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 sympathetic skin response (SSR) is a slow wave resulting from activation of the sudomotor sympathetic efferent fibers. Records are usually made with surface electrodes on hand or foot after the electrical stimulation. Either the amplitude or the latency of the response varies greatly on consecutive stimulations and there is also a remarkable tendency to habituation. Therefore SSR is considered abnormal if no significant responses are detected. SSR is well correlated with other autonomic function tests and its abnormality is documented in a variety of neurologic disorders such as diabetic neuropathy, cerebrovascular disease and Parkinson's disease. In good methodological conditions, SSR is a simple, reliable indicator of sympathetic sudomotor outflow in central and peripheral nervous system disorders.
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PMID:[Sympathetic skin response (SSR)]. 161 56

We measured six apolipoproteins (AI, AII, B, CII, CIII, and E) in the serum of patients with several kinds of neural diseases [diabetic neuropathy and neural degenerative disorders (motor neuron degenerative disorders, spinocerebellar degeneration, Parkinson's disease)], comparing them to the age-matched healthy controls using the immunoturbidimetric method. Statistically significant decreases of serum apo-AI, apo-A-II and increases of apo-CIII, apo-E were observed in neural degenerative diseases; and, particularly, higher apo-B and apo-CII concentrations were observed in diabetic neuropathy. Most neural degenerative disease showed lower apo-AII. However, in motor neuron degenerative disorders, higher apo C-II and apo-E were seen. Lower apo-AI was seen in spinocerebellar degeneration, and lower apo-AII was seen in Parkinson's disease. Higher apo-B, CII, and E levels were observed in females with spinocerebellar degeneration and Parkinson's disease, and lower apo-AII was seen in males with spinocerebellar disease.
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PMID:Preliminary findings on the variation of serum apolipoprotein levels in neural degenerative disorders. 842 69

The cause of cell death in neurodegenerative diseases remains unknown but the formation of free radicals and the occurrence of oxidative stress may be a common component of many, if not all, such disorders. For example, in substantia nigra in Parkinson's diseases key alterations occur, in iron handling, mitochondrial function and antioxidant defences, particularly reduced glutathione. These indices of oxidative stress are accompanied by evidence of free radical mediated damage in the form of increased lipid peroxidation and oxidation of DNA bases. The alterations in oxidative stress occurring in Parkinson's disease appear not be related to the administration of L-DOPA. Some alterations of oxidative stress are found in other basal ganglia in degenerative disorders (multiple system atrophy, progressive supranuclear palsy, Huntington's disease) but these have not been investigated to the same extent. Similarly, examination of biochemical changes occurring in Alzheimer's disease, motor neurone disease and diabetic neuropathy also suggest the involvement of free radical mediated mechanisms as a component of neurodegeneration. It is probable that irrespective of the primary cause of individual neurodegenerative disorder, the onset of oxidative stress is a common mechanism by which neuronal death occurs and which contributes to disease progression. Clearly, therapeutic strategies aimed at limiting free radical production and oxidative stress and/or damage may slow the advance of neurodegenerative disease.
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PMID:Oxidative stress in Parkinson's disease and other neurodegenerative disorders. 873 2

Neuroimmunophilin ligands are a class of compounds that hold great promise for the treatment of nerve injuries and neurological disease. In contrast to neurotrophins (e.g., nerve growth factor), these compounds readily cross the blood-brain barrier, being orally effective in a variety of animal models of ischaemia, traumatic nerve injury and human neurodegenerative disorders. A further distinction is that neuroimmunophilin ligands act via unique receptors that are unrelated to the classical neurotrophic receptors (e.g., trk), making it unlikely that clinical trials will encounter the same difficulties found with the neurotrophins. Another advantage is that two neuroimmunophilin ligands (cyclosporin A and FK-506) have already been used in humans (as immunosuppressant drugs). Whereas both cyclosporin A and FK-506 demonstrate neuroprotective actions, only FK-506 and its derivatives have been clearly shown to exhibit significant neuroregenerative activity. Accordingly, the neuroprotective and neuroregenerative properties seem to arise via different mechanisms. Furthermore, the neuroregenerative property does not involve calcineurin inhibition (essential for immunosuppression). This is important since most of the limiting side effects produced by these drugs arise via calcineurin inhibition. A major breakthrough for the development of this class of compounds for the treatment of human neurological disorders was the ability to separate the neuroregenerative property of FK-506 from its immunosuppressant action via the development of non-immunosuppressant (non-calcineurin inhibiting) derivatives. Further studies revealed that different receptor subtypes, or FK-506-binding proteins (FKBPs), mediate immunosuppression and nerve regeneration (FKBP-12 and FKBP-52, respectively, the latter being a component of steroid receptor complexes). Thus, steroid receptor chaperone proteins represent novel targets for future drug development of novel classes of compounds for the treatment of a variety of human neurological disorders, including traumatic injury (e.g., peripheral nerve and spinal cord), chemical exposure (e.g., vinca alkaloids, Taxol) and neurodegenerative disease (e.g. , diabetic neuropathy and Parkinson's disease).
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PMID:Neuroimmunophilin ligands: evaluation of their therapeutic potential for the treatment of neurological disorders. 1106 Aug 10

Given their clinical importance for the treatment of acute and chronic neurodegenerative diseases in humans including nerve injuries (e.g. Alzheimer's disease, Parkinson's disease, diabetic neuropathy) a number of different approaches were pursued to obtain selectively acting FK506-binding protein (FKBP) ligands: computational methods and target-oriented screening of natural compound and synthetic product libraries. The resulting monofunctional ligands, which inhibit the peptidyl prolyl cis/trans isomerase activity of FKBPs, highlight the role of these enzymes in neuronal signaling. The exploration of the mechanisms of neuroregenerative and neuroprotective action of some of these compounds is the main focus of ongoing neuropharmaceutical research.
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PMID:FKBP ligands as novel therapeutics for neurological disorders. 1236 64

Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system, and mutations in neurofilaments have been linked to some forms of CMT. Neurofilaments are the major intermediate filaments of neurones, but the mechanisms by which the CMT mutations induce disease are not known. Here, we demonstrate that CMT mutant neurofilaments disrupt both neurofilament assembly and axonal transport of neurofilaments in cultured mammalian cells and neurones. We also show that CMT mutant neurofilaments perturb the localization of mitochondria in neurones. Accumulations of neurofilaments are a pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and diabetic neuropathy. Our results demonstrate that aberrant neurofilament assembly and transport can induce neurological disease, and further implicate defective neurofilament metabolism in the pathogenesis of human neurodegenerative diseases.
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PMID:Charcot-Marie-Tooth disease neurofilament mutations disrupt neurofilament assembly and axonal transport. 1239 95

In recent years, VIP/PACAP/secretin family has special interest. Family members are vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, glucagon, glucagon like peptide-1 (GLP(1)), GLP(2), gastric inhibitory peptide (GIP), growth hormone releasing hormone (GHRH or GRF), and peptide histidine methionine (PHM). Most of the family members present both in central nervous system (CNS) and in various peripheral tissues. The family members that are released into blood from periphery, especially gut, circulate the brain and they can cross the blood brain barrier. On the other hand, some of the members of this family that present in the brain, can cross from brain to blood and reach the peripheral targets. VIP, secretin, GLP(1), and PACAP 27 are transported into the brain by transmembrane diffusion, a non-saturable mechanism. However, uptake of PACAP 38 into the brain is saturable mechanism. While there is no report for the passage of GIP, GLP(2), and PHM, there is only one report that shows, glucagon and GHRH can cross the BBB. The passage of VIP/PACAP/secretin family members opens up new horizon for understanding of CNS effects of peripherally administrated peptides. There is much hope that those peptides may prove to be useful in the treatment of serious neurological diseases such as Alzheimer's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS related neuropathy, diabetic neuropathy, autism, stroke and nerve injury. Their benefits in various pathophysiologic conditions undoubtly motivate the development of a novel drug design for future therapeutics.
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PMID:Passage of VIP/PACAP/secretin family across the blood-brain barrier: therapeutic effects. 1513 84

Many concepts about acute and chronic effects of stress depend on alterations in sympathetic nerves supplying the heart. Physiologic, pharmacologic, and neurochemical approaches have been used to evaluate cardiac sympathetic function. This article describes a fourth approach that is based on nuclear scanning to visualize cardiac sympathetic innervation and function and relationships between the neuroimaging findings and those from other approaches. Multiple-system atrophy with orthostatic hypotension (formerly the Shy-Drager syndrome) features normal cardiac sympathetic innervation and normal entry of norepinephrine into the coronary sinus (cardiac norepinephrine spillover), in contrast to Parkinson disease with orthostatic hypotension, which features neuroimaging and neurochemical evidence for loss of cardiac sympathetic nerves. This difference may have important implications not only for diagnosis but also for understanding the etiology of Parkinson disease. By analysis of curves relating myocardial radioactivity with time (time-activity curves) after injection of a sympathoneural imaging agent, it is possible to obtain information about cardiac sympathetic function. Abnormal time-activity curves are seen in common disorders such as heart failure and diabetic neuropathy and provide an independent, adverse prognostic index. Analogous abnormalities might help explain increased cardiovascular risk in psychiatric disorders such as melancholic depression.
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PMID:Functional neuroimaging of sympathetic innervation of the heart. 1524 Mar 74

Apoptosis is an important process in the development of the nervous system. Typically, approximately 50% of the neurons apoptose during neurogenesis before the nervous system matures. However, recent paradigms implicate premature apoptosis and/or aberrations in the fine control of neuronal apoptosis in the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, stroke, brain trauma, spinal cord injury, and diabetic neuropathy. This review will focus on the current concepts salient to understanding the apoptosis death program, the mediators and control of cellular apoptosis, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. The discussion will also highlight current advances in methodology, such as utilization of neuronal cell lines and mutant animal models, in investigations of neuronal apoptotic death. The knowledge of apoptosis mechanisms could underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.
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PMID:Apoptosis: a key in neurodegenerative disorders. 1618 Oct 84

Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
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PMID:Design, synthesis, and biological activity of novel polycyclic aza-amide FKBP12 ligands. 1645 Oct 85


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