a. o. Univ. Prof. Dipl. Ing. Dr. Halina BARAN Kainic Acid (KA ...

a. o. Univ. Prof. Dipl. Ing. Dr. Halina BARAN Kainic Acid (KA ...

2nd International Conference on HIV/AIDS, STDs & STIs October 27-29, 2014 Las Vegas, USA Significant differences between augmentation of kynurenine aminotransferase I and kynurenine aminotransferase II activities in various types of brain pathology after HIV-1 infection Halina Baran, Berthold Kepplinger and Johannes A. Hainfellner Karl Landsteiner Research Institute for Neurochemistry, Neuropharmacology, Neurorehabilitation and Pain Therapy, Landesklinikum Mauer, Amstetten, Senecura Neurorehabilitation Center, Kittsee, Institute of Neurology, Medical University Vienna, Austria Tryptophan is a substrate for the

synthesis of the neurotransmitter Serotonin 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-Daspartate (NMDA) an antagonist at the alpha-7 nicotinic cholinergic receptors (7nACh), whilenACh), while Quinolinic acid is an agonist at the NMDA receptors Classification of Excitatory Amino Acid Receptors in the Mammalian CNS GLUTAMATE NMDA AMPA

KAINATE METABOTROPIC Glutamate Site Glycine Site Agonists: NMDA Glycine D-Serin R-HA966 Quisqualic acid Kainic acid AMPA Domoic acid

ACPD Selective Antagonists:AP-5 KYNA NBQX AP-7 7-Cl-KYNA GYKI 52466 CGS 5,7-Cl-KYNA KYNA CGP MNQX CPP L-689,560

KYNA Channel Blockers: Mg+2,, Memantine Effector pathways: NA+/K+/Ca2+ NA+/K+/Ca2+ CNQX KYNA NA+/K+/Ca2+

L-AP4 MCPG IP3DAG J. R. Cooper. Biochemical Basis of Neuropharmacology, Oxford University Press, 1996 (simplified). Kynurenic acid an endogenous antagonist at the glycine site of the NMDA receptor T. Stone 1983 Kynurenic Acid and Cholinergic Receptor Kynurenic acid

blocks NONcompetitively the nACh), while7nCh Receptor activity. (Hilmas et al 2001 J. of Neuroscience) Kynurenic acid may modulate the synaptic transmission through blockade of the alpha 7 nicotine cholinergic rezeptors (nACh), while7nChRs). (Alkondon et al., J of Neuroscience 2004 /Albuquerque Group) pH optimum of KAT I and KAT II H. Baran, et al., J. Neurochem., 1994 Differences between 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. Rats and humans Kynurenine Aminotransferase (KAT) is preferentially localized in microglia, astrocytes but is also present in discrete neuronal populations as has been

demonstrated by immunhistochemical studies using KATantibodies. (R. C. Roberts et al., J. Comp. Neurol., 1992) A) -Acetylenic GABA (GAG), a potent KAT inhibitor, produces axonsparing neurodegeneration in CA1 and CA3 after focal injection into the rat hippocampus. B) Induced lesions are blocked by the NMDA receptor antagonists MK801

or AP7, indicating that acetylenic GABA caused excytotoxic damage is due to NMDA receptor activation. O.G. McMaster H. Baran et al,. Exper. Neurology, 1993 Kynurenic acid and ageing B. 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 DownSyndrom Alzheimers 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. Tryptophan metabolites KAT I; KAT II Kynurenic acid (KYNA), an intermediate metabolite of Lkynurenine (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. 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. Is the marked increase of KAT I activity mainly due to macrophage invasion in HIV-1 encephalopathy ? 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? KATs KATs It 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. Is the marked increase of KAT I activity mainly due to macrophage invasion in HIV-1 encephalopathy ? 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? Protective effect of Kynurenic Acid against Quinolinic Acid induced

neurotoxicity. a and c: Intrahippocampal injection of saline and Quinolinic Acid (Nissl Staining). b and d: Intrahippocampal injection of Kynurenic and Quinolinic Acid (Nissl Staining). In HIV-1 infected patients QUIN >> KYNA Heyes et al., 1992 A.C. Foster, Neurosci. Lett., 1984

Patients infected with HIV-1 virus frequently present with neuro-psychiatric symptoms. Is the marked increase of KAT I activity mainly due to macrophage invasion in HIV-1 encephalopathy ? 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? Time dipendent increase of Kynurenic acid in tha brain in rat

experimental asphyxia. (H. Baran et al., Life Sciences 2001) H. Baran, et al., Life Sciences, 2001 Patients infected with HIV-1 virus frequently present with neuro-psychiatric symptoms. Is the marked increase of KAT I activity mainly due to macrophage invasion in HIV-1 encephalopathy ? 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? 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) 16 14 * Putamen

Nucleus Caudate 12 * 10 8 6 4 2 0 CO

AD CO AD 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) 1,2 Putamen 1

Nucleus Caudate KAT I * KAT I * KAT II KAT II 0,8 0,6 0,4 0,2 0 CO

AD CO AD CO AD CO AD

After HIV-infection The 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.

Occurrence of bronchopneumonia (BR) and tuberculosis (TB) in different pathological group of patients after HIV-1 infection. Ratio OPP HIV LY INF GD

Number of pathology cases with 9/15 BR/ total number of pathology (60%) cases; expressed in % 1/6 (17%) 3/5 (60%) 2/5 (40%) 2/5

(40%) Number of pathology cases with 2/15 TB/ total number of pathology (13%) cases; expressed in % 2/6 (33%) 1/5 (20%) No case 1/5 with TB (20%)

* . KYNA levels and activity of KAT I and KAT II in the frontal cortex and cerebellum of patients wit bronchopneumonia Brain region KYNA KAT I KAT II

Frontal 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) 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 Treatment It is questionable if above mentioned anti-dementive medication(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 III 120

Figure 1 Cerebrolysin 0,15l Cerebrolysin 1,5 l Cerebrolysin 15 l 100 * * % of control

80 60 * * ** *** *** 40 *** ***

20 *** *** *** 0 KAT I KAT II

KAT III KAT I Rat brain H. Baran and B. Kepplinger (2008) Eur Neuropsychopharmacology KAT II Human brain KAT III 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 (lvarez et al., 2000; (Rther et al., 1994; Ruether et al., 2001; Crook et al., 2005; lvarez 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. Summary

Lowering 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, Alzheimers, HIV-1 infected patients or Parkinsons patients. Conclusions All 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. Thank you for your attention Effect of Cerebrolysin on KAT I, KAT II and KAT III 120 Figure 1 Cerebrolysin 0,15l Cerebrolysin 1,5 l

Cerebrolysin 15 l 100 * * % of control 80 60 *

* ** *** *** 40 *** *** 20 ***

*** *** 0 KAT I KAT II KAT III KAT I Rat brain

H. Baran and B. Kepplinger (2008) Eur Neuropsychopharmacology KAT II Human brain KAT III Kynurenic acid acts as an antagonist at the excitatory amino acid (EAA) receptors triggering neuroproterctive and anticonvulsive activities, and acts as an antagonist at the nicotinic cholinergic Receptors 7-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 Alzheimers 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 Alzheimers and other forms of dementia. -synthese von NO in microglia Glutamatergic neurotransmission 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 death Lowering of Kynurenic acid synthesis Y X

z by blocking KATs activities using GAG and also AOAA (Y) can produce lesions indirectly by - metabolic derangement and /or - inhibition of kynurenic acid formation. In old animals, (Gramsbergen et al., 1992 Brain Res)

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 acids H. Baran et al 1994, J Neurochem

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