Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the etiology of Parkinson's disease (PD) remains elusive, a number of toxins including elevated salsolinol, an endogenous metabolite of dopamine may contribute to its pathology. It was reported recently that nicotine may have protective effects against salsolinol-induced toxicity in human neuroblastoma derived SH-SY5Y cells and that these effects of nicotine are mediated by nicotinic receptors. Donepezil (Aricept) is a reversible non-competitive acetylcholinesterase inhibitor that is approved for use in mild to moderate Alzheimer's disease. The increase in acetylcholine concentrations is believed to be the major contributory factor in donepezil's therapeutic efficacy. However, cholinesterase inhibitors may also directly interact with nicotinic receptors and possess neuroprotective properties. In this study, we sought to determine whether donepezil may have protective effects against salsolinol-induced toxicity in SH-SY5Y cells and whether the combination of donepezil and nicotine may result in additive protection. Moreover, it was of interest to elucidate the role of nicotinic receptors as well as cell cycle and apoptosis in mechanism of action of these compounds. SH-SY5Y cells were exposed to 0.6 mM salsolinol with and without various drug pretreatments for 48 h. Nicotine (50 muM) resulted in approximately 54% protection and donepezil (5 muM) resulted in approximately 40% protection, and the combination of the two resulted in an additive (approximately 93%) protection against salsolinol-induced toxicity. Salsolinol caused an arrest of the cells in G(1)-phase of cell cycle and an increase in apoptotic indices that were blocked by the combination of donepezil and nicotine. Mecamylamine, a non-selective nicotinic receptor antagonist completely blocked the effects of nicotine and partially attenuated the effects of donepezil. A combination of atropine, a muscarinic receptor antagonist and mecamylamine completely blocked the effects of donepezil, indicating involvement of both nicotinic and muscarinic receptors in donepezil's actions. The findings suggest a therapeutic potential for the combination of donepezil and nicotine in PD.
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PMID:Additive protective effects of donepezil and nicotine against salsolinol-induced cytotoxicity in SH-SY5Y cells. 1952 84

Parkinsonism is a characteristic feature of Parkinson's disease and dementia with Lewy bodies and is commonly seen in Alzheimer's disease. Psychosis commonly appears during the course of these illnesses. Treatment of parkinsonism with antiparkinsonian medications constitutes an additional risk factor for the appearance or worsening of psychosis. Conversely, treatment of psychosis with antipsychotic drugs in patients with parkinsonism might worsen the underlying movement disorder, especially in the elderly. In this article, we review parkinsonian conditions in the elderly and offer guidelines to assess and manage comorbid psychosis. We focus on the pharmacologic management of psychosis with atypical antipsychotic medications and briefly review the role of acetylcholinesterase inhibitors.
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PMID:Pharmacological management of psychosis in elderly patients with parkinsonism. 2036 38

Deltamethrin is a pesticide largely used. Acute toxicity of this compound was extensively investigated, whereas less information is available on the effects of subchronic and/or chronic exposure to deltamethrin or on the effects of its dermal absorption. Sparse data are also available on deltamethrin neurotoxicity. This study has assessed in the rat the effects of dermal application of deltamethrin (30 mg/kg/day in cyclohexane for 4 weeks to the skin of the back of the neck) on microanatomy of cerebrocortical areas (frontal cortex and hippocampus) and on cholinergic and dopaminergic neurotransmission markers. Treatment with deltamethrin caused nerve cell loss and the appearance of signs of neuronal sufferance primarily in layer III of frontal cortex as well as in the dentate gyrus and to a lesser extent in the CA1 and CA3 subfields of hippocampus. Deltamethrin induced also astrogliosis. Cholinergic neurotransmission markers investigated in frontal cortex, hippocampus and striatum were acetylcholine (ACh), the synthesizing and catabolic enzymes choline acetyltransferase and acetylcholinesterase and the high affinity ACh uptake system labeled with [(3)H]hemicholinium-3. These markers were unaffected by deltamethrin administration. Dopamine and the dopamine plasma membrane transporter labeled with [(3)H]GBR 12935 were unaffected by treatment with deltamethrin in frontal cortex and decreased significantly in hippocampus and striatum. These findings indicate that dermal exposure to the pyrethroid insecticide deltamethrin using an administration module mimicking a possible long-lasting occupational skin contact is accompanied by cerebrocortical injury and loss of hippocampal and striatal dopamine and dopamine transporter. The sensitivity of dopaminergic system in our experimental model suggests that dermal exposure to deltamethrin could represent a risk factor for Parkinson's disease.
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PMID:Influence of dermal exposure to the pyrethroid insecticide deltamethrin on rat brain microanatomy and cholinergic/dopaminergic neurochemistry. 1974 99

There are currently no Food and Drug Administration-approved treatments for frontotemporal lobar degeneration (FTLD). The objectives of this study were to explore the tolerability of memantine treatment in FTLD and to monitor for possible effects on behavior, cognition, and function. Forty-three individuals who met clinical criteria for FTLD [21 with frontotemporal dementia (FTD), 13 with semantic dementia (SD), and 9 with progressive nonfluent aphasia (PA)] received 26 weeks of open-label treatment with memantine at a target dose of 20 mg daily. Concurrent treatment with acetylcholinesterase inhibitors was prohibited. Cognitive and functional outcome measures included the Mini Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog), clinical dementia rating-sum of boxes, Neuropsychiatric Inventory (NPI), Frontal Behavior Inventory, Executive Interview (EXIT25), Texas Functional Living Scale (TFLS), Geriatric Depression Scale, and Unified Parkinson's Disease Rating Scale-motor scale. Most subjects were able to tolerate the target dose of memantine. A transient improvement was observed on the total NPI score primarily in the FTD group. Variable declines were observed on the ADAS-cog, EXIT25, Frontal Behavior Inventory, NPI, TFLS, and UPDRS scores. The FTD and SD groups declined on most of the cognitive and behavioral outcome measures, but remained stable on the UPDRS, whereas the progressive nonfluent aphasia group remained relatively stable on the ADAS-cog, NPI, and TFLS, but declined on the UPDRS. Memantine was well-tolerated in these subjects. Future placebo-controlled trials of memantine in FTLD are warranted and may have greater power to detect behavioral and cognitive effects if focused on the FTD and SD clinical syndromes.
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PMID:An open-label study of memantine treatment in 3 subtypes of frontotemporal lobar degeneration. 1981 61

Chemical neurotransmission has been the subject of intensive investigations in recent years. Acetylcholine is an essential neurotransmitter in the central nervous system as it has an effect on alertness, memory and learning. Enzymatic hydrolysis of acetylcholine in the synaptic cleft is fast and quickly metabolizes to choline and acetate by acetylcholinesterase. Hence the concentration in the extracellular fluid of the brain is low (0.1-6 nm). Techniques such as microdialysis are routinely employed to measure acetylcholine levels in living brain systems and the microdialysis sample volumes are usually less than 50 microL. In order to develop medicine for the diseases associated with cognitive dysfunction like mild cognitive impairment, Alzheimer's disease, schizophrenia and Parkinson's disease, or to study the mechanism of the illness, it is important to measure the concentration of acetylcholine in the extracellular fluid of the brain. Recently considerable attention has been focused on the development of chromatographic-mass spectrometric techniques to provide more sensitive and accurate quantification of acetylcholine collected from in-vivo brain microdialysis experiments. This review will provide a brief overview of acetylcholine biosynthesis, microdialysis technique and liquid chromatography mass spectrometry, which is being used to quantitate extracellular levels of acetylcholine.
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PMID:Quantification of acetylcholine, an essential neurotransmitter, in brain microdialysis samples by liquid chromatography mass spectrometry. 1987 95

Neurodegenerative diseases like Alzheimer's and Parkinson's disease are associated with elevated levels of iron, copper, and zinc and consequentially high levels of oxidative stress. Given the multifactorial nature of these diseases, it is becoming evident that the next generation of therapies must have multiple functions to combat multiple mechanisms of disease progression. Metal-chelating agents provide one such function as an intervention for ameliorating metal-associated damage in degenerative diseases. Targeting chelators to adjust localized metal imbalances in the brain, however, presents significant challenges. In this perspective, we focus on some noteworthy advances in the area of multifunctional metal chelators as potential therapeutic agents for neurodegenerative diseases. In addition to metal chelating ability, these agents also contain features designed to improve their uptake across the blood-brain barrier, increase their selectivity for metals in damage-prone environments, increase antioxidant capabilities, lower Abeta peptide aggregation, or inhibit disease-associated enzymes such as monoamine oxidase and acetylcholinesterase.
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PMID:Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease. 2016 87

Olfactory dysfunction is common in subjects with Parkinson's disease. The pathophysiology of such dysfunction, however, remains poorly understood. Neurodegeneration within central regions involved in odour perception may contribute to olfactory dysfunction in Parkinson's disease. Central cholinergic deficits occur in Parkinson's disease and cholinergic neurons innervate regions, such as the limbic archicortex, involved in odour perception. We investigated the relationship between performance on an odour identification task and forebrain cholinergic denervation in Parkinson's disease subjects without dementia. Fifty-eight patients with Parkinson's disease (mean Hoehn and Yahr stage 2.5 + or - 0.5) without dementia (mean Mini-Mental State Examination, 29.0 + or - 1.4) underwent a clinical assessment, [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase brain positron emission tomography and olfactory testing with the University of Pennsylvania Smell Identification Test. The diagnosis of Parkinson's disease was confirmed by [(11)C]dihydrotetrabenazine vesicular monoamine transporter type 2 positron emission tomography. We found that odour identification test scores correlated positively with acetylcholinesterase activity in the hippocampal formation (r = 0.56, P < 0.0001), amygdala (r = 0.50, P < 0.0001) and neocortex (r = 0.46, P = 0.0003). Striatal monoaminergic activity correlated positively with odour identification scores (r = 0.30, P < 0.05). Multiple regression analysis including limbic (hippocampal and amygdala) and neocortical acetylcholinesterase activity as well as striatal monoaminergic activity, using odour identification scores as the dependent variable, demonstrated a significant regressor effect for limbic acetylcholinesterase activity (F = 10.1, P < 0.0001), borderline for striatal monoaminergic activity (F = 1.6, P = 0.13), but not significant for cortical acetylcholinesterase activity (F = 0.3, P = 0.75). Odour identification scores correlated positively with scores on cognitive measures of episodic verbal learning (r = 0.30, P < 0.05). These findings indicate that cholinergic denervation of the limbic archicortex is a more robust determinant of hyposmia than nigrostriatal dopaminergic denervation in subjects with moderately severe Parkinson's disease. Greater deficits in odour identification may identify patients with Parkinson's disease at risk for clinically significant cognitive impairment.
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PMID:Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson's disease. 2080 99

Chelators have the potential to treat the underlying cause of Alzheimer's disease (AD), but their therapeutic use is hampered by their poor targeting and poor permeability to the brain and/or toxic effects. Here, we report a new strategy for designing site-activated chelators targeting both acetylcholinesterase (AChE) and monoamine oxidase (MAO). We demonstrated that our lead 2 inhibited both AChE and MAO in vitro, but with little affinity for metal (Fe, Cu, and Zn) ions. Compound 2 can be activated by inhibition of AChE to release an active chelator M30. M30 has been shown to be able to modulate amyloid precursor protein regulation and beta-amyloid reduction, suppress oxidative stress, and passivate excess metal ions (Fe, Cu, and Zn). Compound 2 was less cytotoxic and more lipophilic than the brain-permeable chelator M30. Our new strategy is relatively simple and generally produces small and simple molecules with drug-like properties; it thus holds a potential use in designing site-activated multifunctional chelators with safer and more efficacious properties for treating other metal-related diseases such as Parkinson's disease and cancer where specific elimination of metals in cancer cells is required.
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PMID:Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy. 2045 74

Neurochemical changes in cholinergic neurons in the striatum and ?-aminobutyric acid (GABA)ergic neurons in the midbrain, especially in the basal ganglia, have been examined following the intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is known to cause behavioral changes resembling those in Parkinson's disease due to the destruction of nigro-striatal dopaminergic neurons. Although the adminstration of MPTP (50 mg/kg, once a day for 5 days) to male mice of dd strain did not induce the changes in choline and acethylcholine contents in the striatum, a decrement of GABA content in the midbrain, especially in the substantia nigra, was found in addition to a significant decrease of dopamine content in the striatum. This decrement in GABA content was accompanied by a decrease of turnover rate of GABA in the substantia nigra. Furthermore, it was found that MPTP treatment induced an increase of the GABA(A) receptor-benzodiazepine receptor-chloride channel complex in the substantia nigra in addition to that of dopaminergic D(2) receptor in the striatum. Although the MPTP treatment did not induce significant changes in acetylcholinesterase and choline acetyltransferase activities as well as high affinity choline uptake, this treatment induced a decrease of [(3)H]quinuclidinyl benzilate binding to muscarinic receptor in the striatum. These results suggest that the occurrence of behavioral changes induced by MPTP administration may involve functional alterations in cholinergic interneuron in the striatum as well as those in the striato-nigral GABAergic neuron, which are associated with the destruction of nigro-striatal dopaminergic neuron with this agent.
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PMID:Functional alterations in striatal cholinergic and striato-nigral gabaergic neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. 2050 75

Psychotic symptoms are common in Parkinson's disease (PD), generally associated with the medications used to treat the motor symptoms. On rare occasion they occur in patients not taking medication for PD. Psychotic symptoms are usually hallucinations, typically visual, less commonly auditory, and rarely in other domains. Hallucinations are generally stereotyped and without emotional content. Initially patients usually have insight so that the hallucinations are benign in terms of their immediate impact but have poor prognostic implications, with increased risk of dementia, worsened psychotic symptoms and mortality. Delusions occur in about 5-10% of drug treated patients and are considerably more disruptive, being paranoid in nature, often of spousal infidelity or abandonment by family. Treatment of Parkinson's disease psychosis (PDP) focuses on reducing the psychiatric symptom load while balancing the competing problem of mobility. Contributors to the psychotic symptoms should be searched for, such as systemic illness and other psycho-active medications. If none are identified or can be eliminated then the PD medications should be reduced to the lowest levels that allow tolerable motor function. Once this level has been reached there are two schools of thought on treatment, using either acetylcholinesterase inhibitors or atypical anti-psychotics. Only clozapine has level I evidence to support its use. Quetiapine is the only other anti-psychotic free of motor side effects, but it has failed double blind placebo controlled trials to demonstrate efficacy.
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PMID:Parkinson's disease psychosis 2010: a review article. 2053


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