA) deficiency under degeneration of nigrostriatal dopaminergic (DAergic) neurons, could apparently be improved with neuroprotective therapy, which slows down neurodegeneration and PD progression. For this, it is necessary to have a DAergic cell line for the development of a PD model to screen neuroprotectors. We used immortalized human embryonic mesencephalon LUHMES cells (LCs) differentiated into DAergic neurons.
View Article and Find Full Text PDFThe fight against neurodegenerative diseases, including Parkinson's disease (PD), is among the global challenges of the 21st century. The low efficiency of therapy is due to the late diagnosis and treatment of PD, which take place when there is already significant degradation of the nigrostriatal dopaminergic system, a key link in the regulation of motor function. We have developed a subchronic mouse model of PD by repeatedly administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at gradually increasing doses with a 24 h interval between injections, a period comparable to the time of MPTP metabolism and elimination from the body.
View Article and Find Full Text PDFDopaminergic neurons (DNs) of the nigrostriatal system control the motor function, and their degeneration leads to the development of Parkinson's disease (PD). A stumbling block in the study of DNs in the whole substantia nigra (SN) is the lack of tools to analyze the expression of most of the genes involved in neurotransmission, neurodegeneration, and neuroplasticity, since they are also expressed in other cells of the SN. Therefore, this study aimed to develop a fluorescence-activated cell sorting method for isolating living DNs from the SN of wild-type mice using two fluorescent dyes, DRAQ5 (nuclear stain) and a dopamine uptake inhibitor GBR 12909 coupled to a fluorophore (DN stain).
View Article and Find Full Text PDFWe have recently shown that the periventricular nucleus (PeVN) of adult rats is a "mixed dopaminergic (DAergic) center" containing three thousand neurons: DAergic neurons and those expressing one of the dopamine (DA)-synthesizing enzymes. This study aims to evaluate the development of the PeVN as a mixed DAergic center in rats in the perinatal period, critical for brain morphogenesis. During this period, the PeVN contains DAergic neurons and monoenzymatic neurons expressing individual enzymes of DA synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC).
View Article and Find Full Text PDFSince the discovery of striatal neurons expressing dopamine-synthesizing enzymes, researchers have attempted to identify their phenotype and functional significance. In this study, it was shown that in transgenic mice expressing green fluorescent protein (GFP) under the tyrosine hydroxylase (TH) gene promoter, (i) there are striatal neurons expressing only TH, only aromatic L-amino acid decarboxylase (AADC), or both enzymes of dopamine synthesis; (ii) striatal neurons expressing dopamine-synthesizing enzymes are not dopaminergic since they lack a dopamine transporter; (iii) monoenzymatic neurons expressing individual complementary dopamine-synthesizing enzymes produce this neurotransmitter in cooperation; (iv) striatal nerve fibers containing only TH, only AADC, or both enzymes project into the lateral ventricles, providing delivery pathways for L-3,4-dihydroxyphenylalanine and dopamine to the cerebrospinal fluid; and (v) striatal GFP neurons express receptor genes for various signaling molecules, i.e.
View Article and Find Full Text PDFSince the 1980s, the concept of dopamine-rich brain centers as clusters of only dopaminergic neurons has been fundamentally revised. It has been shown that, in addition to dopaminergic neurons, most of these centers contain neurons expressing one of the enzymes of dopamine synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). We have obtained convincing evidence that in rats, the hypothalamic periventricular nucleus (PeVN) is one of the largest dopamine-rich centers, containing dopaminergic and monoenzymatic neurons.
View Article and Find Full Text PDFThe progressive degradation of the nigrostriatal system leads to the development of Parkinson's disease (PD). The synthesis of dopamine, the neurotransmitter of the nigrostriatal system, depends on the rate-limiting enzyme, tyrosine hydroxylase (TH). In this study, we evaluated the synthesis of dopamine during periods of neurodegradation and neuroplasticity in the nigrostriatal system on a model of the early clinical stage of PD.
View Article and Find Full Text PDFProcesses of intracellular and extracellular transport play one of the most important roles in the functioning of cells. Changes to transport mechanisms in a neuron can lead to the disruption of many cellular processes and even to cell death. It was shown that disruption of the processes of vesicular, axonal, and synaptic transport can lead to a number of diseases of the central nervous system, including Parkinson's disease (PD).
View Article and Find Full Text PDFThis is the first study aiming to develop a method for the long-term visualization of living nigrostriatal dopaminergic neurons using 1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine-BODIPY (GBR-BP), the original fluorescent substance, which is a derivative of GBR-12909, a dopamine uptake inhibitor. This method is based on the authors' hypothesis about the possibility of specifically internalizing into dopaminergic neurons substances with a high affinity for the dopamine transporter (DAT). Using a culture of mouse embryonic mesencephalic and LUHMES cells (human embryonic mesencephalic cells), as well as slices of the substantia nigra of adult mice, we have obtained evidence that GBR-BP is internalized specifically into dopaminergic neurons in association with DAT via a clathrin-dependent mechanism.
View Article and Find Full Text PDFThe fight against neurodegenerative diseases, including Parkinson's disease (PD), is a global challenge of this century. The effectiveness of current PD therapy is limited, since it is diagnosed many years after the onset, following the death of most nigrostriatal dopaminergic neurons regulating motor function. PD treatment could be greatly improved if it was started at an early (preclinical) stage.
View Article and Find Full Text PDFAccording to the literature, the cerebrospinal fluid (CSF) in the cerebral ventricles contains numerous neuron-derived physiologically active substances that can function as neurohormones and contribute to volume neurotransmission in the periventricular region of the brain. This study was aimed at carrying out a comparative analysis of CSF and the blood levels of monoamines in rats during ontogenesis as an indicator of age-related characteristics of monoamine transport to body fluids and their function as neurohormones in volume neurotransmission in the periventricular region of the brain. We have shown that CSF in the perinatal period and adulthood contains the most functionally significant monoamines: dopamine, noradrenaline, and serotonin.
View Article and Find Full Text PDFParkinson's disease (PD) is a neurodegenerative disease incurable due to late diagnosis and treatment. Therefore, one of the priorities of neurology is to study the mechanisms of PD pathogenesis at the preclinical and early clinical stages. Given the important role of sphingolipids in the pathogenesis of neurodegenerative diseases, we aimed to analyze the gene expression of key sphingolipid metabolism enzymes (ASAH1, ASAH2, CERS1, CERS3, CERS5, GBA1, SMPD1, SMPD2, UGCG) and the content of 32 sphingolipids (subspecies of ceramides, sphingomyelins, monohexosylceramides and sphinganine, sphingosine, and sphingosine-1-phosphate) in the nigrostriatal system in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of the preclinical and clinical stages of PD.
View Article and Find Full Text PDFDegeneration of nigrostriatal dopaminergic neurons in Parkinson's disease begins from the axonal terminals in the striatum and, then, in retrograde fashion, progresses to the cell bodies in the substantia nigra. Investigation of the dynamics of axonal terminal degeneration may help in the identification of new targets for neuroprotective treatment and be used as a tool for testing potential drugs. We have shown that the degeneration rate of dopaminergic axonal terminals changes over time, and that the striatal dopamine concentration is the most sensitive parameter to the action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
View Article and Find Full Text PDFEarly (preclinical) diagnosis of Parkinson's disease (PD) is a major challenge in modern neuroscience. The objective of this study was to experimentally evaluate a diagnostic challenge test with monoiodotyrosine (MIT), an endogenous inhibitor of tyrosine hydroxylase. Striatal dopamine was shown to decrease by 34% 2 h after subcutaneous injection of 100 mg/kg MIT to intact mice, with the effect not being amplified by a further increase in the MIT dose.
View Article and Find Full Text PDFDevelopment of differential and early (preclinical) diagnostics of Parkinson's disease (PD) is among the priorities in neuroscience. We searched for changes in the level of catecholamines and α-2-macroglobulin activity in the tear fluid (TF) in PD patients at an early clinical stage. It was shown that TF in patients is characterized by an increased level of noradrenaline mainly on the ipsilateral side of pronounced motor symptoms (72%, = 0.
View Article and Find Full Text PDFZh Nevrol Psikhiatr Im S S Korsakova
January 2021
Objective: To determine changes in the chemical composition of blood plasma in subjects at risk of Parkinson's disease (PD) at the prodromal stage compared with age control.
Material And Methods: Subjects at risk were selected for the presence of characteristic premotor symptoms, including impairments of sleep, olfaction and constipation.The risk group included 12 people, the control group - 8 people.