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)

Nerve cells in the substantia nigra pars compacta (SNPC) are known to express tyrosine hydroxylase (TH). By means of light and electron microscopical immunohistochemical techniques, we have shown that the dopaminergic neurons of SNPC express also kynurenine aminotransferase (KAT-I), the enzyme taking part in the formation of kynurenic acid, a neuroprotectant which is one of the endogeneous antagonists of N-methyl-d-aspartate receptors. It was also found that microglial cells and astrocytes express KAT-I. It has been shown that the highly selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), widely used as a model of Parkinson's disease (PD), affects not only TH of dopaminergic neurons in the SNPC but also their KAT-I immunoreactivity as well: MPTP treatment decreased the number and optical density of KAT-I immunoreactive SNPC neurons. Decrease of KAT-I after MPTP treatment has been proved also by Western blot analysis. MPTP also reduced KAT-I immunoreactivity of microglial cells, except for those involved in reactive gliosis, which were arranged in groups surrounding affected neurons of the SNPC; also the number of KAT-I immunoreactive (IR) astroglial cells was increased in SNPC. We conclude that MPTP treatment may have a dual effect: in addition to being deleterious for neurons expressing TH and KAT-I, it also affects glial cells which could exacerbate the neurodegenerative process characterizing PD.
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PMID:Decreased expression of kynurenine aminotransferase-I (KAT-I) in the substantia nigra of mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. 1520 25

Objective--Excitatory amino acid receptors are involved in the normal physiology of the brain, and may play a role in the pathogenesis of neurological disorders such as Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc. It has been demonstrated that the blockade of one of these receptors ameliorates the symptoms of experimental allergic encephalomyelitis, an animal model of multiple sclerosis (MS). In a recent study, a decreased level of kynurenic acid was found in the cerebrospinal fluid of patients with MS. The only known endogenous excitotoxin receptor antagonist is the tryptophan metabolite kynurenic acid. Another metabolite is quinolinic acid, which exerts different action: it is an excitotoxin receptor agonist. The ratio of these two metabolites is determined by the activities of kynurenine aminotransferase I and II (KAT I and KAT II). In this study, we measured the activities of these enzymes and the concentration of kynurenic acid in the red blood cells (RBC) and in the plasma of patients with MS. KAT activities were detected both in the RBC and in the plasma. As compared with the control subjects, the KAT I and KAT II activities were significantly higher in the RBC of the patients. The concentration of kynurenic acid is elevated in the plasma of MS patients, and there is a tendency to an elevation in the RBC. These changes may indicate a compensatory protective mechanism against excitatory neurotoxic effects. Our data demonstrate the involvement of the kynurenine system in the pathogenesis of MS, which may predict a novel therapeutic intervention.
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PMID:Kynurenine metabolism in multiple sclerosis. 1600 34

Substantial evidence indicates that neuroactive kynurenine metabolites play a role in the normal physiology of the human brain, and are involved in the pathology of neurodegenerative disorders such as Parkinson's disease (PD). A sidearm product of the pathway, kynurenic acid (KYNA), which is synthesized by the irreversible transamination of kynurenine (KYN) by kynurenine aminotransferases (KAT I and KAT II), is an excitatory amino acid receptor antagonist. In the present study we measured the level of KYNA and the activities of the biosynthetic enzyme isoforms KAT I and KAT II in the plasma and in the erythrocytes (RBC) of 19 PD patients and 17 age-matched controls. The KAT I and KAT II activities were significantly lower in the plasma of PD patients, followed by a tendency to a decrease in plasma KYNA. An elevated KYNA level correlated with a significant increase in KAT II activity in the RBC of PD patients. These data support the contribution of an altered KYNA metabolism in the RBC to the pathogenesis of PD. The increased activity of KAT II in correlation with the elevated KYNA level in the RBC may mediate a consecutive protective response against excitatory neurotoxic effects.
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PMID:Kynurenine metabolism in plasma and in red blood cells in Parkinson's disease. 1609 71

Parkinson's disease (PD), a progressive neurodegenerative disorder, is characterized by a preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNPC). Neurons in the SNPC are known to express tyrosine hydroxylase (TH); therefore, in a commonly used PD model, 6-hydroxydopamine (6-OHDA), a selective catecholamine neurotoxin, induces neuronal death in SNPC. We have shown with immunohistochemical techniques that kynurenine aminotransferase-I (KAT-I), the enzyme taking part in the formation of kynurenic acid (KYNA)--the only known endogenous selective NMDA receptor antagonist and a potent neuroprotective agent--is also expressed in the rat SNPC. We found that KAT-I and TH co-exist in the very same neurons of SNPC and that 6-OHDA injected into the lateral ventricle produced loss of the majority of nigral neurons. Densitometric analysis proved that, in consequence of 6-OHDA treatment, not only TH but also KAT-I immunoreactivity diminished considerably in the remaining SNPC neurons. Astrocytes in the substantia nigra were found to express KAT-I under normal conditions; the amount of this enzyme increased after administration of 6-OHDA, whereas microglial cells became KAT-I immunoreactive only after 6-OHDA treatment. Since intrinsic KYNA in SNPC neurons is perceptibly insufficient to protect them from the deleterious effect of 6-OHDA, it is hypothesized that biochemical approaches which increase KYNA content of the central nervous system might prevent the deleterious effect of 6-OHDA and, supposedly, also the neuronal degradation characterizing PD.
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PMID:Effect of 6-hydroxydopamine treatment on kynurenine aminotransferase-I (KAT-I) immunoreactivity of neurons and glial cells in the rat substantia nigra. 1678 21

Substantial evidence indicates that neuroactive kynurenine metabolites play a role in the normal physiology of the human brain, and are involved in the pathology of neurodegenerative disorders such as Parkinson's disease and Huntington's disease. A side-arm product of the pathway, kynurenic acid (KYNA), which is synthesized by the irreversible transamination of kynurenine (KYN) by kynurenine aminotransferases (KAT I and KAT II), is an excitatory amino acid receptor antagonist. In the present study, we measured the level of KYNA and the activities of the biosynthetic enzyme isoforms KAT I and KAT II in the plasma and in the erythrocytes (RBCs) of patients with cervical dystonia or blepharospasm and in age-matched controls. The KAT I and KAT II activities were significantly lower in the plasma of the patients in both subgroups. In the RBCs, only the KAT I activity was elevated significantly. The KYNA concentration was unchanged in both type of patients. These data support the contribution of an altered kynurenine metabolism to the pathogenesis of focal dystonia.
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PMID:Peripheral kynurenine metabolism in focal dystonia. 1750 1

During catabolism of tryptophan through the kynurenine (KYN) pathway, several endogenous metabolites with neuromodulatory properties are produced, of which kynurenic acid (KYNA) is one of the highest significance. The causal role of altered KYNA production has been described in several neurodegenerative and neuropsychiatric disorders (e.g., Parkinson's disease, Huntington's disease, schizophrenia) and therefore kynurenergic manipulation with the aim of therapy has recently been proposed. Conventionally, KYNA is produced from its precursor L-KYN with the aid of the astrocytic kynurenine aminotransferase-2 (KAT-2) in the murine brain. Although the mouse is a standard therapeutic research organism, the presence of KAT-2 in mice has not been described in detail. This study demonstrates the presence of kat-2 mRNA and protein throughout the adult C57Bl6 mouse brain. In addition to the former expression data from the rat, we found prominent KAT-2 expression not only in the astrocyte, but also in neurons in several brain regions (e.g., hippocampus, substantia nigra, striatum, and prefrontal cortex). A significant number of the KAT-2 positive neurons were positive for GAD67; the presence of the KAT-2 enzyme we could also demonstrate in mice brain homogenate and in cells overexpressing recombinant mouse KAT-2 protein. This new finding attributes a new role to interneuron-derived KYNA in neuronal network operation. Furthermore, our results suggest that the thorough investigation of the spatio-temporal expression pattern of the relevant enzymes of the KYN pathway is a prerequisite for developing and understanding the pharmacological and transgenic murine models of kynurenergic manipulation.
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PMID:Astrocytic and neuronal localization of kynurenine aminotransferase-2 in the adult mouse brain. 2756 78

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The neuropathological features of PD are selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta, deficiencies in striatal dopamine levels, and the presence of intracellular Lewy bodies. Interactions among aging and genetic and environmental factors are considered to underlie the common etiology of PD, which involves multiple changes in cellular processes. Recent studies suggest that changes in lysine acetylation and deacetylation of many proteins, including histones and nonhistone proteins, might be tightly associated with PD pathogenesis. Here, we summarize the changes in lysine acetylation of both histones and nonhistone proteins, as well as the related lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), in PD patients and various PD models. We discuss the potential roles and underlying mechanisms of these changes in PD and highlight that restoring the balance of lysine acetylation/deacetylation of histones and nonhistone proteins is critical for PD treatment. Finally, we discuss the advantages and disadvantages of different KAT/KDAC inhibitors or activators in the treatment of PD models and emphasize that SIRT1 and SIRT3 activators and SIRT2 inhibitors are the most promising effective therapeutics for PD.
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PMID:Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson's Disease. 3300 40