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)

Parkinson's disease is a progressive neurodegenerative disorder characterized by selective degeneration of nigrostriatal dopaminergic neurons. Long-term systemic mitochondrial complex I inhibition by rotenone induces selective degeneration of dopaminergic neurons in rats. We have reported dopamine redistribution from vesicles to the cytosol to play a crucial role in selective dopaminergic cell apoptosis. In the present study, we investigated how rotenone causes dopamine redistribution to the cytosol using an in vitro model of human dopaminergic SH-SY5Y cells. Rotenone stimulated nitration of the tyrosine residues of intracellular proteins. The inhibition of nitric-oxide synthase or reactive oxygen species decreased the amount of nitrotyrosine and attenuated rotenone-induced apoptosis. When we examined the intracellular localization of dopamine immunocytochemically using anti-dopamine/vesicular monoamine transporter 2 (VMAT2) antibodies and quantitatively using high-performance liquid chromatography, inhibiting nitration was found to suppress rotenone-induced dopamine redistribution from vesicles to the cytosol. We demonstrated rotenone to nitrate tyrosine residues of VMAT2 using an immunocytochemical method with anti-nitrotyrosine antibodies and biochemically with immunoprecipitation experiments. Rotenone inhibited the VMAT2 activity responsible for the uptake of dopamine into vesicles, and this inhibition was reversed by inhibiting nitration. Moreover, rotenone induced the accumulation of aggregate-like formations in the stained image of VMAT2, which was reversed by inhibiting nitration. Our findings demonstrate that nitration of the tyrosine residues of VMAT2 by rotenone leads to both functional inhibition and accumulation of aggregate-like formations of VMAT2 and consequently to the redistribution of dopamine to the cytosol and apoptosis of dopaminergic SH-SY5Y cells.
 ...
PMID:Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells. 1859 2

The vesicular monoamine transporter-2 (VMAT-2) is an important regulator of intraneuronal monoamine concentrations and disposition as this protein sequesters critical cytoplasmic monoaminergic transmitters and contributes to their subsequent exocytotic release. This review primarily discusses the impact of psychoactive drugs (including those with abuse potential) on dopamine (DA)-related VMAT-2 and its function. In particular, the different responses by DA-related VMAT-2 and associated vesicles to plasmalemmal uptake blockers like methylphenidate and releasers like methamphetamine are presented. Recent preclinical findings suggest that vesicular transporter systems are highly regulatable, both by changes in localization as well as alterations in the kinetics of the VMAT-2 protein. The capacity for such shifts in VMAT-2 functions suggests the presence of physiological regulation that likely influences the activity of DA systems. In addition, these findings may contribute to our understanding of the pathogenesis of a variety of DA-related disorders such as substance abuse and Parkinson's disease and also suggest new therapeutic targets for treating such diseases.
 ...
PMID:Psychostimulant-induced alterations in vesicular monoamine transporter-2 function: neurotoxic and therapeutic implications. 1866 7

The psychostimulant, methylphenidate (MPD), is commonly prescribed to treat attention-deficit hyperactivity disorder. MPD binds to the neuronal dopamine (DA) transporter, where it blocks the inward transport of DA. The present study expands upon these findings by examining the effects of in vivo MPD administration on the vesicular monoamine transporter-2 (VMAT-2) in membrane-associated vesicle and cytoplasmic vesicle subcellular fractions (i.e., those vesicles that do and do not co-fractionate with synaptosomal membranes after osmotic lysis, respectively) isolated from lysates of rat striatal synaptosomes. The results indicate that a single MPD administration redistributes VMAT-2 and associated vesicles within nerve terminals away from the synaptosomal membranes and into the cytoplasm, as assessed 1 hour after treatment. DA transport is also increased by MPD in both vesicle fractions (on account of vesicle trafficking in the cytoplasmic vesicles and to kinetic upregulation of the VMAT-2 in the membrane-associated vesicles). This, in turn, leads to an increase in the DA content of both vesicle fractions as well as an increase in the velocity and magnitude of K(+)-stimulated DA release from striatal suspensions. Taken together, these data show that the trafficking, DA sequestration function, DA content, and exocytotic DA release function of synaptic vesicles can all be pharmacologically manipulated by in vivo MPD treatment. These findings may provide important insights useful for understanding and treating disorders involving abnormal DA transmission including drug abuse, Parkinson's disease, and attention-deficit hyperactivity disorder.
 ...
PMID:Methylphenidate-induced alterations in synaptic vesicle trafficking and activity. 1899 73

In vivo methylphenidate (MPD) administration decreases vesicular monoamine transporter-2 (VMAT-2) immunoreactivity in membrane-associated vesicles isolated from the striata of treated rats while concurrently kinetically upregulating VMAT-2-mediated vesicular dopamine (DA) sequestration. The functional consequences of these MPD-induced effects include an increase in both vesicular DA content and exocytotic DA release. This report describes experiments designed to develop and validate an in vitro MPD model to further elucidate the molecular mechanism(s) underlying the effects of MPD on the VMAT-2 in membrane-associated vesicles. Method development experiments revealed that in vitro MPD incubation of striatal homogenates, but not striatal synaptosomes, increased DA transport velocities and decreased VMAT-2 immunoreactivity in membrane-associated vesicles. An incubation time of 30min with a MPD concentration of 10mM was optimal. Method validation experiments indicated that in vitro MPD incubation kinetically upregulated VMAT-2 in membrane-associated vesicles, increased vesicular DA content, and increased exocytotic DA release. These results reveal that the in vitro MPD incubation model successfully reproduced the salient features of in vivo MPD administration. This in vitro MPD incubation model may provide novel insights into the receptor-mediated mechanism(s) of action of in vivo MPD in the striatum as well as the physiological regulation of vesicular DA sequestration and synaptic transmission. Accordingly, this in vitro model may help to advance the treatment of disorders involving abnormal DA disposition including Parkinson's disease, attention-deficit hyperactivity disorder, and substance abuse.
 ...
PMID:Method development and validation of an in vitro model of the effects of methylphenidate on membrane-associated synaptic vesicles. 1899 77

The abuse of methamphetamine (METH) is a serious public health problem because METH can cause persistent dopaminergic deficits in the brains of both animal models and humans. Surprisingly, adolescent postnatal day (PND)40 rats are resistant to these METH-induced deficits, whereas young adult PND90 rats are not. Studies described in this report used rotating disk electrode voltammetry and western blotting techniques to investigate whether there are age-dependent differences in monoamine transporter function in PND38-42 and PND88-92 rats that could contribute to this phenomenon. The initial velocities of dopamine (DA) transport into, METH-induced DA efflux from, and DA transporter (DAT) immunoreactivity in striatal suspensions are greater in PND38-42 rats than in PND88-92 rats. DA transport velocities into vesicles that cofractionate with synaptosomal membranes after osmotic lysis are also greater in PND38-42 rats. However, there is no difference in vesicular monoamine transporter-2 (VMAT-2) immunoreactivity between the two age groups in this fraction. This suggests that younger rats have a greater capacity to sequester cytoplasmic DA into membrane-associated vesicles due to kinetically upregulated VMAT-2 and also have increased levels of functionally active DAT. In the presence of METH, these may provide additional routes of cellular efflux for DA that is released from vesicles into the cytoplasm and thereby prevent cytoplasmic DA concentrations in younger rats from rising to neurotoxic levels after drug administration. These findings provide novel insight into the age-dependent physiological regulation of neuronal DA sequestration and may advance the treatment of disorders involving abnormal DA disposition including substance abuse and Parkinson's disease.
 ...
PMID:Age-dependent differences in dopamine transporter and vesicular monoamine transporter-2 function and their implications for methamphetamine neurotoxicity. 1902 Dec 8

The protein alpha-synuclein is central to the pathophysiology of Parkinson's disease (PD) but its role in the development of neurodegeneration remains unclear. alpha-Synuclein-knockout mice develop without gross abnormality and are resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial inhibitor widely used to model parkinsonism. Here we show that differentiated human dopaminergic neuron-like cells also have increased resistance to 1-methyl-4-phenylpyridine (MPP+), the active metabolite of MPTP, when alpha-synuclein is knocked down using RNA interference. In attempting to understand how this occurred we found that lowering alpha-synuclein levels caused changes to intracellular vesicles, dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2), each of which is known to be an important component of the early events leading to MPP+ toxicity. Knockdown of alpha-synuclein reduced the availability of DAT on the neuronal surface by 50%, decreased the total number of intracellular vesicles by 37% but increased the density of VMAT2 molecules per vesicle by 2.8-fold. However, these changes were not associated with any reduction in MPP+ -induced superoxide production, suggesting that alpha-synuclein knockdown may have other downstream effects which are important. We then showed that alpha-synuclein knockdown prevented MPP+ -induced activation of nitric oxide synthase (NOS). Activation of NOS is an essential step in MPTP toxicity and increasing evidence points to nitrosative stress as being important in neurodegeneration. Overall, these results show that as well as having a number of effects on cellular events upstream of mitochondrial dysfunction alpha-synuclein affects pathways downstream of superoxide production, possibly involving regulation of NOS activity.
 ...
PMID:The effect of alpha-synuclein knockdown on MPP+ toxicity in models of human neurons. 1903 94

MN9D cells have been used as a successful model to investigate dopamine pharmacology and to test the specific effects of drugs for the treatment of Parkinson's disease. However, quantitative measurements of quantal release from these cells have not been carried out. In this work, we used amperometry to investigate catecholamine release from MN9D cells. Amperometric events were observed in both undifferentiated and differentiated (butyric acid-treated) cells. An increase in quantal size and half-width was observed for differentiated cells versus undifferentiated cells; however, the number of events per cell and the amplitude remained constant. In transmission electron microscopy images, no obvious cluster of small synaptic vesicles was observed, and large dense-core vesicles were present in the cell body of undifferentiated cells; however, after differentiation, vesicles were concentrated in the cell processes. In differentiated cells, l-DOPA caused an increase in quantal size and half-width, which could be blocked by the vesicular monoamine transporter inhibitor, reserpine.
 ...
PMID:Amperometric measurements of catecholamine release from single vesicles in MN9D cells. 1909 57

Pesticide exposure has been suggested as a risk factor in developing Parkinson's disease (PD). While the molecular mechanism underlying this association is not clear, several studies have demonstrated a role for mitochondrial dysfunction and oxidative damage in PD. Although data on specific pesticides associated with PD are often lacking, several lines of evidence point to the potential involvement of the organochlorine class of pesticides. Previously, we have found that the organochlorine pesticide methoxychlor (mxc) causes mitochondrial dysfunction and oxidative stress in isolated mitochondria. Here, we sought to determine whether mxc-induced mitochondrial dysfunction results in oxidative damage and dysfunction of the dopamine system. Adult female CD1 mice were dosed with either vehicle (sesame oil) or mxc (16, 32, or 64 mg/kg/day) for 20 consecutive days. Following treatment, we observed a dose-related increase in protein carbonyl levels in non-synaptic mitochondria, indicating oxidative modification of mitochondrial proteins which may lead to mitochondrial dysfunction. Mxc exposure also caused a dose-related decrease in striatal levels of dopamine (16-31%), which were accompanied by decreased levels of the dopamine transporter (DAT; 35-48%) and the vesicular monoamine transporter 2 (VMAT2; 21-44%). Because mitochondrial dysfunction, oxidative damage, and decreased levels of DAT and VMAT2 are found in PD patients, our data suggest that mxc should be investigated as a possible candidate involved in the association of pesticides with increased risk for PD, particularly in highly exposed populations.
 ...
PMID:Effects of the organochlorine pesticide methoxychlor on dopamine metabolites and transporters in the mouse brain. 1945 24

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, culminating in severe motor symptoms, including resting tremor, rigidity, bradykinesia, and postural instability. In addition to motor deficits, there are a variety of nonmotor symptoms associated with PD. These symptoms generally precede the onset of motor symptoms, sometimes by years, and include anosmia, problems with gastrointestinal motility, sleep disturbances, sympathetic denervation, anxiety, and depression. Previously, we have shown that mice with a 95% genetic reduction in vesicular monoamine transporter expression (VMAT2-deficient, VMAT2 LO) display progressive loss of striatal dopamine, L-DOPA-responsive motor deficits, alpha-synuclein accumulation, and nigral dopaminergic cell loss. We hypothesized that since these animals exhibit deficits in other monoamine systems (norepinephrine and serotonin), which are known to regulate some of these behaviors, the VMAT2-deficient mice may display some of the nonmotor symptoms associated with PD. Here we report that the VMAT2-deficient mice demonstrate progressive deficits in olfactory discrimination, delayed gastric emptying, altered sleep latency, anxiety-like behavior, and age-dependent depressive behavior. These results suggest that the VMAT2-deficient mice may be a useful model of the nonmotor symptoms of PD. Furthermore, monoamine dysfunction may contribute to many of the nonmotor symptoms of PD, and interventions aimed at restoring monoamine function may be beneficial in treating the disease.
 ...
PMID:Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity. 1982 98

Methylphenidate is a psychostimulant that inhibits the neuronal dopamine transporter. In addition, methylphenidate has the intriguing ability to provide neuroprotection from the neurotoxic effects of methamphetamine and perhaps also Parkinson's disease; both of which may likely involve the abnormal accumulation of cytoplasmic dopamine inside dopaminergic neurons and the resulting formation of dopamine-associated reactive oxygen species. As delineated in this review, the neuroprotective effects of methylphenidate are due, at least in part, to its ability to attenuate or prevent this abnormal cytoplasmic dopamine accumulation through several possible neuropharmacological mechanisms. These may include 1) direct interactions between methylphenidate and the neuronal dopamine transporter which may attenuate or prevent the entry of methamphetamine into dopaminergic neurons and may also decrease the synthesis of cytoplasmic dopamine through a D2 receptor-mediated signal cascade process, and 2) indirect effects upon the functioning of the vesicular monoamine transporter-2 which may increase vesicular dopamine sequestration through both vesicle trafficking and the kinetic upregulation of the vesicular monoamine transporter-2 protein. Understanding these neuropharmacological mechanisms of methylphenidate neuroprotection may provide important insights into the physiologic regulation of dopaminergic systems as well as the pathophysiology of a variety of disorders involving abnormal dopamine disposition ranging from substance abuse to neurodegenerative diseases such as Parkinson's disease.
 ...
PMID:Neuropharmacological mechanisms underlying the neuroprotective effects of methylphenidate. 1958 58


<< Previous 1 2 3 4 5 6 7 8 9 10