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)

The cholinergic neurons located within the pedunculopontine nucleus (Ch5) of patients with Alzheimer's disease (AD; n = 15), Parkinson's disease (PD; n = 2), and neurologically normal (n = 6) subjects were visualized immunohistochemically using choline acetyltransferase, pharmacohistochemically using acetylcholinesterase, or by reduced histochemical methods using nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). Each histochemical procedure localized a well-delineated, compact lateral group and a more diffuse medial group of neurons within the pedunculopontine nucleus. Co-localization experiments revealed that all three enzymes marked the same population of cholinergic neurons. The extent of pathological alterations associated with the cholinergic neurons within the compact lateral sector of the pedunculopontine nucleus was examined in sections that reacted for NADPH-d, counterstained with thioflavin-S. The average number of neurofibrillary tangles within this portion of the pedunculopontine nucleus was 25.4 (range 0-70) in patients with AD, 1.5 (range 1-2) in those with PD, and 1.2 (range 0-4) in aged control subjects. Of the total number of neurofibrillary tangles counted in AD cases, 72.7% were end-stage ghosts and 27.3% were tangle-bearing neurons. The pathological alteration of cholinergic neurons of the compact lateral aspect of the pedunculopontine nucleus may play a role in some of the behavioral features characteristic of AD.
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PMID:Neurofibrillary tangles in cholinergic pedunculopontine neurons in Alzheimer's disease. 320 15

Nitric oxide (NO) is thought to be involved in neurodegenerative processes. Concerning Parkinson's disease (PD) it remains to be elucidated, if NO contributes to pathological alterations in the striatum. The present study evaluates the post-mortem putamen of PD patients and control subjects for distribution patterns of NO-synthase containing neurons, using the NADPH-diaphorase technique. The ratio of positively stained neurons and the total number of cells (control: 1,120 +/- 69 per mm2, n = 5; PD: 575 +/- 164mm2, n = 5) shows striking differences between controls and PD patients. Our findings give reason to conclude that NADPH-diaphorase positive structures may have pathogenetic importance in degenerative processes in PD putamen.
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PMID:NADPH-diaphorase/nitric oxide synthase containing neurons in normal and Parkinson's disease putamen. 753 4

Excitotoxins constitute a group of agents that are capable of activating excitatory amino acid receptors and producing axonsparing neuronal lesions. Focal injections of the exogenous excitotoxins kainic acid and ibotenic acid result in depletion of neurotransmitter markers in neuronal cell bodies located in areas of injection or in terminal zones of their projections. The discovery of endogenous agents that behave as excitotoxins has generated interest in the idea that excitotoxicity may contribute to the neuronal degeneration associated with a number of neurological diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease) which involve selective neurotransmitter deficits. Quinolinic acid (QUIN), a pyridine dicarboxylic acid and metabolite of tryptophan, which has been detected in the central nervous system (CNS), behaves as an excitotoxin. In the mammalian brain QUIN has been localized to glial and immune cells, and its content increases with age. The neuro-excitatory and neurotoxic actions of QUIN are mediated via the Mg(2+)-sensitive N-methyl-D-aspartate (NMDA) receptor. The toxicity of QUIN, like that of kainate, but not ibotenate, is dependent on the presence of an intact glutamate-aspartate afferent input to the target area. Focal injections of QUIN into the nucleus basalis magnocellularis (nbM), a major source of cholinergic innervation to diencephalic areas, produce sustained loss of cholinergic neuron markers in the neocortex and amygdala. The neurotoxic action of QUIN on nbM results in an impairment of performance on memory-related tasks. Cortical and amygdaloid projecting cholinergic neurons show differential sensitivity to QUIN and other excitotoxic agents. This factor may partly explain the reported discrepancy between mnemonic deficits and the loss of cholinergic markers in the cerebral cortex induced by intra-nbM injections of certain excitotoxins. Cortical muscarinic receptor function is not significantly influenced by QUIN injections into the nbM producing loss of cortical cholinergic neurons. In the striatum, focal QUIN injections have been found to largely replicate the neurotransmitter deficits prevailing in Huntington's disease, an inherited movement disorder. Intrastriatal QUIN produces a profound loss of the NADPH diaphorase staining neurons in the area of injection but relatively spares these in the adjacent transition zone. QUIN is also highly damaging to the striatopallidal enkephalinergic neurons. However, at doses that are neurotoxic to striatal neurons, QUIN and several other excitotoxins produce significant elevations in enkephalin levels both in the striatum and globus pallidus. This elevation reflects the presence of a plasticity in the striatal enkephalinergic neuron population. The metabolic pathway yielding QUIN produces a number of intermediates that act as excitotoxin antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The 1993 Upjohn Award Lecture. Quinolinic acid induced brain neurotransmitter deficits: modulation by endogenous excitotoxin antagonists. 773 38

Parkinson's disease is characterized by a loss of dopaminergic neurons in the mesencephalon. Although the mechanism of this neuronal loss is still unknown, oxidative stress is very likely involved in the cascade of events leading to nerve cell death. Since nitric oxide could be involved in the production of free radicals, we analysed, using immunohistochemistry and histochemistry, the production systems of nitric oxide in the mesencephalon of four patients with idiopathic Parkinson's disease and three matched control subjects. Using specific antibodies directed against the inducible isoform of nitric oxide synthase (the enzyme involved in the synthesis of nitric oxide), we found evidence to suggest that this isoform was present solely in glial cells displaying the morphological characteristics of activated macrophages. Immunohistochemical analysis performed with antibodies against the neuronal isoform of nitric oxide synthase, however, revealed perikarya and processes of neurons but no glial cell staining. The number of nitric oxide synthase-containing cells was investigated by histoenzymology, using the NADPH-diaphorase activity of nitric oxide synthase. Histochemistry revealed (i) a significant increase in NADPH-diaphorase-positive glial cell density in the dopaminergic cell groups characterized by neuronal loss in Parkinson's disease and (ii) a neuronal loss in Parkinson's disease that was two-fold greater for pigmented NADPH-diaphorase-negative neurons than for pigmented NADPH-diaphorase-positive neurons. These data suggest a potentially deleterious role of glial cells producing excessive levels of nitric oxide in Parkinson's disease, which may be neurotoxic for a subpopulation of dopaminergic neurons, especially those not expressing NADPH-diaphorase activity. However, it cannot be excluded that the presence of glial cells expressing nitric oxide synthase in the substantia nigra of patients with Parkinson's disease represents a consequence of dopaminergic neuronal loss.
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PMID:Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. 873 6

The substantia nigra (SN) receives afferents from cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg), a neuronal population that shows high levels of nitric oxide synthase (NOS), the enzyme responsible for the synthesis of nitric oxide. We have investigated the effects of the injection in PPTg of two neurotoxins, kainic acid (an excitotoxic neurotoxin), and ethylcholine mustard azirinium ion (AF64A, a non-excitotoxic neurotoxin), upon the SN cells of the rat, by using choline acetyltransferase (ChAT) immunohistochemistry as a marker of cholinergic neurons, and nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry and NOS immunohistochemistry as markers of nitric oxide-producing neurons. Our results show that in normal rats, the SN contains two populations of NOS-positive neurons: large cholinergic neurons of PPTg that invade the caudal region of the SN, and small elongated neurons lying in the SN pars compacta. After ipsilateral PPTg lesion, another population of nigral cells, constituted by medium sized neurons, became NADPHd/NOS-positive. This was much more evident in AF64A-injected rats, in which many medium sized neurons showed enzymatic activity and normal morphological features, at least during the 90 days after injection. Kainic acid-injected rats, in contrast, showed nigral cell degeneration, an effect not found in AF64A material, and only a few NOS-positive neurons. NADPHd/NOS activity was never present in degenerating neurons. These findings suggest that induction of NOS activity is not involved in nigral cell degeneration, and that nitric oxide could have a protective rather than a neurotoxic role. The possible role of nitric oxide in the pathogenesis of Parkinson's disease is discussed.
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PMID:NOS expression in nigral cells after excitotoxic and non-excitotoxic lesion of the pedunculopontine tegmental nucleus. 951 71

The objective of the present study was to investigate the potential role of the free radical nitric oxide (NO) in the development of fetal rat mesencephalic neurons grafted in a 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease. First, using nitric oxide synthase (NOS)-immunocytochemistry and reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry, we investigated the presence of the neuronal isoform of NOS (nNOS) in intrastriatal mesencephalic grafts. During the course of the experiment (16 weeks) an increase in the staining intensity and the number of nNOS/NADPH-d positive cells within the grafts was observed, as well as a gradual maturation of dopaminergic neurons. In addition, within both the host striatal and grafted mesencephalic tissue, a NO-dependent accumulation of cyclic guanosine monophosphate (cGMP) was detected, indicating the presence of guanylate cyclase, i.e., the target-enzyme for NO. Secondly, to determine the impact of NO on the survival of grafted dopaminergic neurons, 6-OHDA lesioned rats received mesencephalic grafts and were subsequently treated with the competitive NOS-inhibitor Nomega-nitro-l-arginine methylester (l-NAME). After chronic treatment for 4 weeks, tyrosine hydroxylase immunocytochemistry revealed no apparent differences between the survival of grafted dopaminergic neurons in control- or l-NAME treated animals, respectively. As the maturation of grafted dopaminergic neurons coincides with a gradual increase in the expression of nNOS within the graft and since dopaminergic cell numbers are not changed upon administration of l-NAME, it is concluded that endogenously produced and potentially toxic NO does not affect the survival of grafted fetal dopaminergic neurons.
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PMID:Sustained pharmacological inhibition of nitric oxide synthase does not affect the survival of intrastriatal rat fetal mesencephalic transplants. 959 18

This study was carried out in order to examine the effects of acute or chronic L-DOPA treatment on striatally expressed FosB- and JunB-like proteins in a rat model of Parkinson's disease. Rats with a unilateral, near-total 6-hydroxydopamine lesion of the ascending mesostriatal projection received either an acute challenge or a one-week treatment with 10 mg/kg/day methyl L-DOPA (combined with 15 mg/mg benserazide), and were killed at either 3 h or two days post-injection. Both acute and chronic L-DOPA treatment caused a pronounced, persistent increase in the number of FosB-like immunoreactive cells in the dopamine-denervated striata (five- and seven-fold increase, respectively, above the levels found in lesioned but non-drug-treated controls), but the two treatment groups differed markedly with respect to both the average amount of staining per cell, which was two-fold larger in the chronic L-DOPA cases, and the anatomical distribution of the labeled cells. After an acute injection of L-DOPA, FosB-positive cells were distributed rather uniformly across all striatal subregions, whereas chronic L-DOPA treatment induced discrete clusters of strongly FosB-like immunoreactive cells within medial and central striatal subregions, as well as in a large, yet sharply defined portion of the lateral caudate-putamen. Strongly labeled cell clusters that appeared in the medial and central caudate-putamen were preferentially located within calbindin-poor, mu-opioid receptor-rich striosomes, whereas the lateral area displaying FosB activation encompassed both striosomal and matrix domains. In both the medial and the lateral striatum a near-total overlap was found between strongly FosB-like immunoreactive cell groups and areas showing pronounced dynorphin expression. NADPH-diaphorase-positive striatal interneurons did not express FosB-like immunoreactivity after a 6-hydroxydopamine lesion alone, a negligible proportion of them did after an acute L-DOPA challenge, but about 8% of these interneurons were FosB positive following chronic L-DOPA treatment. Like FosB, JunB was induced in the DA-denervated striatum by both acute and chronic L-DOPA treatment, and exhibited similar distribution patterns. However, JunB did not exhibit prolonged expression kinetics, and was somewhat down-regulated in the chronically compared with the acutely L-DOPA-treated rats. The present results show that L-DOPA administration produces a long-lasting increase in the levels of FosB-, but not JunB-like immunoreactivity in the dopamine-denervated striatum. More importantly, these data show that striatal induction of FosB- and JunB-like proteins by chronic L-DOPA treatment exhibits both regional and compartmental specificity.
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PMID:Changes in the regional and compartmental distribution of FosB- and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-dopa treatment. 1057 13

The loss of dopaminergic neurones in the substantia nigra with Parkinson's disease may result from inflammation-induced proliferation of microglia and reactive macrophages expressing inducible nitric oxide synthase (iNOS). We have investigated the effects of the supranigral administration of lipopolysaccharide on iNOS-immunoreactivity, 3-nitrotyrosine formation and tyrosine hydroxylase-immunoreactive neuronal number, and retrogradely labelled fluorogold-positive neurones in the ventral mesencephalon in male Wistar rats. Following supranigral lipopolysaccharide injection, 16-18 h previously, there was intense expression of NADPH-diaphorase and iNOS-immunoreactivity in non-neuronal, macrophage-like cells. This was accompanied by intense expression of glial fibrillary acidic protein-immunoreactive astrocytosis in the substantia nigra. There were also significant reductions in the number of tyrosine hydroxylase(50-60%)- and fluorogold (65-75%)-positive neurones in the substantia nigra. In contrast, tyrosine hydroxylase-immunoreactivity in the ventral tegmental area was not altered. Pre-treatment of animals with the iNOS inhibitor, S-methylisothiourea (10 mg kg(-1), i.p.), led to a significant reduction of lipopolysaccharide-induced cell death. Similar reduction of tyrosine hydroxylase-immunoreactivity and fluorogold-labelled neurones in the substantia nigra following lipopolysaccharide administration suggests dopaminergic cell death rather than down-regulation of tyrosine hydroxylase. We conclude that the expression of iNOS- and 3-nitrotyrosine-immunoreactivity and reduction of cell death by S-methylisothiourea suggest the effects of lipopolysaccharide may be nitric oxide-mediated, although other actions of lipopolysaccharide (independent of iNOS induction) cannot be ruled out.
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PMID:Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. 1188 72

High levels of neuropeptide Y (NPY) are found in basal ganglia where it is co-localised with somatostatin (SOM) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH/d) in a population of striatal GABA containing interneurones. Although alterations occur in the levels of various neuropeptides in basal ganglia in Parkinson's disease (PD), it is not known whether NPY is affected. Using in situ hybridisation immunohistochemistry, we have examined the distribution of NPY mRNA in the caudate nucleus, putamen and nucleus accumbens of normal individuals and patients with PD. NPY mRNA was weakly expressed in the caudate nucleus, putamen and nucleus accumbens in normal individuals with a scattered labelling of neurones. However, there was no regional localisation within any brain area and no obvious differences between brain regions. In PD, the number of NPY mRNA-expressing cells was increased as was the density of the silver grains overlying each positive cell. The increase was more pronounced in the nucleus accumbens and in the ventral part of the caudate nucleus. The increase in NPY mRNA expression observed in patients with PD may reflect the loss of dopaminergic tone on striatal NPY containing interneurones, although a role for chronic L-DOPA therapy cannot be ruled out.
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PMID:Increased neuropeptide Y mRNA expression in striatum in Parkinson's disease. 1259 Nov 54

Rotenone, a widely used pesticide, causes a syndrome in rats that mimics, both behaviorally and pathologically, the symptoms of Parkinson's disease. The present study evaluated the role of nitric oxide in rotenone-induced nigro-striatal injury. After administration of rotenone in rats for 40 days, there was a moderate but significant injury of the nigro-striatal pathway indicated by a 47% decrease in striatal dopamine levels and a 28% loss of substantia nigra tyrosine hydroxylase-immunopositive neurons. Furthermore, a significant (37%) increase in the number of cells positive for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in the striatum was observed, accompanied by a 83% increase in nitric oxide synthase (NOS) activity and a significant increase in the production of 3-nitrotyrosine (3-NT). There was a significant increase (45%) in the optical density of NADPH-d staining and an increase (72%) in NOS activity in the substantia nigra. Moreover, administration of the neuronal NOS inhibitor 7-nitroindazole significantly attenuated the increased NOS activity and 3-NT production, and provided significant protection against rotenone-induced nigro-striatal injury. Our data suggest that chronic rotenone administration can lead to significant injury to the nigro-striatal system, mediated by increased generation of nitric oxide.
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PMID:Role of nitric oxide in rotenone-induced nigro-striatal injury. 1295 Apr 43


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