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)

The role of the D(3) receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D(3) receptor. The D(3) receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D(3) receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinson's disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D(3) receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D(3) receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.
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PMID:The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. 1661 52

Similar to embryonic forebrain, the embryonic mesencephalon contains Fibroblast Growth Factor 2 (FGF2)- and Epidermal Growth Factor (EGF)-responsive progenitors that can be isolated as neurospheres. Developmentally, the FGF2-responsive population appears first and is thought to give rise to EGF-responsive neural stem cells. It is not known whether following this developmental switch of growth factor responsiveness ventral mesencephalic (VM)-derived neural stem cells display distinct region-specific properties. We found that murine VM- and dorsal mesencephalic (DM)-derived primary neurospheres isolated with EGF at embryonic day 14.5 differed with respect to neurosphere formation efficacy and size. VM- but not DM-derived spheres expressed En1, the molecular marker of isthmic organizer, and contained transcripts of BDNF, FGF2, IGF-I and NT-3. Both VM and DM primary neurospheres were self-renewing and gave rise to astroglial cells, but 20% of VM spheres also generated neurons. According to in vitro properties, DM- and majority of VM-derived EGF-responsive progenitors represent glial precursors. VM- but not DM-derived primary neurospheres enriched their respective conditioned medium with factors that promoted the survival of dopaminergic neurons in vitro, suggesting that ventral mesencephalic EGF-responsive progenitors are endowed with the potential to provide trophic support to nearby nascent dopaminergic neurons. These data may have implications in the treatment of Parkinson's disease.
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PMID:Murine embryonic EGF-responsive ventral mesencephalic neurospheres display distinct regional specification and promote survival of dopaminergic neurons. 1662 6

The subthalamic nucleus and the striatum are input regions of the basal ganglia. This study used the unilateral 6-OHDA rat model of Parkinson's disease to examine effects of l-DOPA on the expression of c-fos and BDNF mRNAs in these nuclei. Dopamine depletion per se did not affect c-fos or BDNF. Both a single and repeated injections of l-DOPA induced c-fos, but not BDNF, in the dopamine-depleted striatum. However, repeated l-DOPA treatment increased c-fos and BDNF in the dopamine-depleted subthalamic nucleus. These molecular adaptations may reflect changes in neuronal plasticity that underlie some therapeutic actions and/or side effects of l-DOPA in Parkinson's disease.
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PMID:Repeated l-DOPA treatment increases c-fos and BDNF mRNAs in the subthalamic nucleus in the 6-OHDA rat model of Parkinson's disease. 1672 25

Parkinson disease is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra. Long term epidemiological studies have implicated exposure to agricultural pesticides as a significant risk factor. Systemic administration of rotenone, a widely used pesticide, causes selective degeneration of nigral DA neurons and Parkinson disease-like symptoms in rats. Our previous study has shown that the microtubule depolymerizing activity of rotenone plays a critical role in its selective toxicity on DA neurons. Rotenone toxicity is mimicked by the microtubule-depolymerizing drug colchicine and attenuated by the microtubule-stabilizing agent taxol. Here we show that nerve growth factor (NGF) significantly reduced rotenone toxicity on TH(+) neurons in midbrain neuronal cultures. The protective effect of NGF was completely abolished by inhibiting the microtubule-associated protein kinase kinase (MEK) and partially reversed by blocking phosphatidylinositol 3-kinase. In addition, NGF decreased colchicine toxicity on TH(+) neurons in a manner dependent on MEK but not phosphatidylinositol 3-kinase. The protective effect of NGF against rotenone toxicity was occluded by the microtubule-stabilizing drug taxol. In a MEK-dependent manner, NGF significantly attenuated rotenone- or colchicine-induced microtubule depolymerization and ensuing accumulation of vesicles in the soma and elevation in protein carbonyls. Moreover, other neurotrophic factors such as brain-derived neurotrophic factor and glia cell line-derived neurotrophic factor also reduced rotenone- or colchicine-induced microtubule depolymerization and death of TH(+) through a MEK-dependent mechanism. Thus, our results suggest that neurotrophic factors activate the microtubule-associated protein kinase pathway to stabilize microtubules, and this action significantly attenuates rotenone toxicity on dopaminergic neurons.
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PMID:Neurotrophic factors stabilize microtubules and protect against rotenone toxicity on dopaminergic neurons. 1688 4

Rats were injected (i.p.) once daily with either 1 mg/kg CGP 56999A, a gamma-aminobutyric acid(B) (GABA(B)) receptor antagonist, or an equivalent volume of saline beginning 7 days prior to, and continuing for 7 days following, a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine (DA) pathway. At the end of the CGP 56999A treatment period the concentrations of DA and dihydroxyphenylacetic acid (DOPAC), as well as the expression of brain-derived neurotrophic factor (BDNF), were analyzed in corpus striatum ipsilateral and contralateral to the lesioning. No significant differences in these parameters were noted in the contralateral striatum between saline- and CGP 56999A-treated subjects. In contrast, as compared to animals receiving saline only, daily treatment with the GABA(B) receptor antagonist significantly attenuated the 6-hydroxydopamine-induced decline in DA and increased the expression of BDNF in the ipsilateral striatum. The results indicate that CGP 56999A enhances BDNF gene expression in the rat corpus striatum and prevents the decline in DA content that is a characteristic sequela of 6-hydroxydopapmine lesions of the nigrostraital dopamine pathway. These findings suggest that GABA(B) receptor antagonists may be of value in the treatment of Parkinson's disease and other conditions that would benefit from an enhanced production of neurotrophic factors in brain.
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PMID:CGP 56999A, a GABA(B) receptor antagonist, enhances expression of brain-derived neurotrophic factor and attenuates dopamine depletion in the rat corpus striatum following a 6-hydroxydopamine lesion of the nigrostriatal pathway. 1689 Mar 50

Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.
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PMID:Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. 1696 67

We investigated whether the cytokines produced in activated microglia in the substantia nigra (SN) and putamen in sporadic Parkinson's disease (PD) are neuroprotective or neurotoxic. In autopsy brains of PD, the number of MHC class II (CR3/43)-positive activated microglia, which were also ICAM-1 (CD 54)-, LFA-1 (CD 11a)-, TNF-alpha-, and IL-6-positive, increased in the SN and putamen during progress of PD. At the early stage activated microglia were mainly associated with tyrosine hydroxylase (TH)-positive neurites in the putamen, and at the advanced stage with damaged TH-positive neurons in the SN. The activated microglia in PD were observed not only in the nigro-striatal region, but also in various brain regions such as the hippocampus and cerebral cortex. We examined the distribution of activated microglia and the expression of cytokines and neurotrophins in the hippocampus of PD and Lewy body disease (LBD). The levels of IL-6 and TNF-alpha mRNAs increased both in PD and LBD, but those of BDNF mRNA and protein drastically decreased specifically in LBD, in which neuronal loss was observed not only in the nigro-striatum but also in the hippocampus. The results suggest activated microglia in the hippocampus to be probably neuroprotective in PD, but those to be neurotoxic in LBD. As an evidence supporting this hypothesis, two subsets of microglia were isolated from mouse brain by cell sorting: one subset with high production of reactive oxygen species (ROS) and the other with no production of ROS. When co-cultured with neuronal cells, one microglia clone with high ROS production was neurotoxic, but another clone with no ROS production neuroprotective. On the other hand, Sawada with coworkers found that a neuroprotective microglial clone in a culture experiment converted to a toxic microglial clone by transduction of the HIV-1 Nef protein with increasing NADPH oxidase activity. Taken together, all these results suggest that activated microglia may change in vivo from neuroprotective to neurotoxic subtsets as degeneration of dopamine neurons in the SN progresses in PD. We conclude that the cytokines from activated microglia in the SN and putamen may be initially neuroprotective, but may later become neurotoxic during the progress of PD. Toxic change of activated microglia may also occur in Alzheimer's disease and other neurodegenerative diseases in which inflammatory process is found.
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PMID:Role of cytokines in inflammatory process in Parkinson's disease. 1701 56

Since its' discovery over 20 years ago, BDNF has been shown to play a key role in neuronal survival, in promoting neuronal regeneration following injury, regulating transmitter systems and attenuating neural-immune responses. Estrogen's actions in the young and mature brain, and its role in neurodegenerative diseases in many cases overlaps with those observed for BDNF. Reduced estrogen and BDNF are observed in patients with Parkinson's disease and Alzheimer's disease, while high estrogen levels are a risk factor for development of multiple sclerosis. Estrogen receptors, which transduce the actions of estrogen, colocalize to cells that express BDNF and its receptor trkB, and estrogen further regulates the expression of this neurotrophin system. This review describes the distribution of BDNF and trkB expressing cells in the forebrain, and the roles of estrogen and the BDNF-trkB neurotrophin system in Parkinson's disease, Alzheimer's disease and multiple sclerosis.
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PMID:Estrogen-BDNF interactions: implications for neurodegenerative diseases. 1706 77

Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here.
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PMID:BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups. 1722 24

Neural precursor (NP) cells from adult mammalian brains can be isolated, expanded in vitro, and potentially used as cell replacement source material for treatment of intractable brain disorders. Reduced ethical concerns, lack of teratoma formation, and possible ex vivo autologous transplantation are critical advantages to using adult NP donor cells over cells from fetal brain tissue or embryonic stem cells. However, the usage of adult NP cells is limited by the ability to induce specific neurochemical phenotypes in these cells. Here, we demonstrate induction of a dopaminergic phenotype in NP cells isolated from the subventricular zone (SVZ) and white matter of rodent adult brains using overexpression of the nuclear receptor Nurr1 in vitro. Forced expression of Nurr1, a transcriptional factor specific to midbrain dopamine (DA) neuron development, caused in the adult cells an acquisition of the DA neurotransmitter phenotype and sufficient differentiation toward morphologically, phenotypically, and ultrastructurally mature DA neurons. Co-expression of neurogenic factor Mash1 and treatment with neurogenic cytokines brain-derived neurotrophic factor and neurotrophin-3 greatly enhanced Nurr1-induced DA neuron yield. The Nurr1-induced DA neurons demonstrated in vitro presynaptic DA neuronal functionality, releasing DA neurotransmitter in response to depolarization stimuli and specific DA reuptake. Furthermore, Nurr1-engineered adult SVZ NP cells survived, integrated, and differentiated into DA neurons in vivo that can reverse the behavioral deficit in the host striatum of parkinsonian rats. These findings open the possibility for the use of precursor cells from adult brains as a cell source for neuronal replacement treatment of Parkinson disease. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Generation of functional dopamine neurons from neural precursor cells isolated from the subventricular zone and white matter of the adult rat brain using Nurr1 overexpression. 1723 94


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