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)

Postmortem studies in brains from parkinsonian patients consistently reveal a minimum loss of 75% of the nigrostriatal dopamine neurons. This indicates that over a prolonged period, before Parkinson's disease is clinically evident, there is a physiological compensation for the slow loss of dopamine neurons (i.e. compensated stage of Parkinson's disease). Only when the dopamine neuron loss is sufficiently severe (greater than 75% of nigrostriatal dopamine neurons) does the disease become clinically evident (decompensated state). Postmortem examination of Parkinson's disease brains and study of animal models indicate that the following mechanisms may contribute to this CNS compensation: 1) A decrease in striatal cholinergic activity, in an attempt to maintain a critical DA:ACh balance; and 2) A decrease in activity of GABA neurons in the striatum and substantia nigra, resulting in an increased firing rate of nigral dopamine cells. These mechanisms allow the brain to readjust to the initial dopamine cell loss in Parkinson's disease.
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PMID:CNS compensation to dopamine neuron loss in Parkinson's disease. 93 Jul 46

Slices of the rabbit caudate nucleus were incubated with [3H]choline or [3H]dopamine and then superfused continuously with Mg(++)-free medium. Stimulation with N-methyl-D-aspartate (NMDA), alpha-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA), L-glutamate and kainic acid (in that rank order of potencies) caused a concentration-dependent increase in [3H]ACh efflux, which was abolished in the presence of Mg++. This kind of release was Ca(++)-dependent and tetrodotoxin-sensitive. In contrast, NMDA was hardly effective in stimulating [3H]ACh release from hippocampal or cortical slices, as well as [3H]dopamine release from slices of rabbit caudate nucleus. Hence, the presence of cell bodies of stimulated neurons seems to be a prerequisite for the induction of release via NMDA receptors. Dizocilpine [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate] at nanomolar concentrations, as well as memantine and amantadine at low micromolar concentrations, inhibited the L-glutamate- and NMDA-evoked [3H]ACh release in a concentration-dependent, noncompetitive and use-dependent manner. Also (+/-)-2-amino-5-phosphopentanoic acid at micromolar concentrations depressed the L-glutamate- and NMDA-induced release, acting, however, in a competitive manner. It is concluded that, by antagonizing NMDA receptor-mediated ACh release, memantine and amantadine may act as functional "anticholinergics" when administered clinically to treat Parkinson's disease.
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PMID:Inhibitory effects of the antiparkinsonian drugs memantine and amantadine on N-methyl-D-aspartate-evoked acetylcholine release in the rabbit caudate nucleus in vitro. 135 11

An in vitro mammalian model neuronal system to evaluate the intrinsic toxicity of soman and other neurotoxicants as well as the efficacy of potential countermeasures was investigated. The link between soman toxicity, glutamate hyperactivity and neuronal death in the central nervous system was investigated in primary dissociated cell cultures from rat hippocampus and cerebral neocortex. Exposure of cortical or hippocampal neurons to glutamate for 30 min produced neuronal death in almost 80% of the cells examined at 24 h. Hippocampal neurons exposed to soman for 15-120 min at 0.1 microM concentration caused almost complete inhibition (> or = 90%) of acetylcholinesterase but failed to show any evidence of effects on cell viability, indicating a lack of direct cytotoxicity by this agent. Acetylcholine (ACh, 0.1 mM), alone or in combination with soman, did not potentiate glutamate toxicity in hippocampal neurons. Memantine, a drug used for the therapy of Parkinson's disease, spasticity and other brain disorders, significantly protected hippocampal and cortical neurons in culture against glutamate and N-methyl-D-aspartate (NMDA) excitotoxicity. In rats a single dose of memantine (18 mg/kg) administered 1 h prior to a s.c. injection of a 0.9 LD50 dose of soman reduced the severity of convulsions and increased survival. Survival, however, was accompanied by neuronal loss in the frontal cortex, piriform cortex and hippocampus.
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PMID:Assessment of primary neuronal culture as a model for soman-induced neurotoxicity and effectiveness of memantine as a neuroprotective drug. 749 76

Visual evoked potentials were measured on patients with Parkinson's disease and Alzheimer's disease and normal controls to assess the function of dopamine and acetylcholine in the visual system. Dopamine is a neurotransmitter known to be present in the retina of primates and is found to be severely depleted in the substantia nigra of patients with Parkinson's disease. Acetylcholine is also known to be present in the retina, visual cortex, and superior colliculus and is found to be grossly reduced in patients with Alzheimer's disease. Stimuli were designed to preferentially activate functionally separate pathways in the visual system described as magnocellular and parvocellular. The four stimuli were a diffuse flash; an achromatic, 73' check counterphasing at 6 Hz at a contrast of 30%; an achromatic 10' check counterphasing at 2 Hz at a contrast of 85%; and an isoluminant red/green grating of 4 cpd presented using an on and off cosine ramp of 200 ms. The results indicate that an acetylcholine deficit produces a delay to the flash P2 component of the visual evoked potential. No change was detected when other stimuli were used.
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PMID:Effect of dopamine and acetylcholine on the visual evoked potential. 791 38

Acetylcholine (ACh) release was measured by microdialysis. Addition of 10 nM L-DOPA to the perfusate significantly decreased ACh release, from the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), but not sham-operated rats. The L-DOPA-induced decrease was not affected by (-)-sulpiride which completely blocked D2- and D3-agonist-induced decrease in ACh release in lesioned rats. Neither 10 nM D-DOPA nor 100 nM dopamine caused by any change in ACh release. These findings suggest that L-DOPA-sensitive mechanisms are supersensitized in Parkinson's disease model rats.
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PMID:L-DOPA inhibits spontaneous acetylcholine release from the striatum of experimental Parkinson's model rats. 858 84

L-DOPA is proposed to be a neurotransmitter and/or neuromodulator in CNS. It is released probably from neurons, which may contain L-DOPA as an end-product, and/or from some compartment other than catecholamine-containing vesicles. The L-DOPA itself produces presynaptic and postsynaptic responses. All are stereoselective and most are antagonized by competitive antagonist. In striatum, L-DOPA is neuromodulator, mother of catecholamines, not only a precursor for dopamine but also a potentiator of children for presynaptic beta-adrenoceptors to facilitate dopamine release and postsynaptic D2 receptors, and ACh release inhibitor. All may cooperate for Parkinson's disease. Meanwhile, supersensitization of increase in L-glutamate release to nanomolar levodopa was seen in Parkinson's model rats, which may relate to dyskinesia or "on-off" during chronic therapy. In lower brainstem, L-DOPA tonically activates postsynaptic depressor sites of NTS and CVLM and pressor sites of RVLM. L-DOPA is probably a neurotransmitter of primary baroreceptor afferents terminating in NTS. GABA, the inhibitory neuromodulator for baroreflex in NTS, tonically functions to inhibit, via GABAA receptors, L-DOPA release and depressor responses to levodopa. Levodopa inversely releases GABA. L-DOPAergic monosynaptic relay from NTS to CVLM and from PHN to RVLM is suggested. Tonic L-DOPAergic baroreceptor-aortic nerve-NTS-CVLM relay seems to carry baroreflex information. Disturbance of neuronal activity to release L-DOPA in NTS, loss of the activity in CVLM, enhancement of the activity with decreased decarboxylation and increase in sensitivity to levodopa in RVLM may be involved in maintenance of hypertension in SHR. This is a story of "L-DOPAergic receptors" with extremely high affinity and low density.
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PMID:Neurobiology of L-DOPAergic systems. 889 95

Nicotinic cholinergic systems are involved with several important aspects of cognitive function including attention, learning and memory. Nicotinic cholinergic receptors are located in many regions of the brain, including areas important for cognitive function such as the hippocampus and frontal cortex. Nicotinic agonists have been found in rodent and non-human primate studies to improve performance on a variety of memory tasks. In a complementary fashion, nicotinic antagonists such as mecamylamine impair working memory function. In humans, similar effects have been seen. Nicotinic agonist treatment can improve attention, learning and memory and nicotinic antagonist treatment can cause deficits. To define the neural substrates of nicotinic involvement in cognitive function, three areas of investigation are underway. 1) Critical neuroanatomic loci for nicotinic effects are beginning to be determined. The hippocampus, frontal cortex and midbrain dopaminergic nuclei have been found to be important sites of action for nicotinic involvement in memory function. 2) Nicotinic receptor subtype involvement in cognitive function is being studied. There has been considerable recent work identifying nicotinic receptor subunit conformation including alpha and beta subunits. Nicotinic receptor subtypes appear to be associated with different functional systems; however, much remains to be done to determine the precise role each subtype plays in terms of cognitive function. 3) Nicotinic interactions with other transmitter systems are being assessed. Nicotine receptors interact in important ways with other systems to affect cognitive functioning, including muscarinic ACh, dopamine, norepinepherine, serotonin, glutamate, and other systems. Nicotinic function in clinical populations and potential for therapeutics has been investigated for Alzheimer's disease, Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder. Areas which need to receive greater attention are the exact anatomical location and the specific receptor subtypes critically involved in nicotine's effects. In addition, more work needs to be done to develop and determine the efficacy and safety of novel nicotinic ligands for use in the long-term treatment of human cognitive disorders.
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PMID:Nicotinic acetylcholine involvement in cognitive function in animals. 972 45

The cholinergic system is one of the most important modulatory neurotransmitter systems in the brain and controls activities that depend on selective attention, which are an essential component of conscious awareness. Psychopharmacological and pathological evidence supports the concept of a 'cholinergic component' of conscious awareness. Drugs that antagonize muscarinic receptors induce hallucinations and reduce the level of consciousness, while the nicotinic receptor is implicated as being involved in the mechanism of action of general (inhalational) anaesthetics. In degenerative diseases of the brain, alterations in consciousness are associated with regional deficits in the cholinergic system. In Alzheimer's disease (AD), there is a loss of explicit (more than implicit) memory and hypoactivity of cholinergic projections to the hippocampus and cortex, while the visual hallucinations experienced by subjects with Dementia with Lewy bodies (DLB) are associated with reductions in neocortical ACh-related activity. In Parkinson's disease, the additional loss of pedunculopontine cholinergic neurones, which control REM (rapid eye movement) sleep or dreaming, is likely to contribute to REM abnormalities, which also occur in DLB. Widespread basal-forebrain and rostral brainstem cholinergic pathways, which include converging projections to the thalamus, appear to be located strategically for generating and integrating conscious awareness. Alleviation of a range of cognitive and non-cognitive symptoms by drugs that modulate the cholinergic system, which are being developed for the treatment of AD and related disorders, could be caused by changes in consciousness.
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PMID:Acetylcholine in mind: a neurotransmitter correlate of consciousness? 1054 30

Isatin (indole-2,3-dione), an endogenous inhibitor of monoamine oxidase (MAO), has several physiological properties for stress and anxiety. We previously identified isatin in the brain of stroke-prone spontaneously hypertensive rats (SHRSP) using gas-chromatography mass spectrometry. This study elucidated the effects of isatin on the ACh and DA levels of brain tissues in rats. Furthermore, we evaluated the effect of isatin on DA levels in a rat model of Parkinson's disease induced by Japanese encephalitis virus. Striatal ACh and DA levels significantly increased at 2 hours after isatin (50-200 mg/kg, i.p.) administration. Perfused through a microdialysis probe, isatin (10(-6)-10(-4) M) also produced a significant and concentration-dependent increase in the ACh and DA concentrations in the perfusate from the rat striatum. Furthermore, urinary isatin concentrations in patients with Parkinson's disease tend to increase according to the severity of disease. Isatin (100 mg/kg, i.p.) significantly increased striatal DA levels in a rat model of Parkinson's disease. These results suggest that urinary isatin may become a diagnostic marker for the clinical severity of Parkinson's disease and that endogenous isatin, a new biological modulator, may play a role in the regulation of the brain levels of ACh by increasing the level of DA under stress.
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PMID:[Effects of isatin, an endogenous MAO inhibitor, on dopamine (DA) and acetylcholine (ACh) concentrations in rats]. 1062 78

Striatal spiny neurones serve as a major anatomical locus for the relay of cortical information flow through the basal ganglia. these projection neurones also represent the main synaptic target of cholinergic interneurones, whose physiological role in striatal activity still remains largely enigmatic. The striatal cholinergic system has been implicated in the pathophysiology of movement disorders such as Parkinson's disease, but the cellular mechanisms underlying cholinergic-neurone function are still unknown. On the basis of in vitro electrophysiological evidence, obtained from a rat corticostriatal-slice preparation, we propose that endogenous ACh exerts a complex modulation of striatal synaptic transmission, which produces both short-term and long-term effects. ACh-mediated mechanisms might be of crucial importance in processing the cortical inputs to the striatum.
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PMID:Acetylcholine-mediated modulation of striatal function. 1067 16


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