M V Ugrumov

Russian Academy of Sciences, Moskva, Moscow, Russia

Are you M V Ugrumov?

Claim your profile

Publications (88)193.97 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Besides dopaminergic (DA-ergic) neurons having all enzymes of DA synthesis, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC), "monoenzymatic" neurons expressing only one of them were found in the brain, mostly in the mediobasal hypothalamus (MBH). The aim of this study was to test our hypothesis that DA is synthesized by monoenzymatic neurons, i.e. L-3,4-dihydroxyphenylalanine (L-DOPA), which is produced in the monoenzymatic TH neurons is transported to the monoenzymatic AADC neurons for DA synthesis. Incubation of MBH in Krebs-Ringer solution with L-leucine, a competitive inhibitor of L-DOPA uptake, was used to prevent a hypothetical L-DOPA capture into AADC-containing neurons. Incubation of the substantia nigra containing DA-ergic neurons under the same conditions served as the control. According to our data, the L-leucine administration provoked a decrease of DA concentration in MBH and in the incubation medium but not in the substantia nigra and respective incubation medium, showing a decrease of cooperative synthesis of DA in MBH. This conclusion was supported by an observation of higher concentration of L-DOPA in the incubation medium under perfusion of MBH with Krebs-Ringer solution containing tolcapone, an inhibitor of catechol-O-methyltransferase, and L-leucine than under perfusion with the same solution, but without L-leucine. Functional interaction between monoenzymatic TH and AADC neurons was indirectly confirmed by finding in electron microscopy their close relations in MBH. Besides monoenzymatic AADC neurons, any AADC-possessing neurons, catecholaminergic and serotoninergic, apparently, could participate in DA synthesis together with monoenzymatic TH neurons. This idea was confirmed by the observation of close topographic relations between monoenzymatic TH neurons and those containing both enzymes, i.e. DA-ergic, noradrenergic or adrenergic. Thus, monoenzymatic neurons possessing TH or AADC and being in close topographic relations can synthesize DA in cooperation.
    Neuroscience 07/2014; · 3.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Progressive degeneration of nigrostriatal dopaminergic (DA-ergic) neurons is a key component in the pathogenesis of Parkinson’s disease, which develops for a long time at the preclinical stage with no motor dysfunctions due to the initiation of compensatory processes. The goal of this study was to evaluate the changes in surviving nigrostriatal DA-ergic neurons with focus on tyrosine hydroxylase (TH) in MPTP-treated mice at the presymptomatic and early symptomatic stages of parkinsonism. According to our data, a partial degeneration of DA-ergic neurons at the presymptomatic stage was accompanied by: (i) no change in TH mRNA content in the substantia nigra (SN) suggesting a compensatory increase of TH gene expression in individual neurons; (ii) a decrease of TH protein content in the nigrostriatal system and no change in individual neurons, suggesting a slowdown of TH translation. When comparing DA-ergic neurons at the early symptomatic stage and presymptomatic stage, it becomes evident: (i) a decrease of TH mRNA content in the SN and hence gene expression in individual neurons; (ii) a decrease of TH content in the striatum and its increase in the SN and individual neurons suggesting an acceleration of TH translation. TH activity, an index of the rate of DA synthesis, was unchanged in the SN and decreased in the striatum to the same degree at both stages of parkinsonism. Meantime TH activity in individual neurons appeared to be compensatory increased, but to a higher degree at the symptomatic stage than at the presymptomatic one. These data first show that DA depletion, which provokes motor dysfunction, is not a result of the decrease of TH activity and the rate of DA synthesis but is rather related to either a decrease of DA release or an increase of DA uptake in striatal DA-ergic axons.
    Journal of the neurological sciences 01/2014; · 2.32 Impact Factor
  • Doklady Biological Sciences 01/2014; 454(1):5-8.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To date, etiopathogenesis of early stages of Parkinson’s disease (PD) remains largely obscure. One of the main approaches to the study of this problem is the investigation of the transcriptome changes in PD. In connection with the above we analyzed transcriptome alterations in MPTP mouse models of presymptomatic and early symptomatic stages of PD. Methods: As part of this objective we extracted total RNA from substantia nigra and striatum of mice with pre-symptomatic and early symptomatic stages of PD. Further, we analyzed levels of transcripts using the MouseRef-8 v2.0 Expression BeadChip Kit (Illumina) and Genome Studio (Illumina). Next we conducted a bioinformatic analysis using DAVID Bioinformatics Resources. After selection of seven transcripts we performed additional analysis of relative expression of these genes in substantia nigra, striatum, and frontal cortex of mice with pre-symptomatic and early symptomatic stages of PD using reverse transcription reaction and real-time PCR. Results: As a result of the experimental and bioinformatics analysis, we selected 60 genes, which may be involved in the pathogenesis of PD. These genes take part in neurosynaptic signal transmission, endo- and exocytosis, protein transport, protein catabolism (including ubiquitin-mediated). Thus, we selected Drd2, Clb2, Cplx2, Exoc4, Snca, Epsn2, and Ntrk2 genes from the 60 previously described for more detailed analysis. Our results will help to build a complete picture of all molecular and genetic processes, involved in the etiopathogenesis of the disease, in the future and will help to understand mechanisms of functioning of individual neurons and the whole nervous system better. These data also will allow us to select transcriptomic markers for development of a panel of biomarkers for diagnosis of PD on early stages.
    The Third World Parkinson Congress, Montreal, Canada; 10/2013
  • Michael V Ugrumov
    [Show abstract] [Hide abstract]
    ABSTRACT: In addition to catecholaminergic neurons possessing all the enzymes of catecholamine synthesis and the specific membrane transporters, neurons partly expressing the catecholaminergic phenotype have been found a quarter of a century ago. Most of them express individual enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH), or aromatic l-amino acid decarboxylase (AADC), lacking the DA membrane transporter and the vesicular monoamine transporter, type 2. These so-called monoenzymatic neurons are widely distributed throughout the brain in ontogenesis and adulthood being in some brain regions even more numerous than dopaminergic (DA-ergic) neurons. Individual enzymes of DA synthesis are expressed in these neurons continuously or transiently in norm and pathology. It has been proven that monoenzymatic TH neurons and AADC neurons are capable of producing DA in cooperation. It means that l-3,4-dihydroxyphenylalanine (l-DOPA) synthesized from l-tyrosine in monoenzymatic TH neurons is transported to monoenzymatic AADC neurons for DA synthesis. Such cooperative synthesis of DA is considered as a compensatory reaction under a failure of DA-ergic neurons, for example, in neurodegenerative diseases like hyperprolactinemia and Parkinson's disease. Moreover, l-DOPA, produced in monoenzymatic TH neurons, is assumed to play a role of a neurotransmitter or neuromodulator affecting the target neurons via catecholamine receptors. Thus, numerous widespread neurons expressing individual complementary enzymes of DA synthesis serve to produce DA in cooperation that is a compensatory reaction at failure of DA-ergic neurons.
    Advances in pharmacology (San Diego, Calif.) 01/2013; 68:37-91.
  • Doklady Biological Sciences 09/2012; 446(1):286-9.
  • Doklady Biological Sciences 10/2011; 440:284-6.
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study was aimed to test our hypothesis that the developing brain operates as an endocrine organ before the establishment of the blood-brain barrier (BBB), in rats up to the first postnatal week. Dopamine (DA) was selected as a marker of the brain endocrine activity. The hypothesis was supported by the observations in rats of: (i) the physiological concentration of DA in peripheral blood of fetuses and neonates, before the BBB establishment, and its drop by prepubertal period, after the BBB development; (ii) a drop of the DA concentration in the brain for 54% and in blood for 74% on the 3rd postnatal day after the intraventricular administration of 50 μg of α-methyl-p-tyrosine, an inhibitor of DA synthesis, with no changes in the DA metabolism in peripheral DA-producing organs. Thus, the developing brain is a principal source of circulating DA which is capable of providing an endocrine regulation of peripheral organs and the brain.
    Molecular and Cellular Endocrinology 07/2011; 348(1):78-86. · 4.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Degeneration of dopaminergic (DAergic) neurons of the nigrostriatal system is the key stage in the pathogenesis of Parkinson's disease. The first symptoms of this disease are observed after degeneration of 70-80% neurons, which occurs over 20-30 years. The clinical stage of Parkinson's disease begins after this period. Late diagnostics of Parkinson's disease contributes to low efficiency of therapy for this disorder. Detailed study of the pathogenesis and development of preclinical diagnostic methods for Parkinson's disease are the urgent problems. This work was designed to develop a new experimental model of the preclinical and clinical stages of the disease. Experimental modeling was performed on C57Bl/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This agent is converted into the MPP(+)-neurotoxin in brain DAergic neurons. We showed that MPTP in a dose of 4 mg/kg has no effect on the nigrostriatal DAergic system. MPTP in a dose of 8-16 mg/kg produced the toxic effect only on DAergic axons, which simulates the preclinical stage of Parkinson's disease. MPTP in a dose of 20-40 mg/kg had the toxic effect on neuronal axons and bodies, which simulates the clinical stage of Parkinson's disease. The data suggest that progressive degeneration of DAergic neurons is accompanied by activation of compensatory mechanisms for functional deficiency of these cells.
    Bulletin of Experimental Biology and Medicine 03/2011; 150(5):566-9. · 0.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A degradation of the nigrostriatal dopaminergic (DA-ergic) system is the key component of pathogenesis of Parkinson's disease (PD). Initial clinical symptoms appear 20-30 years after the onset of neurodegeneration, at a 70% DA depletion in the striatum and a 50% loss of nigral DA-ergic neurons. Low efficacy of the therapy might be improved if preclinical diagnostics and preventive therapy are developed. The development of appropriate experimental models should precede clinical trials. This multidisciplinary study first managed to model in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) all together the following stages of parkinsonism: (a) the early presymptomatic stage manifested by a subthreshold degeneration of axons and DA depletion in the striatum without loss of nigral cell bodies; (b) the advanced presymptomatic stage manifested by a subthreshold degeneration of striatal axons and DA depletion and by a subthreshold loss of nigral cell bodies; (c) the advanced presymptomatic stage characterized by threshold depletion of striatal DA and a loss of DA-ergic axons and nigral cell bodies resulting in motor dysfunction. The degeneration of axons proceeds and prevails that of cell bodies suggesting higher sensitivity to MPTP of the former. Compensatory processes were developed in parallel to neurodegeneration that was manifested by the increase of the DA content in individual nigral cell bodies and DA turnover in the striatum. The developed models might be exploited for: (a) an examination of pathogenetic mechanisms not only in the nigrostriatal system but also in other brain regions and in the periphery; (b) a study of the compensatory mechanisms under DA deficiency; (c) a search of precursors of motor disorders and peripheral biomarkers in presymptomatic parkinsonism; (d) the development of preventive therapy aiming to slow down the neurodegeneration and strengthen compensatory processes. Thus, the models of the early and advanced presymptomaic stages and of the early symptomatic stage of parkinsonism were developed in mice with MPTP.
    Neuroscience 03/2011; 181:175-88. · 3.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We tested our hypothesis that dopamine (DA) is secreted from the brain to the blood during the perinatal period of rat ontogeny when rats have no blood-brain barrier. We developed a specific pharmacological model to inhibit DA synthesis in the brain and maintain its constant level on the periphery using α-methyl-p-tyrosine (αMPT), an inhibitor of the key enzyme of DA synthesis tyrosine hydroxylase. On the basis of preliminary systemic administration of αMPT (200, 100, 80, and 50 μg), we selected a dose of the inhibitor of 50 μg, which excluded its effects on DA metabolism in peripheral organs. In subsequent experiments, αMPT was stereotaxically administered into the lateral brain ventricles of three-day-old rats at the selected dose. After this, we measured the concentration of catecholamines and metabolites using high performance liquid chromatography with electrochemical detection in the brain, Zuckerkandl’s organ, kidneys, adrenals, and plasma. We found that in 4 h after administration of the inhibitor, the DA concentration decreased in the brain by 54% and in the plasma by 74%, whereas in the peripheral organs it remained unchanged. Thus, we directly showed that DA is secreted from the brain in the general blood circulation before the formation of the BBB.
    Neurochemical Journal 01/2011; 5(3). · 0.24 Impact Factor
  • M A Abramova, A Calas, M Ugrumov
    [Show abstract] [Hide abstract]
    ABSTRACT: Osmotic stimulation (OS) of vasopressin (VP) neurons of the supraoptic nucleus (SON) promotes VP secretion and tyrosine hydroxylase (TH) expression in adult mammals. VP secretion is under a noradrenaline control, whereas the regulation of TH expression remains uncertain. This study was aimed to determine at what period of ontogenesis: (1) VP neurons begin to react to OS by modifying simultaneously VP and TH gene expression and synthesis, (2) the noradrenergic control of VP neurons is established. Rats on the 21st embryonic day (E), third postnatal day (P), P13 were salt loaded or salt loaded and treated with an antagonist (prazosin) or agonist (phenylephrine) of α1-adrenoreceptors. According to our immunocytochemical and in situ hybridization data, OS resulted in an increased amount of VP mRNA in each age group and of VP on E21 and P3. TH gene and synthesis was initially expressed under OS on P3. The number of TH-expressing neurons diminished by threefold in salt loaded rats from P3 to P13. OS combined with prazosin administration resulted in an increased level of VP mRNA on P3 and P13, but not on E21 suggesting the onset of the noradrenaline inhibitory control after birth. OS together with prazosin treatment stimulated TH expression on P3 and P13, whereas phenylephrine provided an opposite effect. Thus, VP neurons begin to react to OS by an increased VP synthesis at the end of fetal life and by the onset of TH expression shortly after birth; the expression of both substances appears to be under the inhibitory control of noradrenaline.
    Brain Structure and Function 01/2011; 215(3-4):195-207. · 7.84 Impact Factor
  • M V Ugrumov
    [Show abstract] [Hide abstract]
    ABSTRACT: The maintaining of homeostasis in the organism in response to a variable environment is provided by the highly hierarchic neuroendocrine-immune system. The crucial component of this system is the hypothalamus providing the endocrine regulation of key peripheral organs, and the adenohypophysis. In this case, neuron-derived signaling molecules (SM) are delivered to the blood vessels in hypothalamic "neurohaemal organs" lacking the blood-brain barrier (BBB), the posterior lobe of the pituitary and the median eminence. The release of SM to the blood vessels in most other brain regions is prohibited by BBB. According to the conventional concept, the development of the neuroendocrine system in ontogenesis begins with the "maturation" of peripheral endocrine glands which first are self-governed and then operate under the adenohypophysial control. Meantime, the brain maturation is under the control of SM secreted by endocrine glands of the developing organism and coming from the placenta and maternal organism. The hypothalamus is involved in the neuroendocrine regulation only after its full maturation that is followed by the conversion of the opened-looped neuroendocrine system to the closed-looped system as in adulthood. Neurons of the developing brain begin to secrete SM shortly after their origin and long before the establishment of specific interneuronal relations providing initially autocrine and paracrine morphogenetic influence on differentiating target neurons. Taking into account that the brain lacks BBB over this ontogenetic period, we hypothesized that it operates as the multipotent endocrine gland secreting SM to the general circulation and thereby providing the endocrine regulation of peripheral organs and the brain. The term "multipotent" means that the spectrum of the brain-derived circulating SM and their occupancy at the periphery in the developing organism should greatly exceed those in adulthood. In order to test this hypothesis, gonadotropin-releasing hormone (GnRH), dopamine (DA), and serotonin (5-hydroxytryptamine, 5-HT) were chosen as the markers of the presumptive endocrine function of the brain in ontogenesis. According to our data, the concentrations of GnRH, DA, and 5-HT in the rat general circulation during the perinatal period, i.e. before the establishment of BBB, was as high as those in the portal circulation in adulthood. The concentrations of circulating GnRH and DA dropped to almost undetectable level after the development of BBB suggesting their brain origin. This suggestion has been proven by showing an essential decrease of GnRH, DA, and 5-HT concentrations in general circulation of perinatal rats after microsurgical elimination of synthesizing neurons or the inhibition of specific syntheses in the brain before the establishment of BBB. GnRH, DA, and 5-HT apparently as dozens of other brain-derived SM appear to be capable of providing the endocrine influence on their peripheral targets like the adenohypophysis, gonads, kidney, heart, blood vessels, and the brain (endocrine autoregulation). Although the ontogenetic period of the brain operation as the multipotent endocrine gland is relatively short, the brain-derived SM are thought to be capable of providing long-lasting morphogenetic effects on peripheral targets and the brain. Thus, the developing brain operates as the multipotent endocrine gland from the onset of neurogenesis to the establishment of BBB providing the endocrine regulation of the developing organism.
    Neurochemical Research 02/2010; 35(6):837-50. · 2.13 Impact Factor
  • M V Ugrumov
    [Show abstract] [Hide abstract]
    ABSTRACT: Besides the dopaminergic (DA-ergic) neurons possessing the whole set of enzymes of DA synthesis from l-tyrosine and the DA membrane transporter (DAT), the neurons partly expressing the DA-ergic phenotype have been first discovered two decades ago. Most of the neurons express individual enzymes of DA synthesis, tyrosine hydroxylase (TH) or aromatic l-amino acid decarboxylase (AADC) and lack the DAT. A list of the neurons partly expressing the DA-ergic phenotype is not restricted to so-called monoenzymatic neurons, e.g. it includes some neurons co-expressing both enzymes of DA synthesis but lacking the DAT. In contrast to true DA-ergic neurons, monoenzymatic neurons and bienzymatic non-dopaminergic neurons lack the vesicular monoamine transporter 2 (VMAT2) that raises a question about the mechanisms of storing and release of their final synthetic products. Monoenzymatic neurons are widely distributed all through the brain in adulthood being in some brain regions even more numerous than DA-ergic neurons. Individual enzymes of DA synthesis are expressed in these neurons continuously or transiently in norm or under certain physiological conditions. Monoenzymatic neurons, particularly those expressing TH, appear to be even more numerous and more widely distributed in the brain during ontogenesis than in adulthood. Most populations of monoenzymatic TH neurons decrease in number or even disappear by puberty. Functional significance of monoenzymatic neurons remained uncertain for a long time after their discovery. Nevertheless, it has been shown that most monoenzymatic TH neurons and AADC neurons are capable to produce l-3,4-dihydroxyphenylalanine (L-DOPA) from l-tyrosine and DA from L-DOPA, respectively. L-DOPA produced in monoenzymatic TH neurons is assumed to play a role of a neurotransmitter or neuromodulator acting on target neurons via catecholamine receptors. Moreover, according to our hypothesis L-DOPA released from monoenzymatic TH neurons is captured by monoenzymatic AADC neurons for DA synthesis. Such cooperative synthesis of DA is considered as a compensatory reaction under a failure of DA-ergic neurons, e.g. in neurodegenerative diseases like hyperprolactinemia and Parkinson's disease.Thus, a substantial number of the brain neurons express partly the DA-ergic phenotype, mostly individual complementary enzymes of DA synthesis, serving to produce DA in cooperation that is supposed to be a compensatory reaction under the failure of DA-ergic neurons.
    Journal of chemical neuroanatomy 09/2009; 38(4):241-56. · 1.75 Impact Factor
  • Doklady Biological Sciences 01/2009; 426:213-5.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hyperprolactinemia is neurodegenerative disease that develops in humans as a result of degeneration of dopaminergic (DA-ergic) neurons of the arcuate nucleus, which synthesize DA, a neurohormone inhibiting prolactin secretion by pituitary lactotropes. The design and detailed analysis of good experimental models of hyperprolactinemia may help us to understand the causes and mechanisms of the disease development and develop early diagnostics and treatment of the disease. Hyperprolactinemia is usually modeled in experiments using 6-hydroxydopamine (6-HDA), a neurotoxin causing degeneration of DA-ergic neurons of the arcuate nucleus. However, 6-HAD also induces degeneration of noradrenergic (NA-ergic) axons involved in the regulation of prolactin secretion. Therefore, in this study, we evaluated the role of NA in the development of hyperprolactinemia during degeneration of DA-ergic neurons of the arcuate nucleus. To this aim, we compared changes in DA and NA metabolism in the arcuate nucleus and the blood level of prolactin in rats after treatment with 6-HDA alone and 6-HDA in the presence of desmethylimipramine, drug that prevents degeneration of NA-ergic neurons. Studies were performed in 14 days after toxin administration, i.e., at a time point when toxin-induced degenerative processes are finished, and in 45 days, i.e., after initiation of compensatory processes. We found that, in 14 days after administration of pharmacological agents, hyperprolactinemia, which resulted from DA deficit due to degeneration of DA-ergic neurons of the arcuate nucleus, is enhanced when NA-ergic afferents are protected, which may be related to the inhibitory effect of NA on DA synthesis. The latter hypothesis is supported by the fact that in 45 days after treatment with 6-HDA alone, i.e., after combined degeneration of DA-ergic and NA-ergic neurons, DA synthesis in the arcuate nucleus returns back to the normal level, which is accompanied by recovery of the normal blood level of prolactin. In contrast, in 45 days after administration of 6-HDA and desmethylimipramine, NA synthesis increases to the normal level but DA synthesis in the arcuate nucleus remains at low level, which is accompanied by an increased blood level of prolactin. Thus, our data suggest that NA inhibits DA synthesis in the arcuate nucleus and prevents a compensatory increase in DA synthesis and the normalization of the blood level of prolactin during degeneration of DA-ergic neurons.
    Neurochemical Journal 01/2009; 3(4):288-296. · 0.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Catecholamines (CA) play an important role in the regulation of GnRH neurons in adults, and it is probable that they control GnRH-neuron development. Migration of GnRH neurons was evaluated in male and female rats at the 17th embryonic day (E17) and E21, following the daily treatment of their pregnant mothers from the 11th to the 16th and 20th day of gestation with alpha-methyl-para-tyrosine (alphaMPT), an inhibitor of catecholamine synthesis. High-performance liquid chromatography with electrochemical detection (HPLC-ED) was used to specify the alphaMPT-induced CA depletion. There was a 50-70% decrease in dopamine and noradrenaline content in the nose and in the brain of alphaMPT-treated foetuses, proving the efficacy of this pharmacological model. Immunohistochemistry was used to evaluate the percentage (%) of GnRH neurons along their migration pathway from the vomeronasal organ (VNO) in the nose to the septo-preoptic area in the forebrain which is considered as an index of neuron migration. Special attention was paid to the topographic relationships of GnRH neurons with catecholaminergic fibres. These were observed in apposition with GnRH neurons in the entrance to the forebrain. In CA-deficient foetuses, the percentage of GnRH neurons located in the rostral regions extending from the VNO to the septum was greater than in controls. However, no statistically significant difference was found in the forebrain which extended from the septum to the retrochiasmatic area. In conclusion, these data suggest that endogenous catecholamines stimulate the GnRH neuron migration in ontogenesis.
    Brain Structure and Function 11/2008; 213(3):289-300. · 7.84 Impact Factor
  • M. V. Ugrumov
    [Show abstract] [Hide abstract]
    ABSTRACT: In addition to the monoaminergic (MA-ergic) neurons possessing the whole set of enzymes of monoamine (MA) synthesis from the precursor amino acid and the MA membrane transporter, the neurons partly expressing the MA-ergic phenotype have been first discovered almost twenty years ago. Most of the neurons expressing individual enzymes of MA synthesis lack the MA transporter. These so-called monoenzymatic neurons are widely distributed throughout the brain in adult mammals being even more numerous than MA-ergic neurons. Individual enzymes of MA synthesis are expressed continuously or transiently over certain periods of ontogenesis and in adulthood under functional insufficiency of the MA-ergic neurons, e.g., under their chronic stimulation or in certain neurodegenerative diseases. The earlier data suggest an important functional role of monoenzymatic neurons. Most monoenzymatic neurons possess enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH), or aromatic l-amino acid decarboxylase (AADC). TH and AADC are enzymatically active in a substantial number of monoenzymatic neurons being capable to convert l-tyrosine to l-3,4-dihydroxyphenylalanine (l-DOPA) and L-DOPA to DA or serotonin, respectively. L-DOPA produced in monoenzymatic TH-neurons is supposed to play a role of a neurotransmitter or a neuromodulator providing its action on the target neurons via catecholamine receptors. Moreover, l-DOPA released from the monoenzymatic TH-neurons is captured by monoenzymatic AADC-neurons or dopaminergic (DA-ergic) and serotoninergic neurons for DA synthesis (Kannari et al., 2006). Such cooperative synthesis of MAs is considered as a compensatory reaction under the failure of MA-ergic neurons, e.g., in neurodegenerative diseases like hyperprolactinemia and Parkinson's disease which are developed primarily because of the degeneration of DA-ergic neurons of the tuberoinfundibular system and the nigrostriatal system, respectively. Noteworthy, the neurotoxin-induced increased level of prolactin returns with time to the normal level due to stimulation of DA synthesis by the neurons of the tuberoinfundibular system, most probably because of the turning on cooperative synthesis of DA by monoenzymatic neurons. The same compensatory mechanism is supposed to be used under the failure of the nigrostriatal DA-ergic system that is manifested by the increased number of monoenzymatic neurons in the striatum of animals with neurotoxin-induced parkinsonism and in humans with Parkinson's disease. Expression of the enzymes of MA synthesis in non-MA-ergic neurons is controlled by intercellular signals such as classical neurotransmitters (catecholamines), neurotrophic factors (brain-derived neurotrophic factor, glia-derived neurotrophic factor), and perhaps hormones (prolactin, estrogens, progesterone). Thus, a substantial number of the brain neurons express partly the MA-ergic phenotype, mostly individual complementary enzymes of MA synthesis, serving to produce MAs in cooperation that is considered as a compensatory reaction under the failure of MA-ergic neurons.
    02/2008: pages 21-73;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The study has been carried out to verify the authors’ hypothesis that degeneration of dopaminergic (DA-ergic) neurons of the hypothalamic tuberoinfundibular system and concomitant development of hyperprolactinemia are accompanied by involvement of compensatory synthesis of dopamine (DA) by non-dopaminergic neurons expressing single complementary enzymes of synthesis of this neurotransmitter. Degeneration of DA-ergic neurons was produced by a stereotaxic injection into the brain lateral ventricles of 6-hydroxydopamine (6-HDA)—a specific neurotoxin of DA-ergic neurons. 14 and 45 days after the toxin administration there were determined concentration of prolactine in peripheral blood by methods of immunoenzyme and radioimmunological analyses as well as the DA amount in the arcuate nucleus by the method of highly efficient liquid chromatography with electrochemical detection. In a part of the animals, sections were prepared from the mediobasal hypothalamus (arcuate nucleus and medial eminence) and perfused with Krebs—Ringer medium; then the DA concentration was determined in the sections and in the incubation medium. 14 days after the neurotoxin administration there were revealed an increase of blood prolactine concentration and a decrease of DA concentration in the arcuate nucleus in vivo as well a decrease of the total DA amount in the sections and incubation medium in experiments in vitro. 45 days after the neurotoxin administration, all the above parameters returned to the normal level. Thus, the obtained data indicate that the hyperlactinemia and DA deficit appearing during degeneration of the arcuate nucleus DA-ergic neurons seem to be compensated due to an enhancement of DA synthesis by non-dopaminergic monoenzyme neurons of arcuate nucleus. Key wordsdopamine–arcuate nucleus–6-hydroxydopamine–prolactine–rat
    Journal of Evolutionary Biochemistry and Physiology 01/2008; 44(1):82-88. · 0.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The work has been carried out on mice of the Tg8 line with knockout of gene of monoamineoxidase A with an increase of serotonin and noradrenaline content in the brain, and on mice of the C3H line with unchanged genome and normal concentration of monoamines. An immunocytochemical study has been performed of development of neurons producing gonadotropin-releasing hormone (GnRH) under conditions of excess of serotonin and noradrenaline in the mice in embryogenesis. The GnRH-neurons were revealed at the 18th day of embryonic development in telencephalon along trajectory of their migration from olfactory bulbs to the retrochiasmatic area. In telencephalon of mouse embryos of the Tg8 line, a redistribution of the GnRH-neurons along their migration trajectory was observed as compared with embryos of the C3H line mice. The percent of the GnRH-neurons in the Tg8 mouse embryos in caudal parts of the migration trajectory was lower than in rostral parts, the opposite distribution of the neurons being observed in the C3H line mouse embryos; at the excess of serotonin and noradrenaline in the Tg8 line mouse embryos, the total amount of GnRH-neurons in the brain was lower than in the C3H mice. In males of the Tg8 line mice under conditions of excess of serotonin and noradrenaline the optical density of neurons, which correlated with the GnRH concentration in the cell, was higher than in control mice. Thus, in the Tg8 mice under conditions of the serotonin and noradrenaline excess, migration of the GnRH-neurons to their final anlage in hypothalamus is accelerated as well as the total number of the GnRH-neurons decreases, which indicates a decrease of proliferation of cells-precursors and the earlier differentiation of neurons.
    Journal of Evolutionary Biochemistry and Physiology 01/2007; 43(3):356-364. · 0.21 Impact Factor

Publication Stats

797 Citations
193.97 Total Impact Points

Institutions

  • 1979–2014
    • Russian Academy of Sciences
      • • Institute of Developmental Biology
      • • Koltzov Institute of Developmental Biology
      • • Laboratory of Hormonal Regulations
      Moskva, Moscow, Russia
  • 2000–2008
    • Russian Academy of Medical Sciences
      Moskva, Moscow, Russia
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2006
    • P.K. Anokhin Institute of Normal Physiology
      Московский, Moskovskaya, Russia
  • 2005
    • Max Planck Institute for Developmental Biology
      Tübingen, Baden-Württemberg, Germany
    • Russian Academy of Education
      Moskva, Moscow, Russia
  • 2002–2005
    • State University of New York Upstate Medical University
      • Department of Surgery
      Syracuse, NY, United States
  • 1986
    • Unité Inserm U1077
      Caen, Lower Normandy, France