Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using mono and dualprobe(s) microdialysis in the basal ganglia of the freely moving rat evidence has been obtained that neurotensin (NT) in threshold concentrations can counteract the D(2) agonist (intrastriatally perfused) induced inhibition of striatal dopamine (DA) release and of pallidal GABA release from the striato-pallidal GABA pathway, effects that are blocked by a NTR(1) antagonist SR48692. These results indicate the existence of antagonistic intramembrane NTR/D(2) receptor interactions in the striatal DA terminals and in the somato-dendritic regions of the striato-pallidal GABA neurons. By the NT-induced reduction of the D(2) mediated signals at the striatal pre- and postjunctional level DA transmission is switched towards a D(1) mediated transmission leading to increased activity in the striatopallidal and striatonigral GABA pathways. The former action will contribute to the motor inhibition and catalepsy found with NT treatment and underlies the use of NT receptor antagonists as a treatment strategy for Parkinson's disease. Nigral NT by an antagonistic NTR/D(2) receptor interaction in the DA cell body and dendrites may also increase nigral DA release leading to a D(2) mediated inhibition of the nigrothalamic GABA pathway. Such an effect, will instead result in antiparkinsonian actions. Thus, increases in NT transmission will have different consequences for the motor system depending upon where in the basal ganglia the increase takes place.
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PMID:Receptor-receptor interactions as studied with microdialysis. Focus on NTR/D2 interactions in the basal ganglia. 1698 83

Recently we showed that the neurotensin polyplex is a nanoparticle carrier system that targets reporter genes in nigral dopamine neurons in vivo. Herein, we report its first practical application in experimental parkinsonism, which consisted of transfecting dopamine neurons with the gene coding for human glial cell line-derived neurotrophic factor (hGDNF). Hemiparkinsonism was induced in rats by a single dose of 6-hydroxydopamine (30 microg) into the ventrolateral part of the striatum. We showed that transfection of the hGDNF gene into the substantia nigra of rats 1 week after the neurotoxin injection produced biochemical, anatomical, and functional recovery from hemiparkinsonism. RT-PCR analysis showed mRNA expression of exogenous hGDNF in the transfected substantia nigra. Western blot analysis verified transgene expression by recognizing the flag epitope added at the C-terminus of the hGDNF polypeptide, which was found mainly in dopamine neurons by double immunofluorescence techniques. These data indicate that the neurotensin polyplex holds great promise for the neuroprotective therapy of Parkinson disease.
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PMID:Neurotensin polyplex as an efficient carrier for delivering the human GDNF gene into nigral dopamine neurons of hemiparkinsonian rats. 1701 39

The extracellular accumulation of glutamate and the excessive activation of glutamate receptors, in particular N-methyl-D-aspartate (NMDA) receptors, have been postulated to contribute to the neuronal cell death associated with chronic neurodegenerative disorders such as Parkinson's disease. Findings are reviewed indicating that the tridecaptide neurotensin (NT) via activation of NT receptor subtype 1 (NTS1) promotes and reinforces endogenous glutamate signalling in discrete brain regions. The increase of striatal, nigral and cortical glutamate outflow by NT and the enhancement of NMDA receptor function by a NTS1/NMDA interaction that involves the activation of protein kinase C may favour the depolarization of NTS1 containing neurons and the entry of calcium. These results strengthen the hypothesis that NT may be involved in the amplification of glutamate-induced neurotoxicity in mesencephalic dopamine and cortical neurons. The mechanisms involved may include also antagonistic NTS1/D2 interactions in the cortico-striatal glutamate terminals and in the nigral DA cell bodies and dendrites as well as in the nigro-striatal DA terminals. The possible increase in NT levels in the basal ganglia under pathological conditions leading to the NTS1 enhancement of glutamate signalling may contribute to the neurodegeneration of the nigro-striatal dopaminergic neurons found in Parkinson's disease, especially in view of the high density of NTS1 receptors in these neurons. The use of selective NTS1 antagonists together with conventional drug treatments could provide a novel therapeutic approach for treatment of Parkinson's disease.
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PMID:Neurotensin receptor mechanisms and its modulation of glutamate transmission in the brain: relevance for neurodegenerative diseases and their treatment. 1767 54

Functional studies have provided evidence supporting the concept that the tridecapeptide neurotensin (NT) acts in the central nervous system as a classical neurotransmitter and/or as an important modulator of neuronal signalling. The role of NT in the regulation of the striatal amino acidergic transmission, mainly by antagonising D2 receptor function, will be analysed. In addition, in different rat brain regions, including the basal ganglia, the contribution of NT receptors in modulating and reinforcing glutamate signalling will be shown including the involvement of interactions between NT and NMDA receptors. Since the enhancement of glutamate transmission and in particular the excessive activation of NMDA receptors, has been postulated to be an important factor in the induction of glutamate-mediated neuronal damage, the involvement of NT in the glutamate-induced neurodegenerative effects will be discussed. Moving from these observations and in order to further investigate this issue, results from preliminary behavioural, functional and biochemical experiments will be presented on the putative neuroprotective effect obtained by the blockade of NT receptor 1 (NTS1) via the systemic administration of the selective NTS1 antagonist SR48692 in an in vivo animal model of Parkinson's disease [unilateral nigral 6-hydroxydopamine (6-OHDA) induced lesion of the nigrostriatal pathway].
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PMID:Neurotensin receptors as modulators of glutamatergic transmission. 1809 38

The aim of the present study is to provide a review of the expression and action of trophic factors in the carotid body. In glomic type I cells, the following factors have been identified: brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, artemin, ciliary neurotrophic factor, insulin-like growth factors-I and -II, basic fibroblast growth factor, epidermal growth factor, transforming growth factor-alpha and -beta1, interleukin-1beta and -6, tumour necrosis factor-alpha, vascular endothelial growth factor, and endothelin-1 (ET-1). Growth factor receptors in the above cells include p75LNGFR, TrkA, TrkB, RET, GDNF family receptors alpha1-3, gp130, IL-6Ralpha, EGFR, FGFR1, IL1-RI, TNF-RI, VEGFR-1 and -2, ETA and ETB receptors, and PDGFR-alpha. Differential local expression of growth factors and corresponding receptors plays a role in pre- and postnatal development of the carotid body. Their local actions contribute toward producing the morphologic and molecular changes associated with chronic hypoxia and/or hypertension, such as cellular hyperplasia, extracellular matrix expansion, changes in channel densities, and neurotransmitter patterns. Neurotrophic factor production is also considered to play a key role in the therapeutic effects of intracerebral carotid body grafts in Parkinson's disease. Future research should also focus on trophic actions on carotid body type I cells by peptide neuromodulators, which are known to be present in the carotid body and to show trophic effects on other cell populations, that is, angiotensin II, adrenomedullin, bombesin, calcitonin, calcitonin gene-related peptide, cholecystokinin, erythropoietin, galanin, opioids, pituitary adenylate cyclase-activating polypeptide, atrial natriuretic peptide, somatostatin, tachykinins, neuropeptide Y, neurotensin, and vasoactive intestinal peptide.
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PMID:Trophic factors in the carotid body. 1877 56

The globus pallidus is a nucleus in the indirect pathway of the basal ganglia circuits. Neurotensin has been reported to play an important role in the central nervous system. Functional study revealed that systemic administration of neurotensin produced antiparkinsonian effects. The aim of the present study was to investigate the effects of neurotensin on the firing rate of globus pallidus neurons in 6-hydroxydopamine-lesioned parkinsonian rats. Micropressure ejection of neurotensin increased the spontaneous firing rate of globus pallidus neurons on both lesioned and unlesioned sides. Furthermore, the neurotensin-induced increase in firing rate on the unlesioned side (95.9%) was stronger than that on the lesioned side (37.3%). The neurotensin receptor antagonist, SR48692, prevented neurotensin-induced increase in firing rate. Based on the excitatory effects of neurotensin in globus pallidus of parkinsonian rats, we hypothesize that the pallidal neurotensinergic system may be involved in its possible therapy in Parkinson's disease.
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PMID:Electrophysiological effects of neurotensin on globus pallidus neurons of 6-hydroxydopamine-lesioned rats. 1920 46

Neurotensin (NT) is a 13 amino acid neurohormone and/or neuromodulator, located in the synaptic vesicles and released from the neuronal terminals in a calcium-dependent manner. This peptide is present among mammalian and nonmammalian species, mainly in the central nervous system and the gastrointestinal tract. Due to its neuroendocrine activity, NT has been related to the pathophysiology of a series of disorders, such as schizophrenia, drug-abuse, Parkinson's disease, cancer, stroke, eating disorders and other neurodegenerative conditions. Moreover, NT participates in the physiology of pain-induction, central blood pressure control and inflammation. NT also plays an important interactive role in all components of the hypothalamic-anterior pituitary circuit, which is mediated by an endocrine, paracrine or/and autocrine manner, towards most of the anatomical regions that define this circuit. A considerable amount of data implicates NT in thyroid-related regulation through this circuit, the exact mechanisms of which should be further investigated for the potential development of more targeted approaches towards the treatment of thyroid-related endocrine diseases. The aim of this study was to provide an up-to-date review of the literature concerning the regulatory role of NT on the hypothalamic-anterior pituitary axons, with an emphasis on the control of thyroid-related functions.
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PMID:The regulatory role of neurotensin on the hypothalamic-anterior pituitary axons: emphasis on the control of thyroid-related functions. 1987 95

The role that the tridecapeptide neurotensin (NT) plays in the modulation of the aminoacidergic transmission is analyzed in different rat brain regions. NT exerts its effects through the activation of different receptor subtypes, NTR1, NTR2 and NTR3. The contribution of NTR1 receptor in modulating and reinforcing glutamate signalling will be shown including the involvement of interactions between NT and N-methyl-D-aspartate (NMDA) receptors. Extracellular accumulation of glutamate and the excessive activation of glutamate receptors, in particular NMDA receptors, is known to represent an important factor in the induction of glutamate-mediated neuronal damage occurring in Parkinson's disease and in pathologic events such as hypoxia and ischemia. An enhancing action of NT on glutamate-induced neurodegenerative effects is shown and NTR1 receptor antagonists could therefore become novel pharmaceutics in the treatment of neurodegenerative disease.
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PMID:Emerging evidence for neurotensin receptor 1 antagonists as novel pharmaceutics in neurodegenerative disorders. 1992 16

Human embryonic stem (hES) cell differentiation into dopamine neurons is considered a promising strategy for cell replacement therapy in Parkinson's disease, yet the functional properties of hES cell-derived dopamine neurons remain poorly defined. The objective of this study was to characterize intracellular calcium (Ca(2+)) and sub-plasma membrane cyclic AMP-signaling properties in hES cell-derived dopamine neurons. We found that hES cell-derived dopamine neurons and neural progenitors raised Ca(2+) from intra- and extracellular compartments in response to depolarization, glutamate, ATP, and dopamine D(2) receptor activation, while undifferentiated hES cells only mobilized Ca(2+) from intracellular stores in response to ATP and D(2) receptor-induced activation. Interestingly, we also found that hES cell-derived dopamine neurons in addition to primary ventral midbrain dopamine neurons were more prone to release Ca(2+) from intracellular stores than non-dopamine neurons following treatment with the neuropeptide neurotensin. Furthermore, hES cell-derived dopamine neurons showed cAMP elevations in response to forskolin and 3-isobutyl-methylxanthine, similar to primary dopamine neurons. Taken together, these results unravel the temporal sequence by which hES cells acquire Ca(2+) and cAMP signaling competence during dopamine differentiation.
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PMID:Ca2+ and cAMP signaling in human embryonic stem cell-derived dopamine neurons. 2004 54

Neurotensin is a tridecapeptide that was isolated 15 years ago from bovine hypothalamus and, since then, has been shown to fulfill the major criteria that define a neurotransmitter/neuromodulator. There is considerable evidence that neurotensin interacts with mesencephalic dopamine systems. Anatomical and functional data indicate that neurotensin modulates dopamine neurotransmission at all levels along nigrostriatal and mesolimbic dopamine pathways. The peptide appears to functionally antagonize the effects that the amine exerts via both presynaptic (auto) and postsynaptic dopamine receptors. This confers a neuroleptic-like pharmacological profile to neurotensin. In addition, extensive neurotensin/dopamine colocalization occurs in a subpopulation of mesencephalic dopamine neurons that project to the prefrontal cortex. Recently, the neurotensin precursor has been shown to contain another neurotensin-like peptide, neuromedin N, that binds with high affinity to brain neurotensin receptors and displays some neuroleptic-like effects. Therefore, neuromedin N may be considered as a potential comodulator (with neurotensin) of dopamine functions. Given the implications of dopamine systems in certain neuropathological and psychotic disorders such as Parkinson's disease and schizophrenia it is likely, as already suggested by some experimental evidence, that neurotensin plays an important role in the etiology and pathogenesis of these diseases.
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PMID:Neurotensin modulates dopamine neurotransmission at several levels along brain dopaminergic pathways. 2050 6


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