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)

Brain function can be affected by the availability of dietary precursors of neurotransmitters. This occurs because the rate-limiting synthetic enzymes are not "saturated" with substrate under normal circumstances. Tyrosine affects catecholaminergic neurons that fire rapidly, whether in the brain stem to decrease blood pressure in hypertension or in the adrenal gland to increase blood pressure in hypotension, and has been used in the treatment of Parkinson's disease and depression. Choline forms acetylcholine and has been used successfully in the treatment of tardive dyskinesia and memory disorders. Tryptophan, which forms serotonin, has been used for chronic pain therapy, sleep disorders, depression, and appetite control. Although these substances may lack the potency of traditionally used agonists, they offer an increase in specificity because the enzymes necessary to convert them to neurotransmitters are found only in neurons. Precursors are also "physiological"; they are consumed as foods and, therefore, should be relatively safe therapeutic agents.
 ...
PMID:Neurotransmitter precursors and brain function. 612 95

Griffin and Greene ("Social Interaction and Symptom Sequences," this issue) present evidence linking patterns of family interaction with the expression of disease symptoms, in this case orofacial bradykinesia in a patient with Parkinson's disease. They argue that symptom expression may be influenced by family interaction for many diseases or chronic conditions and advocate the use of behavioral observation and microanalytic coding of behavior sequences as a means of studying this linkage. They note that the success of this approach will depend on the temporal characteristics of symptom fluctuation and suggest that observational strategies will be primarily useful for studying symptoms that fluctuate across seconds or minutes rather than across days. What kinds of conditions might this include? Griffin and Greene mention three categories: (1) mental and emotional disorders; (2) chronic pain; (3) neurological conditions.
 ...
PMID:Neurological trauma and family functioning: toward a social neuropsychology. 780 Jul 74

A pathology of brain serotonergic (5-HT) systems has been found in psychiatric disturbances, normal aging and in neurodegenerative disorders including Alzheimer's and Parkinson's disease. Despite the clinical importance of 5-HT, little is known about the endogenous factors that have neurotrophic influences upon 5-HT neurons. The present study examined whether chronic pain parenchymal administration of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or NGF could prevent the severe degenerative loss of serotonergic axons normally caused by the selective 5-HT neurotoxin p-chloroamphetamine (PCA). The neurotrophins (5-12 micrograms/d) or the control substances (cytochrome c or PBS vehicle) were continuously infused into the rat frontoparietal cortex using an osmotic minipump. One week later, rats were subcutaneously administered PCA (10 mg/kg) or vehicle, and the 5-HT innervation was evaluated after two more weeks of neurotrophin infusion. As revealed with 5-HT immunocytochemistry, BDNF infusions into the neocortex of intact (non-PCA-lesioned) rats caused a substantial increase in 5-HT axon density in a 3 mm diameter region surrounding the cannula tip. In PCA-lesioned rats, intracortical infusions of BDNF completely prevented the severe neurotoxin-induced loss of 5-HT axons near the infusion cannula. In contrast, cortical infusions of vehicle or the control protein cytochrome c did not alter the density of serotonergic axons in intact animals, nor did control infusions prevent the loss of 5-HT axons in PCA-treated rats. NT-3 caused only a modest sparing of the 5-HT innervation in PCA-treated rats, and NGF failed to prevent the loss of 5-HT axon density. The immunocytochemical data were supported by neurochemical evaluations which showed that BDNF attenuated the PCA-induced loss of 5-HT and 5-HIAA contents and 3H-5-HT uptake near the infusion cannula. Thus, BDNF can promote the sprouting of mature, uninjured serotonergic axons and dramatically enhance the survival or sprouting of 5-HT axons normally damaged by the serotonergic neurotoxin PCA.
 ...
PMID:Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. 861 31

Tachykinins belong to an evolutionarily conserved family of peptide neurotransmitters. The mammalian tachykinins include substance P, neurokinin A and neurokinin B, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated NK1, NK2 and NK3, respectively. Tachykinin receptors have been cloned and contain seven segments spanning the cell membrane, indicating their inclusion in the G-protein-linked receptor family. The continued development of selective agonists and antagonists for each receptor has helped elucidate roles for these mediators, ranging from effects in the central nervous system to the perpetuation of the inflammatory response in the periphery. Various selective ligands have shown both inter- and intraspecies differences in binding potencies, indicating distinct binding sites in the tachykinin receptor. The interaction of tachykinin with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with tachykinins, there is scope for numerous therapeutic possibilities. With the development of potent, selective non-peptide antagonists, there could be potential benefits in the treatment of a variety of clinical conditions, including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma.
 ...
PMID:Tachykinins: receptor to effector. 892 4

A 65-year-old woman with chronic pain was admitted to the hospital for severe recurrent major depression complicating Parkinson's disease (PD). Pain complaints were closely related to the fluctuating motor syndrome of PD. Specifically, pain was experienced in conjunction with hypomobility, and, as a result, she self-medicated with extra carbidopa/levodopa. A regimen of tramadol and cyclobenzaprine, along with sustained-release carbidopa/levodopa for PD and buproprion for her depression resulted in sustained symptomatic and functional improvement. Craving for, and self-medication with, supplemental carbidopa/levodopa ceased. Theoretical support for synergism among dopamine and opioid neurotransmitter systems can be found in recent literature.
 ...
PMID:Chronic pain in the setting of Parkinson's disease and depression. 937 71

Transplantation has become a successful method for the management of functional failure of a variety of tissues or organs. However, the majority of clinical transplantations use non-autologous allogeneic donor tissue implanted from one human to another. In order to prevent rejection of the allogeneic tissue, methods to overcome the immune barrier are necessary. Although prevention of organ rejection is currently achieved with pharmacological immune suppression, the undesirable side effects of this method have incited interest in novel methods to overcome the immune barrier. One such novel method of preventing immune reaction is immuno-isolation, in which the non-autologous tissues are physically isolated from the host tissues by placement in devices with perm-selective membranes. The membranes of these devices allow release of the therapeutic product required from the transplanted tissues, as well as diffusion of nutrients and waste necessary for survival of the non-autologous tissues. The membranes also prevent host immune mediators from contacting the non-autologous cells, thus preventing immune rejection. This technology has been tested for efficacy in large animal models, and is currently in the process of clinical trials in humans. This review will discuss the progress made in using immuno-isolation of non-autologous tissues in large animals. Immuno-isolation can be subdivided into two major areas of interest based on whether the non-autologous tissue used in the immuno-isolation device is genetically altered (gene therapy) or not. Studies using non-genetically altered non-autologous cells for immune-isolation have been dominated by the use of pancreatic islet cells for the treatment of diabetes. This work has been tested in large animal models of diabetes, including canine and primate model animals, and human clinical trials are underway. As well, there has also been work on treatment of neurological disorders such as Parkinson's disease or chronic pain using non-autologous immuno-isolated adrenal chromaffin cells or dopaminergic PC12 cells in large animals such as sheep and primates. This work will be reviewed in detail as to the types of disorders, immuno-isolation devices used and the type of large animals involved. Immune-isolation for gene therapy is a more recently developed field of research. In this case, the non-autologous cells used are first genetically altered to secrete a recombinant therapeutic product before placement in the immune-isolation devices. Genetic engineering of the non-autologous cells is beneficial, as it allows the use of a cell type that tolerates well the environment of the immune-isolation device, while still delivering the therapeutic product of interest. This form of gene therapy has been tested in our laboratory for delivery of marker products such as human growth hormone to canines. As several large animal models of human genetic disorders are available, such as canines affected with hemophilia or the lysosomal storage disease mucopolysaccharidosis, testing the efficacy of immuno-isolation for gene therapy in large animal models is an important prelude to human clinical trials. This review will discuss the topics outlined above, as well as some further considerations of the usefulness of large animal models in studying immune-isolation for non-autologous transplantation. Large animals may be more appropriate model organisms than rodents in which to study immune-isolation, as issues such as biocompatibility and immune response in a larger animal can be addressed. As well, large animal studies of immune isolation may provide data that are more relevant than rodent studies to the eventual application to human clinical trials.
 ...
PMID:Non-autologous transplantation with immuno-isolation in large animals--a review. 961 31

Thalamic neurons are known to switch their firing from a tonic pattern during wakefulness to a bursting pattern during sleep. Several studies have described the existence of bursting activity in awake chronic pain patients and have suggested that this activity is abnormal and may be related to their pain. However, we have frequently observed bursting activity in awake non-pain patients suggesting that there may not be a causal relationship between thalamic bursting activity and chronic pain. To examine this issue more rigorously we compared the incidence and pattern of bursting activity of lateral thalamic neurons of both pain and non-pain patients in a state of wakefulness. Recordings were obtained from lateral thalamic areas of different groups of patients (n = 91) suffering from pain disorders (e.g. anaesthesia dolorosa, phantom limb pain, trigeminal neuralgia, post-stroke pain) and motor disorders (e.g. Parkinson's disease, essential tremor) during stereotactic surgical procedures for the treatment of pain and movement disorders. Burst indices (the number of bursting cells per electrode track) were computed for all the explorations in the two groups. The burst indices in the pain and non-pain groups (1.73 +/- 0.28 and 1.14 +/- 0.16, respectively) were not significantly different from each other. The bursts were analyzed to see if they fulfilled the criteria of low-threshold calcium spike (LTS)-evoked bursts characterized by (i) a shortening of the first interspike interval with an increase in the number of interspike intervals in the burst and also (ii) a progressive prolongation of successive interspike intervals. LTS-evoked bursts were identified in 27/47 (57%) bursting cells in pain patients and 15/32 (47%) cells in non-pain patients. These data demonstrate that the occurrence of bursting activity and of LTS-evoked bursts in the human thalamus is prevalent in both pain and non-pain patients. This suggests that the bursting activity of thalamic neurons in pain patients is not necessarily related to the occurrence of their pain.
 ...
PMID:A comparison of the burst activity of lateral thalamic neurons in chronic pain and non-pain patients. 1034 18

N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS) to symptomatic treatment (e.g. epilepsy, Parkinson's disease, drug dependence, depression, anxiety and chronic pain). However, many NMDA receptor antagonists also produce highly undesirable side effects at doses within their putative therapeutic range. This has unfortunately led to the conclusion that NMDA receptor antagonism is not a valid therapeutic approach. However, memantine is clearly an uncompetitive NMDA receptor antagonist at therapeutic concentrations achieved in the treatment of dementia and is essentially devoid of such side effects at doses within the therapeutic range. This has been attributed to memantine's moderate potency and associated rapid, strongly voltage-dependent blocking kinetics. The aim of this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal models of chronic neurodegenerative diseases. The ultimate purpose is to provide evidence that it is indeed possible to develop clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine.
 ...
PMID:Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist--a review of preclinical data. 1046 80

Antagonists of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors and agonists of the glycine-B coagonist site of these receptors have been important tools for characterizing the contributions of NMDA receptor pathophysiology to a large number of neuropsychiatric conditions and for treating these conditions. Among these disorders are Alzheimer's disease, chronic pain syndromes, epilepsy, schizophrenia, Parkinson's disease, Huntington's disease, addiction disorders, major depression, and anxiety disorders. This review will examine pathophysiological and therapeutic hypotheses generated or supported by clinical studies employing NMDA antagonists and glycine-B agonists and partial agonists. It will also consider ethical issues related to human psychopharmacological studies employing glutamatergic probes.
 ...
PMID:NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. 1048 32

Over the last decade, neural transplantation has progressed from being an experimental technique for studying regeneration and plasticity in the brain to clinical trials of reconstructive surgery in human neurodegenerative disease. Whereas clear evidence is only available at present for the viability of this technique in Parkinson's disease, applications to several other diseases, including Huntington's disease, multiple sclerosis, spinal cord injury, and chronic pain are currently under active consideration. It is clear that the techniques of transplantation can be functionally viable under certain well-defined biological circumstances, but significant problems remain in the availability of suitable donor tissues and defining the optimal conditions for reliable survival of the implanted cells. If we are to obtain improved reliability of the present techniques or identify suitable alternatives, we need a better understanding of the conditions for the survival and integration of grafts into the host brain, and the mechanisms by which they influence host function. In this review I consider the nature of the structural reconstruction required to achieve repair in animal models of Parkinson's and Huntington's diseases, contrasting the replacement of deficient neurochemicals within the striatum in the former case, and the need for reconstruction of input and output connections of the striatal circuitry in the latter.
 ...
PMID:Repair of the damaged brain. The Alfred Meyer Memorial Lecture 1998. 1056 24


1 2 3 4 5 6 7 8 9 10 Next >>