| Sıra | DOSYA ADI | Format | Bağlantı |
|---|---|---|---|
| 01. | Alzheimers Alteration Cortex Antagonists | pptx | Sunumu İndir |
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2nd International Conference on HIV/AIDS, STDs & STIs October 27-29, 2014 Las Vegas, USA Halina Baran, Berthold Kepplinger and Johannes A. HainfellnerKarl Landsteiner Research Institute for Neurochemistry, Neuropharmacology, Neurorehabilitation and Pain Therapy, Landesklinikum Mauer, Amstetten, Senecura Neurorehabilitation Center, Kittsee, Institute of Neurology, Medical University Vienna, AustriaSignificant differences between augmentation of kynurenine aminotransferase I and kynurenine aminotransferase II activities in various types of brain pathology after HIV-1 infection
Tryptophan is a substrate for the synthesis of the neurotransmitterSerotonin
Kynurenine Pathway is the major road of L-Tryptophan catabolism.
Kynurenic acid (KYNA) is an endogenous metabolite in the “kynurenine pathway” of tryptophan degradation and is • an antagonist at the glycine site of the N-methyl-D-aspartate (NMDA) • an antagonist at the alpha-7 nicotinic cholinergic receptors (7αnACh), whileQuinolinic acid is an agonist at the NMDA receptors
Classification of Excitatory Amino Acid Receptors in the Mammalian CNSGLUTAMATE NMDA AMPA KAINATE METABOTROPIC Glutamate Site Glycine SiteAgonists: NMDA Glycine Quisqualic acid Kainic acid L-AP4 D-Serin AMPA Domoic acid ACPD R-HA966SelectiveAntagonists:AP-5 KYNA NBQX CNQX MCPG AP-7 7-Cl-KYNA GYKI 52466 KYNA CGS 5,7-Cl-KYNA KYNA CGP MNQX CPP L-689,560KYNAChannelBlockers: Mg+2,, MemantineEffectorpathways: NA+/K+/Ca2+ NA+/K+/Ca2+ NA+/K+/Ca2+ IP3DAGJ. R. Cooper. Biochemical Basis of Neuropharmacology, Oxford University Press, 1996 (simplified).
Kynurenic acid – an endogenous antagonist at the glycine site of the NMDA receptorT. Stone 1983
Kynurenic acid may modulate the synaptic transmission through blockade of the alpha 7 nicotine cholinergic rezeptors (α7nChRs). (Alkondon et al., J of Neuroscience 2004 /Albuquerque Group)Kynurenic Acid and Cholinergic ReceptorKynurenic acid blocks NON-competitively the α7nCh Receptor activity. (Hilmas et al 2001 J. of Neuroscience)
H. Baran, et al., J. Neurochem., 1994pH optimum of KAT I and KAT II
In contrast to KAT II, which is not affected dramatically by • pH changes, • and shows no particular preference for aminoacceptors , • and is not inhibited by millimolar concentrations of amino acids (substrate for KAT), KAT I is highly dependent on the composition of the incubation medium.Differences between KAT I and KAT II
Rat‘s and human‘s Kynurenine Amino-transferase (KAT) is preferentially localized in microglia, astrocytes but is also present in discrete neuronal populations as has been demonstrated by immunhistochemical studies using KAT-antibodies.(R. C. Roberts et al., J. Comp. Neurol., 1992)
B) Induced lesions are blocked by the NMDA receptor antagonists MK801 or AP7, indicating that γ-acetylenic GABA caused excytotoxic damage is due to NMDA receptor activation. A) γ-Acetylenic GABA (GAG), a potent KAT inhibitor, produces axon-sparing neurodegeneration in CA1 and CA3 after focal injection into the rat hippocampus.O.G. McMaster H. Baran et al,. Exper. Neurology, 1993
Kynurenic acid and ageingB. Kepplinge H. Baran et al., 2005 Neurosignals
Alterations of L-Kynurenine Metabolism in Neurodegenerative and Neuropsychiatric Diseases• Chorea Huntington• Olivo-Ponto-Cerebellar Atrophy • Temporal Lobe Epilepsy• Hepatic Encephalopathy• Cerebral Ischemia including Stroke• Hypoglycemia• AIDS• Polyneuropathy• Down‘Syndrom• Alzheimer‘s• and in other conditions including aging
We evaluated the biosynthetic machinery of kynurenic acid e.g. the content of L-kynurenine and kynurenic acid, as well as the activity of enzymes synthesizing kynurenic acid, kynurenine aminotransferases I and kynurenine aminotransferase II (KAT I and KAT II) in the frontal cortex and cerebellum of HIV-1 infected patients in respect to different types of pathology and these were classified as follows: HIV in brain (HIV); opportunistic infection (OPP); infarction of brain (INF); malignant lymphoma of brain (LY); and glial dystrophy (GD) and of control subjects.
Kynurenic acid (KYNA), an intermediate metabolite of L-kynurenine (L-KYN) , is a competitive antagonist of inotropic EAA receptors and a non competitive antagonist of 7 alpha nicotine cholinergic receptors and its involvement in memory deficit and cognition impairment has been suggested. Alterations of kynurenic acid metabolism in the brain after HIV-1 infection have been demonstrated. Tryptophan metabolitesKAT I; KAT II
HIV (HIV in brain); OPP (opportunistic infection); LY (malignant lymphoma of brain); INF (infarction of brain); and GD (glial dystrophy) and of control (control subjects).
HIV (HIV in brain); OPP (opportunistic infection); LY (malignant lymphoma of brain); INF (infarction of brain); GD (glial dystrophy) and Control (control subjects).
HIV (HIV in brain); OPP (opportunistic infection); LY (malignant lymphoma of brain); INF (infarction of brain); GD (glial dystrophy) and Control (control subjects).
• HIV (HIV in brain) ; opportunistic infection (OPP); malignant lymphoma of brain (LY); infarction of brain (INF); and glial dystrophy (GD) and of control subjects (control).
Statistical correlations
Patients infected with HIV-1 virus frequently present with neuro-psychiatric symptoms.Do elevated KYNA levels mitigate the cytotoxic effects of Quinolinic and Glutamic Acids in the brain of HIV-1 patients?Do elevated KYNA levels play a role in the high lethality by patients with bronchopneumonia or after HIV-1 infection?Does the alteration of KYNA metabolism in the brain of HIV-1 infected subjects play a similar function as suggested in Alzheimer Dementia?Is the marked increase of KAT I activity mainly due to macrophage invasion in HIV-1 encephalopathy ?
KATsKATsIt is likely that the marked increase of KAT I activity is due to macrophage invasion in HIV-1 encephalopathy.
Patients infected with HIV-1 virus frequently present with neuro-psychiatric symptoms.Do elevated KYNA levels mitigate the cytotoxic effects of Quinolinic and Glutamic Acids in the brain of HIV-1 patients?Do elevated KYNA levels play a role in the high lethality by patients with bronchopneumonia or after HIV-1 infection?Does the alteration of KYNA metabolism in the brain of HIV-1 infected subjects play a similar function as suggested in Alzheimer Dementia?Is the marked increase of KAT I activity mainly due to macrophage invasion in HIV-1 encephalopathy ?
Protective effect of Kynurenic Acid against Quinolinic Acid induced neurotoxicity.A.C. Foster, Neurosci. Lett., 1984b and d: Intrahippocampal injection of Kynurenic and Quinolinic Acid (Nissl Staining).a and c: Intrahippocampal injection of saline and Quinolinic Acid (Nissl Staining).In HIV-1 infected patients QUIN >> KYNA Heyes et al., 1992
Patients infected with HIV-1 virus frequently present with neuro-psychiatric symptoms.Do elevated KYNA levels mitigate the cytotoxic effects of Quinolinic and Glutamic Acids in the brain of HIV-1 patients?Do elevated KYNA levels play a role in the high lethality by patients with bronchopneumonia or after HIV-1 infection?Does the alteration of KYNA metabolism in the brain of HIV-1 infected subjects play a similar function as suggested in Alzheimer Dementia?Is the marked increase of KAT I activity mainly due to macrophage invasion in HIV-1 encephalopathy ?
(H. Baran et al., Life Sciences 2001)Time dipendent increase of Kynurenic acid in tha brain in rat experimental asphyxia.
H. Baran, et al., Life Sciences, 2001
Patients infected with HIV-1 virus frequently present with neuro-psychiatric symptoms.Do elevated KYNA levels mitigate the cytotoxic effects of Quinolinic and Glutamic Acids in the brain of HIV-1 patients?Do elevated KYNA levels play a role in the high lethality by patients with bronchopneumonia or after HIV-1 infection?Does the alteration of KYNA metabolism in the brain of HIV-1 infected subjects play a similar function as suggested in Alzheimer Dementia?Is the marked increase of KAT I activity mainly due to macrophage invasion in HIV-1 encephalopathy ?
Increased kynurenic acid levels in Putamen and Nucleus Caudate in Alzheimer's Disease (AD) but not in Frontal Cortex, Hippocampus and Cerebellum(H. Baran et al., J. Neural. Transm. 1999)0246810121416CO AD CO ADPutamenNucleus Caudate**
Increased activities of KAT I and KAT II in Putamen and Nucleus Caudate of Alzheimer's Disease (AD) but not in Frontal cortex, Hippocampus and Cerebellum. (H. Baran et al., J. Neural. Transm. 1999)00,20,40,60,811,2AD COCO AD CO AD CO ADPutamen Nucleus CaudateKAT IKAT IIKAT IKAT II* *
After HIV-infectionThe KAT I activity increased significantly in the frontal cortex of all pathological subgroups, i.e. OPP = 433 % > INF > LY > HIV > GD = 182 % of CO In the cerebellum, too, all pathological subgroups showed marked increase of KAT I activity OPP = 326 % > LY, HIV > GD > INF = 181 % of CO. On contrary, the activity of KAT II was moderately, but significantly, increased only in the frontal cortex of INF and OPP (174 and 160 % of CO) in the cerebellum of HIV, OPP and LY was comparable to control, while mildly reduced in INF and GD.
*Ratio OPP HIV LY INF GDNumber of pathology cases with BR/ total number of pathology cases; expressed in %9/15(60%)1/6(17%)3/5(60%)2/5(40%)2/5(40%)Number of pathology cases with TB/ total number of pathology cases; expressed in %2/15(13%)2/6(33%)1/5(20%)No case with TB 1/5(20%)Occurrence of bronchopneumonia (BR) and tuberculosis (TB)in different pathological group of patients after HIV-1 infection.
*Brain region KYNA KAT I KAT IIFrontal cortex;(in % of CO)13.383 2.290(383 % of CO)**3.603 1.226(877 % of CO)**0.511 0.028(101 % of CO)Cerebellum(in % of CO)2.117 0.005(76 % of CO)1.371 0.680(479 % of CO)*0.513 0.168(127 % of CO).KYNA levels and activity of KAT I and KAT II in the frontal cortex and cerebellum of patients wit bronchopneumonia
An increase of KYNA levels in the human central nervous system (CNS) is due to significant increase of KAT I activity and to lesser extend due to increase of KAT II activity. Blockade of glutamate NMDA and nicotine acetylcholinergic receptors is in part responsible for impaired memory, learning and cognition in various disorders.
Dementia and TreatmentIt is questionable if above mentioned anti-dementivemedication(s) influence(s) the Kynurenic acid synthesis(blockade).• Acetylcholine Esterase Inhibitors• NMDA Receptor Blocker – Memantine• Nootropica: Piracetam, Ginko biloba• Cerebrolysin
Effect of Cerebrolysin on KAT I, KAT II and KAT III020406080100120% of controlKAT I KAT II KAT III KAT I KAT II KAT IIIHuman brainFigure 1Cerebrolysin 0,15µlCerebrolysin 1,5 µlCerebrolysin 15 µl**************************Rat brain*H. Baran and B. Kepplinger (2008) Eur Neuropsychopharmacology
Clinical significances Human studies indicated that Cerebrolysin improves dementia symptoms and cognitive performance • in patients with Alzheimer's disease (AD) and • in other types of senile dementia and • in elderly control subjects (Álvarez et al., 2000; (Rüther et al., 1994; Ruether et al., 2001; Crook et al., 2005; Álvarez et al., 2006; Muresanu et al., 2008) .
D-Cycloserine, known as a partial agonist at the glycine modulatory site of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, exerts anticonvulsive activities and improves cognitive function and….
SummaryLowering of KYNA content due to D-cycloserine inhibition of KATs activities might be involved in the postulated mechanism for D-cycloserine to act as a partial agonist at the glycine site of the NMDA receptor. We propose that this mechanism(s) is in part responsible for the improvement of symptoms like dementia, cognition and/or delusion in schizophrenia patients, Alzheimer’s, HIV-1 infected patients or Parkinson’s patients.
ConclusionsAll these observations, together with the fact that KYNA dose dependently increases oxygen consumption and decreases ATP synthesis of rat heart mitochondria (Baran et al., 2003), suggest the improvement of cell function in pathological conditions due to D-cycloserine action of lowering KYNA formation.
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Effect of Cerebrolysin on KAT I, KAT II and KAT III020406080100120% of controlKAT I KAT II KAT III KAT I KAT II KAT IIIHuman brainFigure 1Cerebrolysin 0,15µlCerebrolysin 1,5 µlCerebrolysin 15 µl**************************Rat brain*H. Baran and B. Kepplinger (2008) Eur Neuropsychopharmacology
• Kynurenic acid acts as an antagonist at the excitatory amino acid (EAA) receptors trigger-ing neuroproterctive and anticonvulsive acti-vities, and acts as an antagonist at the nicotinic cholinergic Receptors 7α-Ach-R.• Quinolinic acid is a powerful agonist at the EAA receptors with excitotoxic, convulsive activities.• 3-OH-kynurenine and 3-OH-anthranilic acid are free radical generators.• 3-OH-kynurenine is a cytotoxic agent.• 3-OH-anthranilic acid is carcinogenic agent with respect to bladder and brest malignants and • the function of anthranilic acid is still unknown.
In Alzheimer‘s there was found also a significant change of glutamatergic transmission - (Glu ↑) beside the dysfunktion of the cholinergic neurotransmission.NMDA AMPA, KA-decrease of Glu carrier (EAA2) in astroglia -elevated resp. reduced number of glutamatergic receptors Glu R (NMDA)-synthesis of unknown NMDA agonists.-NMDA antagonist MEMANTINE clinically effective in Alzheimer‘s and other forms of dementia.-synthese von NO in microglia
Overactivation of Glutamate neurons Released of Glutamate Activation of the postsynaptic and presynaptic EAA receptors: - ionotropic NMDA, AMPA, KA and - eight metabotropic receptors Metabolic disturbance Cell deathGlutamatergic neurotransmission
Lowering of Kynurenic acid synthesis by blocking KATs activities using GAG and also AOAA (Y)can produce lesions indirectly by- metabolic derangement and /or- inhibition of kynurenic acid formation.XzY
(Gramsbergen et al., 1992 Brain Res)In old animals, • decline in the cerebral excitatory amino acid receptor densities with age corresponds with increased production of KYNA and with• age-related changes in astrocytes (hypertrophy).Age related changes in astrocytes are likely responsible for the increase in KYNA formation with age and may be involved in cognitive and memory dysfunction.
or fluctuation in the intracellular concentration of amino acidsH. Baran et al 1994, J Neurochem
Alzheimers Alteration Cortex Antagonists
Yıl : 2020
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