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)

The availability of radiolabelled ligands selective for various putative neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pathway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the periphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the vomiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethasone and the cannabinoids is still obscure. Some drugs act on more than 1 receptor subtype. Metoclopramide may inhibit both dopamine D2- and 5-HT3 receptors in producing its antiemetic effect. Both metoclopramide and domperidone appear to have additional peripheral actions that contribute to their effectiveness. The cannabinoids are effective in cytotoxic-induced vomiting, perhaps acting via endorphin receptors or by inhibiting prostaglandin synthesis. The effectiveness of 5-HT3 receptor antagonists may depend on the block of both central and peripheral neuronal 5-HT3 receptors. Vomiting constitutes a major disadvantage to the use of many drugs; vomiting induced by aminoglycoside antibiotics appears to be due to ototoxicity and is relieved by histamine H1-receptor antagonists. The protracted vomiting associated with the use of some cytotoxics in cancer chemotherapy may involve psychic components, the chemoreceptor trigger zone and peripheral sensory neurons. Both 5-HT3 and dopamine D2-receptor antagonists exert some control, the former being more effective with cytotoxics of high emetogenic potential, such as cisplatin. Serotonin 5-HT3 receptor antagonists or high doses of metoclopramide in combination with anxiolytics and steroids as well as greater attention to pharmacokinetic profiles of the drugs involved would appear to offer improved control. The use of dopamine receptor antagonists in controlling emesis induced by dopamine agonists used in Parkinson's disease poses theoretical problems which can be overcome by using drugs with selectivity for the chemoreceptor trigger zone, such as domperidone or metoclopramide. However, higher doses of these drugs may produce some impairment of therapeutic responses to the agonists. Muscarinic and nicotinic agonists currently under investigation in Alzheimer's disease pose another therapeutic dilemma as emesis is due to a central action of these compounds. Several sites may be involved including the chemoreceptor trigger zone and frontal lobes. Opiates may act through dopamine receptors or mu-receptors on dopaminergic nerves, but serotonergic mechanisms may also be involved in the action of some opiates.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Pharmacological agents affecting emesis. A review (Part I). 137 16

The application of the technique of in vitro receptor autoradiography to the study of neurotransmitter receptor alterations associated with human brain diseases is reviewed. Focus is made on receptor alterations in Parkinson's disease and Senile Dementia. Different types of modifications have been found. The most important are 1) receptor changes related to a specific neuronal loss; 2) receptor regulation associated with modifications of presynaptic input; 3) receptor changes which cannot directly be related to neuronal loss or presynaptic changes. The possible value as a diagnostic tool and the utility of receptor autoradiography in neuropathology is discussed.
 ...
PMID:Receptors in human brain diseases: a use for receptor autoradiography in neuropathology. 283 27

Autoradiography allows precise anatomical matching as well as quantification of receptor density and is an ideal procedure to investigate neurotransmitter receptor distribution. Post mortem tissue from the caudate and putamen was investigated in cases of Parkinson's disease, Alzheimer's disease and age matched controls. Autoradiography was used to determine benzodiazepine, muscarinic cholinergic, D1 and D2 dopamine receptor density in these regions. This work shows that within the control group there is significantly higher benzodiazepine receptor density in the medial portion of the caudate and putamen when compared to lateral region. In the caudate nucleus there is a 15% (not significant) decrease of these receptors from rostral to caudal, no such decrease was present in the putamen. Muscarinic and both D1 and D2 dopamine receptors were evenly distributed in the control cases. Significant abnormalities in Parkinson's disease included loss of benzodiazepine receptors in the mid and caudal portions of the putamen and a decrease in muscarinic receptor density in the rostral putamen in Parkinson's disease.
 ...
PMID:A detailed anatomical analysis of neurotransmitter receptors in the putamen and caudate in Parkinson's disease and Alzheimer's disease. 804 95

A robust feature of mammalian aging associated with diminished motor control is the loss of dopamine D2 receptors from the neostriatum. Decline in this neurotransmitter receptor is also observed in neurodegenerative disorders, such as Huntington's disease and late-stage Parkinson's disease. We have constructed a replication-deficient adenoviral vector to transfer rat dopamine D2 receptor cDNA to brain as a possible therapeutic strategy. Using tissue culture cells infected with this vector, we detected dopamine D2 receptor mRNA by Northern analysis and functional receptor protein in membrane preparations as specific binding of the dopamine D2 receptor ligand, [3H]spiperone. In vivo demonstration involved autoradiographic analysis of [3H]spiperone binding in rat striatum following injection of the adenoviral vector. Dopamine D2 receptor expression was amplified markedly above normal concentrations in the injection site, whereas no increased expression was observed in sites receiving control treatments. These results demonstrate the potential of gene therapy using adenoviral vectors to transfer neurotransmitter receptor proteins to the brain to reverse deficiencies in specific neurodegenerative disorders.
 ...
PMID:Adenovirus-mediated gene transfer of dopamine D2 receptor cDNA into rat striatum. 875 Aug 35

One recent strategy of gene therapy is to have cells express the lacking substances. Decline in dopamine D2 receptors (D2R) is observed in late-stage Parkinson's disease. We have constructed a replication-deficient adenovirus vector to transfer rat D2R cDNA (AdCMV.DopD2R) to the brain as a possible therapeutic strategy and a replication-deficient adenovirus vector to express nothing (AdCMV.Null) as a control. Using tissue culture cells infected with this vector, we detected D2 R cDNA by Northern analysis and receptor protein in membrane preparations as specific binding of the D2R ligand, [3H] spiperone. In vivo demonstration involved autoradiographic analysis of [3H] spiperone binding in rat striatum, D2R expression was amplified above normal concentrations in the injection site. We investigated the expression and functionality of the adenoviral vector. Comparative analysis of the autoradiographic images from the striatum injected with AdCMV.DopD2R and the contralateral striatum injected with a control vector, AdCMV. Null, in male rats indicated that D2R binding was increased by 40-60% on days 3 and 5 after injection, but then declined to baseline levels by day 21. When injected with apomorphine on days 3 and 7 after vector injection, experimental groups that had received unilateral striatal injections of AdCMV. DopD2R exhibited a distinct and significant laterality in rotational behavior. These results provide the first demonstration of an adenovirally mediated, intracerebral delivery of a functional neurotransmitter receptor.
 ...
PMID:[Gene therapy to treat Parkinson's disease]. 1036 27

In the past 10 years, significant progress on the development of new brain-imaging agents for single-photon emission computed tomography has been made. Most of the new radiopharmaceuticals are designed to bind specific neurotransmitter receptor or transporter sites in the central nervous system. Most of the site-specific brain radiopharmaceuticals are labeled with (123)I. Results from imaging of benzodiazepine (gamma-aminobutyric acid) receptors by [(123)I]iomazenil are useful in identifying epileptic seizure foci and changes of this receptor in psychiatric disorders. Imaging of dopamine D2/D3 receptors ([(123)I]iodobenzamide and [(123)I]epidepride) and transporters [(123)I]CIT (2-beta-carboxymethoxy-3-beta(4-iodophenyl)tropane) and [(123)I]FP-beta-CIT (N-propyl-2-beta-carboxymethoxy-3-beta(4-iodophenyl)-nortropane has proven to be a simple but powerful tool for differential diagnosis of Parkinson's and other neurodegenerative diseases. A (99m)Tc-labeled agent, [(99m)Tc]TRODAT (technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino] ethanethiolato(3-)]oxo-[1R-(exo-exo)]-), for imaging dopamine transporters in the brain has been successfully applied in the diagnosis of Parkinson's disease. Despite the fact that (123)I radiopharmaceuticals have been widely used in Japan and in Europe, clinical application of (123)I-labeled brain radiopharmaceuticals in the United States is limited because of the difficulties in supplying such agents. Development of (99m)Tc agents will likely extend the application of site-specific brain radiopharmaceuticals for routine applications in aiding the diagnosis and monitoring treatments of various neurologic and psychiatric disorders.
 ...
PMID:Radiopharmaceuticals for single-photon emission computed tomography brain imaging. 1260 53

Several years ago ubiquitin immunocytochemistry first demonstrated that ubiquitin protein conjugates are present in intraneuronal inclusions in all the major human chronic neurodegenerative diseases, as well as in inclusions in cerebellar astrocytomas and in hepatocytes in alcoholic liver disease. Unexpectedly, further studies showed that Lewy bodies are present in the cortex. Lewy bodies were originally described in the brain stem and are pathogonomic in the neuropathological diagnosis of Parkinson's disease. A balanced interpretation of further elegant experimental approaches, including transgenesis, suggests that the formation of intraneuronal inclusions is cytoprotective. Putative oligomeric proaggregates (prefibrillar entities) of cellular proteins inhibit the 26S proteasome and promote apoptosis. In the last few years a clutch of distinct experimental approaches have focused on the roles of ubiquitin-related processes in the development of the nervous system and neurohomeostasis. It is now clear that the ubiquitin/proteasome system (UPP) has a pivotal role in synaptogenesis, the formation of neuromuscular junctions and neurotransmitter receptor function. The inhibitory GABA(A) receptor, alpha1 glycine receptor, beta(2)-adrenergic receptor and arrestin, opiate receptors and the excitatory metabotropic glutamate receptor (mGluR1alpha) are regulated by the UPP. It is also increasingly clear that the regulation of long-term synaptic plasticity, and therefore memory, is dependent on both protein synthesis and protein degradation. Therefore, for the first time we have the opportunity to dissect the substrate of memory and the basis of cognitive decline in aging and in chronic neurodegenerative disease. Clearly, further understanding will provide a platform for novel drug development to treat chronic neurodegenerative diseases, including Alzheimer- and Parkinson-related conditions, and possibly psychiatric disorders.
 ...
PMID:From neurodegeneration to neurohomeostasis: the role of ubiquitin. 1279 71

Loss-of-function mutations of the parkin gene causes an autosomal recessive juvenile-onset form of Parkinson's disease (AR-JP). Parkin was shown to function as a RING-type E3 ubiquitin protein ligase. However, the function of parkin in neuronal cells remains elusive. Here, we show that expression of parkin-potentiated adenosine triphosphate (ATP)-induced currents that result from activation of the P2X receptors which are widely distributed in the brain and involved in neurotransmission. ATP-induced inward currents were measured in mock-, wild-type or mutant (T415N)-parkin-transfected PC12 cells under the conventional whole-cell patch clamp configuration. The amplitude of ATP-induced currents was significantly greater in wild-type parkin-transfected cells. However, the immunocytochemical study showed no apparent increase in the number of P2X receptors or in ubiquitin levels. The increased currents were attenuated by inhibition of cAMP-dependent protein kinase (PKA) but not protein kinase C (PKC) or Ca2+ and calmodulin-dependent protein kinase (CaMKII). ATP-induced currents were also regulated by phosphatases and cyclin-dependent protein kinase 5 (CDK5) via dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32), though the phosphorylation at Thr-34 and Thr-75 were unchanged or rather attenuated. We also tried to investigate the effect of alpha-synuclein, a substrate of parkin and also forming Lysine 63-linked multiubiquitin chains. Expression of alpha-synuclein did not affect the amplitude of ATP-induced currents. Our finding provides the evidence for a relationship between parkin and a neurotransmitter receptor, suggesting that parkin may play an important role in synaptic activity.
 ...
PMID:Parkin potentiates ATP-induced currents due to activation of P2X receptors in PC12 cells. 1682 4

Our paper on loss of neurons in the Nucleus Basalis of Meynert (now considered part of the cholinergic basal forebrain) in Alzheimer disease (AD) stimulated scientific interest in this little studied brain region. Our subsequent studies associated pathology in the basal forebrain with other dementias, such as Parkinson's disease, and with neurotransmitter receptor changes, such as in nicotinic receptors. We and many others worked to develop medications to treat AD through cholinergic mechanisms and eventually four cholinesterase inhibitors were approved. However the effect sizes of currently available drugs are modest and ethical issues in conducting research in dementia are challenging. In Cleveland we came to focus on the goals of improving quality of life and the importance on non-pharmacological approaches to treatment. International efforts were organized to improve the efficiency of drug development and to focus on important cultural and pharmacoeconomic issues. Eventually I became concerned about the very way we conceive AD and related concepts like MCI (mild cognitive impairment). As the hundredth anniversary of the first case approaches I am helping to organize meetings to reflect deeply on what we have learned and how to imagine creating a more positive future for persons affected by what I used to call AD.
 ...
PMID:Quality of life: the bridge from the cholinergic basal forebrain to cognitive science and bioethics. 1691 84

We studied whether striatal alpha(2)-adrenoceptors or N-methyl-d-aspartate (NMDA) receptors influence descending regulation of neuropathic hypersensitivity in the rat by microinjecting an alpha(2)-adrenoceptor agonist or NMDA-receptor antagonist into the dorsal striatum in animals with a spinal nerve ligation-induced neuropathy. Hypersensitivity was assessed in the hind limb by monofilaments and paw pressure test. Various neurotransmitter receptor antagonists were administered into the striatum or intrathecally to determine striatal and spinal neurotransmitters mediating the modulatory influence. The results indicate that the striatum has a dual effect on neuropathic hypersensitivity via two distinct pathways descending to the spinal cord. First, hypersensitivity is reduced following activation of noradrenergic alpha(2)-adrenoceptors and downstream dopamine D2 receptors in the striatum. This antihypersensitivity effect is predominantly ipsilateral and it descends via parallel dopaminergic and serotoninergic pathways to act on spinal dopamine D2 and 5-HT(1A) receptors, respectively. Second, tonic activation of striatal NMDA receptors promotes hypersensitivity by suppressing spinal GABAergic inhibition. The antihypersensitivity actions induced by striatal drug administrations were not associated with motor effects as suggested by lack of effect on the threshold of the uninjured limb or amplitude of the innocuous H-reflex. Involvement of striatal dopamine D2 receptors in the noradrenergic pain inhibitory circuitry may explain why disorders causing hypofunction of the striatal dopaminergic system, such as in Parkinson's disease, have been associated with pain. Furthermore, our findings indicate that striatal NMDA receptors provide a tonic supramedullary drive for medullospinal facilitatory influence that is known to be of importance for neuropathic hypersensitivity.
 ...
PMID:Dual influence of the striatum on neuropathic hypersensitivity. 1787 Feb 40


1 2 Next >>