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

Parkinson's disease (PD) is characterized by the selective loss of dopamine (DA) neurons in the substantia nigral brain region. Currently, there is no cure or treatment that prevents such neuronal loss. Brain-derived neurotrophic factor (BDNF) has been found to support the survival of DA neurons in animal models and in primary cell cultures. However, the large molecular size of BDNF, coupled with the blood brain barrier, prevents its delivery to DA neurons to promote cell survival in the PD brain. The nigral DA neurons have the ability to produce BDNF for neuroprotection via either autocrine or paracrine mechanisms. Low mol. wt compounds were tested to see whether they could increase the production of BDNF in the DA neurons. The compounds tested include neurotransmitters, neuropeptides, intracellular signaling agents, known neuroprotective agents and growth factors. Our results demonstrate that salicyclic acid, cGMP analog, okadaic acid, IBMX, dipyridamole and glutamate significantly enhance BDNF production in DA neuronal cells.
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PMID:Identification of potential compounds promoting BDNF production in nigral dopaminergic neurons: clinical implication in Parkinson's disease. 1071 5

Brain-derived neurotrophic factor (BDNF) has potent effects on survival and morphology of dopaminergic neurons and thus its loss could contribute to death of these cells in Parkinson's disease (PD). In situ hybridization revealed that BDNF mRNA is strongly expressed by dopaminergic neurons in control substantia nigra pars compacta (SNpc). In clinically and neuropathologically typical PD, SNpc BDNF mRNA expression is reduced by 70% (P = 0.001). This reduction is due, in part, to loss of dopaminergic neurons which express BDNF. However, surviving dopaminergic neurons in the PD SNpc also expressed less BDNF mRNA (20%, P = 0.02) than their normal counterparts. Moreover, while 15% of control neurons had BDNF mRNA expression >1 SD below the control mean, twice as many (28%) of the surviving PD SNpc dopaminergic neurons had BDNF mRNA expression below this value. This 13% difference in proportions (95% CI 8-17%, P < or = 0.000001) indicates the presence of a subset of neurons in PD with particularly low BDNF mRNA expression. Moreover, both control and PD neurons displayed a direct relationship between the density of BDNF mRNA expression per square micrometer of cell surface and neuronal size (r(2) = 0.93, P </= 0.00001) which was lost only in PD neurons expressing the lowest levels of BDNF mRNA. If BDNF is an autocrine/paracrine factor for SNpc dopaminergic neurons, loss of BDNF-expressing neurons may compromise the well-being of their surviving neighbors. Moreover, neurons expressing particularly low levels of BDNF mRNA may be those at greatest risk of injury in PD and possibly the trigger for the degeneration itself.
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PMID:Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra. 1103 Oct 89

Brain-derived neurotrophic factor (BDNF) is a small dimeric protein, structurally related to nerve growth factor, which is abundantly and widely expressed in the adult mammalian brain. BDNF has been found to promote survival of all major neuronal types affected in Alzheimer's disease and Parkinson's disease, like hippocampal and neocortical neurons, cholinergic septal and basal forebrain neurons, and nigral dopaminergic neurons. In this article, we summarize recent work on the molecular and cellular biology of BDNF, including current ideas about its intracellular trafficking, regulated synthesis and release, and actions at the synaptic level, which have considerably expanded our conception of BDNF actions in the central nervous system. But our primary aim is to review the literature regarding BDNF distribution in the human brain, and the modifications of BDNF expression which occur in the brain of individuals with Alzheimer's disease and Parkinson's disease. Our knowledge concerning BDNF actions on the neuronal populations affected in these pathological states is also reviewed, with an aim at understanding its pathogenic and pathophysiological relevance.
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PMID:Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. 1104 Apr 19

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.
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PMID:BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. 1133 82

Brain-derived neurotrophic factor (BDNF; 50 ng/ml), dopamine (DA; 10 microM) and forskolin (Fsk; 10 microM) have previously been shown by this and other laboratories to induce the tyrosine hydroxylase (TH) enzyme in foetal human and rat cerebral cortex during specified sensitive developmental periods. In the present study, these findings were extended for human and rat cells by showing that the induced TH+ cells also produce dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). In addition to this, TH induction and DA plus DOPAC production was observed in foetal human and rat cerebral cortex by using glial-cell derived neurotrophic factor (GDNF) in place of BDNF. The degree of induction by GDNF (1-10 ng/ml) was similar to that produced by BDNF and did not increase further when the two neurotrophic factors were used together. The time-course of induction in human cultures was followed: GDNF was found to cause a more rapid induction process than BDNF during the first 2 weeks. However the degree of induction after 3 weeks was the same for both neurotrophic factors. Inhibitors of transcription (actinomycin D) or of translation (cycloheximide) eliminated all the increase in DA+DOPAC contents elicited by these compounds, indicating that de novo transcription and translation were required for increased expression of the TH and other related enzymes. The intracellular pathways by which these molecules exert this dopaminergic phenotype induction effect are discussed. This study indicates a new source of dopaminergic brain tissue for use as transplants to neurosurgically treat Parkinson's disease patients.
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PMID:Parallel induction of the formation of dopamine and its metabolites with induction of tyrosine hydroxylase expression in foetal rat and human cerebral cortical cells by brain-derived neurotrophic factor and glial-cell derived neurotrophic factor. 1133 98

Brain-derived neurotrophic factor (BDNF) belongs to a family of proteins related to nerve growth factor, which are responsible for neuron proliferation, survival and differentiation. A more diverse role for BDNF as a neuronal extracellular transmitter has, nevertheless, been proposed. The dopamine D(3) receptor has been implicated in neuropsychiatric disorders including schizophrenia, drug addiction, depression and Parkinson's disease. Its expression during development and in adulthood is highly dependent on dopaminergic innervation. Here we show that BDNF synthesized by dopamine neurons is responsible for the appearance of the D(3) receptor during development and maintains D(3) receptor expression in adults. Moreover, BDNF triggers D(3) receptor overexpression and behavioral sensitization to levodopa in denervated animals. These results suggest that BDNF, by controlling the expression of specific genes such as the D(3) receptor gene, may be an important factor in neurodevelopmental psychiatric diseases.
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PMID:Brain-derived neurotrophic factor controls dopamine D3 receptor expression: implications for neurodevelopmental psychiatric disorders. 1270 5

Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases but its etiology is unclear. Alpha-synuclein (alpha-SN) is a major component of Lewy bodies and Lewy neurites, and its missense mutations, A30P and A53T, cause familial PD. In PD, alpha-SN-positive glial inclusions are distributed mainly in the dorso-medial region of the substantia nigra, which contains most of the surviving dopaminergic neurons, suggesting that alpha-SN expression might have a neuroprotective function in glial cells. To investigate this hypothesis, we established alpha-SN transfected C6 glioma cell line clones and evaluated the expression of neurotrophins using semi-quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Brain-derived neurotrophic factor (BDNF) was induced by overexpression of wild-type alpha-SN but not by that of A30P and A53T. These data suggest that the pathogenic alpha-SN mutations, A30P or A53T, are linked to the loss of BDNF production in glial cells.
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PMID:BDNF is induced by wild-type alpha-synuclein but not by the two mutants, A30P or A53T, in glioma cell line. 1511 Jul 60

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of trophic factors. BDNF is widely and abundantly expressed in the CNS and is available to some peripheral nervous system neurons that uptake the neurotrophin produced by peripheral tissues. BDNF promotes survival and differentiation of certain neuronal populations during development. In adulthood, BDNF can modulate neuronal synaptic strength and has been implicated in hippocampal mechanisms of learning and memory and spinal mechanisms for pain. Several CNS disorders are associated with a decrease in trophic support. As BDNF and its high affinity receptor are abundant throughout the whole CNS, and BDNF is a potent neuroprotective agent, this trophic factor is a good candidate for therapeutic treatment of some of CNS disorders. This review aims to correlate the features of some CNS disorders (Parkinson's disease, Alzheimer's disease, depression, epilepsy and chronic pain) to changes in BDNF expression in the brain. The cellular and molecular mechanism by which BDNF might be a therapeutic strategy are critically examined.
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PMID:Brain-derived neurotrophic factor as a drug target for CNS disorders. 1546 90

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family which interacts with high-affinity protein kinase receptors (Trk) and the unselective p75(NGFR) receptor. The BDNF gene has a complex structure with multiple regulatory elements and four promoters that are differentially expressed in central or peripheral tissue. BDNF expression is regulated by neuronal activity or peripheral hormones. Neurotrophins regulate the survival and differentiation of neurons during development but growing evidence indicates that they are also involved in several functions in adulthood, including plasticity processes. BDNF expression in the central nervous system (CNS) is modified by various kinds of brain insult (stress, ischemia, seizure activity, hypoglycemia, etc.) and alterations in its expression may contribute to some pathologies such as depression, epilepsy, Alzheimer's, and Parkinson's disease. Apart from very traumatic situations, the brain functioning is resilient to stress and capable of adaptive plasticity. Neurotrophins might act as plasticity mediators enhancing this trait which seems to be crucial in adaptive processes. In addition to documenting all of the topics mentioned above in the CNS, we review the state of the art concerning neurotrophins and their receptors, including our personal contribution which is essentially focused on the stress response.
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PMID:Physiology of BDNF: focus on hypothalamic function. 1557 56

Brain-derived neurotrophic factor (BDNF) promotes survival of injured dopaminergic nigrostriatal neurons of the adult rodent substantia nigra pars compacta, as well their development in vitro. BDNF deficiency may play a role in Parkinson's disease, as the surviving dopaminergic nigrostriatal neurons have reduced levels of BDNF, and a BDNF gene polymorphism is present in a subpopulation of patients. Here, we investigated whether a lack of BDNF in early postnatal BDNF-/- mice or a chronic 50% reduction in BDNF levels in aging BDNF+/- mice would affect the survival of the dopaminergic nigrostriatal neurons. In general terms, BDNF-/- and BDNF+/- mice had morphologically and quantitatively normal nigrostriatal neurons at any time between postnatal day 14 (P14) and 18 months, when compared to their wild-type littermates. BDNF-/- mice (P14 and P21 only) had fewer dopaminergic dendrites in the substantia nigra, suggesting that BDNF plays a role in phenotypic maturation, but not in neuronal birth or survival. BDNF-/- mice also had aberrant tyrosine hydroxylase (TH) positive cell bodies in the pars reticulata. During adulthood and aging, BDNF+/- mice performed equally well as their wild-type littermates in tests of motor coordination, and both showed aging-related decreases in the size of the dopaminergic neurons as well as in motor coordination. These results suggest that chronic deficits in BDNF alone do not affect survival or function of dopaminergic nigrostriatal neurons during aging or potentially even in Parkinson's disease.
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PMID:Maturation but not survival of dopaminergic nigrostriatal neurons is affected in developing and aging BDNF-deficient mice. 1578 Oct 60


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