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The Kynurenine Pathway

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The Kynurenine Pathway The Kynurenine pathway. Malaria today afflicts ~500 million people throughout the tropical world. ~1 million, mainly children, die each year Fig.?1 NMDAR model showing binding sites for agonists and antagonists. The extracellular portions of NR1 and NR2 subunits consist of two domains, the modulatory domain and the agonist binding domain. Glycine and D-serine are agonists for NR1 subu... Mehdi Ghasemi , Steven C. Schachter The NMDA receptor complex as a therapeutic target in epilepsy: a review Epilepsy &amp; Behavior Volume 22, Issue 4 2011 617 - 640 http://dx.doi.org/10.1016/j.yebeh.2011.07.024 Malaria today afflicts ~500 million people throughout the tropical world. ~1 million, mainly children, die each year KMO inhibition protects mice against cerebral malaria • Plasmodium berghei infected mice die in 7-9 days showing neurological dysfunction • Treat with 200mg/Kg Ro-61-8048 over 12 days (every 1 or 2 days); parasitaemia the same but no neurological dysfunction • Euthanasied at 21 days, pronounced anaemia Kynurenic Anthranilic Quinolinic Treatment Picolinic acid acid acid acid MIP-1α Control + 309 ± 49 1.3 ± 0.5 2.0 ± 0.3 144 ± 34 0.58 ± 0.06 vehicle Control + Ro- 265 ± 32 10.2 ± 1.5 76.9 ± 23.3 150 ± 32 0.57 ± 0.09 61-8048 P. berghei 1,077 ± 265b 3.5 ± 0.9 2.7 ± 0.6 186 ± 28 4.11 ± 0.18c ANKA + vehicle P. berghei 300 ± 72 35.6 ± 6.0d 487 ± 96d 170 ± 29 2.26 ± 0.28d ANKA + Ro- 61-8048 Figure 2 Molecular interplay between endothelium and astrocytes, with some functional consequences ? the example of cerebral malaria (CM). In this case the pathogen (<ce:italic> Plasmodium falciparum</ce:italic> -infected red blood cell, <ce:ital... Trypanosomes in blood CNS stage model Trypanosoma brucei brucei GVR35 murine model Well established & characterised International standard for CNS disease T.b. GVR35 investigations Monitor parasitem ia in blood 7 14 21 28 35 Early CNS Acute Infection stage Late CNS stage Trypanosome •Parasites proliferate in the haemo- •Parasites established within s identified in lymphatic system and peripheral the CNS the inter- tissues •Stage 1 treatments are no ventricular •Infection can be cured by treatment longer effective foramen with stage 1 drugs Evaluating chemotherapy T.b. GVR35 Administer Drugs +ve Monitor Treatment unsuccessful 21 Up to 180 -ve days Parasites +ve in CNS Treatment successful Up to 180 days Takes too long -ve Develop improved models to assess drugs against Human African Trypanosomiasis Tryp-2-Viz In Vivo Imaging System Multi-Photon Laser Scanning Magnetic Resonance Imaging (IVIS) Microscopy (MPLSM) (MRI) Use of IVIS imaging to monitor CNS stage disease Use of IVIS imaging to monitor CNS stage disease Organs of GVR35-infected mice imaged ex vivo Day 35 post infection Use of IVIS imaging to monitor CNS stage disease Brains of GVR35-infected mice imaged ex vivo Day 13 olfactory bulbs brainstem Suramin Current Drugs Pentamidine Melarsoprol Eflornithine Nifurtimox Use of IVIS imaging to monitor chemotherapy Melarsoprol treatment at day 21 post infection Topical application: 3.6 mg x 3 days Use of IVIS imaging to monitor chemotherapy Diminazene aceturate (Berenil) treatment at day 21 post infection 40mg/kg x 1 injected intraperitoneally Multi-photon Laser Scanning Microscopy Imaging from the superficial meninges and into the brain parenchyma Microscope objective Skull bone (autofluores cent) (Bone removed) Dura Arachnoid layer Blood labelled with Level of tight Collagen dextran-rhodamine, 70 kD junctions jac 120331 Picture by Richard Wheeler, www.richardwheeler.net Multi-photon Laser Scanning Microscopy Trypanosomes in pial vessels in the brain in vivo D3 post infection T. bb 427 + mCherry Blood vessels labelled with FITC-dextran Multi-photon Laser Scanning Microscopy Trypanosomes in the superficial meninges in vivo 1000 Real time 100 (removed) D13 post in SA space 2 10 infection Thinned skull N/mm Dura 0 1 0 10 20 30 Arachnoid40 Days since infection GVR35 + Pia mater mCherry 400 300 Coles 2012 GVR35 Blood vessels 200 labelled with in SA space 2 FITC-dextran 100 S427 N/mm 0 5 6 7 8 9 25-30 micron below skull Log(N/mL in blood) The number of extravascular trypanosomes per unit area of superficial meninges depends on time since infection, not blood parasitaemia. Roles in inflammation & cancer The major cellular and molecular targets of kynurenic acid. Blockade of <ce:italic> N</ce:italic> -methyl-<ce:small-caps> D</ce:small-caps> - aspartic acid receptors was the first specific site of action to be identified <ce:cross-ref ref... Figure 3 Potential sites at which kynurenine, long regarded as biologically inactive, may act to regulate the balance of cells produced in the immune system. Trevor W. Stone , Nicholas Stoy , L. Gail Darlington An expanding range of targets for kynurenine metabolites of tryptophan Trends in Pharmacological Sciences null 2012 null http://dx.doi.org/10.1016/j.tips.2012.09.006 The first enzyme in the kynurenine pathway, indolamine-2,3-dioxygenase (IDO), plays a key role in regulation of the immune system by virtue of its activation by mediators such as interferon-?. In addition to the effects of kynurenic acid... Trevor W. Stone , Nicholas Stoy , L. Gail Darlington Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection FEBS Journal Volume 279, Issue 8, pages 1386-1397, 27 MAR 2012 DOI: 10.1111/j.1742-4658.2012.08487.x http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2012.08487.x/full#f1 FEBS Journal Volume 279, Issue 8, pages 1386-1397, 27 MAR 2012 DOI: 10.1111/j.1742-4658.2012.08487.x http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2012.08487.x/full#f2 Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection structures are shown of several of the glutamate receptor blocking compounds based on the structure of kynurenic acid. Most act at the glycine- B receptor site on the NMDA receptor, the preferred site of action of kynurenic acid. Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection The structures are shown of the two main inhibitors of the kynurenine pathway that are neuroprotective and prevent excitotoxicity by blocking kynureninase or KMO. FEBS Journal Volume 279, Issue 8, pages 1386-1397, 27 MAR 2012 DOI: 10.1111/j.1742-4658.2012.08487.x http://onlinelibrary.wiley.com/doi/10.1111/j.1742-4658.2012.08487.x/full#f3 Putative arginase Polyamine pathway 50000000 5000000 1000000 800000 700000 40000000 4000000 800000 600000 30000000 3000000 600000 500000 400000 20000000 2000000 400000 300000 10000000 1000000 200000 200000 100000 0 0 0 0 24 48 72 0 24 48 72 0 24 48 72 0 0 24 48 72 hours hours hours hours Not Ornithine Aminopropyl- Arginase decarboxylase transferase L-Arginine L-Ornithine Putrescine Spermidine 1400000 250000 1200000 200000 1000000 800000 150000 600000 100000 400000 200000 50000 N-Acetylputrescine N-Acetylornithine 0 0 0 24 48 72 0 24 48 72 hours hours Putative arginase Most significant effects (top 10 & bottom 10) Cofactors Cofactors ??? Mass RT Formula Isomers Metabolite Pathway 1 2 135.068 Phenylalanine Multiple substrates 4 5.51 C8H9NO 4 2-Phenylacetamide metabolism 5.71 1.22 161.047 6 7.95 C9H7NO2 7 2-Indolecarboxylic acid N/A 5.4 1.71 175.063 11.1 3 0 C10H9NO2 12 3-Indoleglycolaldehyde Tryptophan metabolism 5 2.41 335.148 1 9.42 C16H21N3O5 1 Gly-Pro-Tyr Peptide(tri-) 4.73 1.71 Multiple products 189.042 5 7.34 C10H7NO3 6 Kynurenate Tryptophan metabolism 4.48 0.99 175.063 2 5.71 C10H9NO2 12 Indole-3-acetate Tryptophan metabolism 4.45 1.36 196.063 7 5.40 C12H8N2O 2 2-hydroxyphenazine Secondary Metabolism 4.24 1.62 145.052 8 5.54 C9H7NO 7 3-Methyleneoxindole N/A 3.73 1.3 Cofactors 1 is essential 250.062 (NAD+) 4 9.31 C8H14N2O5S 2 Glu-Cys Peptide(di-) 3.45 1.38 236.079 10.5 6 5 C11H12N2O4 2 L-Formylkynurenine Tryptophan metabolism 3.41 1.51 301.142 8 9.41 C16H19N3O3 3 Trp-Pro Peptide(di-) 0.33 0.74 264.153 18.1 Putative arginase Most significant effects (top 10 & bottom 10) Cofactors Cofactors Mass RT Formula Isomers Metabolite Pathway 1 2 135.068 Phenylalanine Multiple substrates 4 5.51 C8H9NO 4 2-Phenylacetamide metabolism 5.71 1.22 • Tryptophan 161.047 6 7.95 C9H7NO2 7 2-Indolecarboxylic acid N/A 5.4 1.71 • Trp peptides 175.063 11.1 3 0 C10H9NO2 12 3-Indoleglycolaldehyde Tryptophan metabolism 5 2.41 335.148 1 9.42 C16H21N3O5 1 Gly-Pro-Tyr Peptide(tri-) 4.73 1.71 Multiple products 189.042 5 7.34 C10H7NO3 6 Kynurenate Tryptophan metabolism 4.48 0.99 • Tryptophan pathway 175.063 • Oxidoreductase (or 2 5.71 C10H9NO2 12 Indole-3-acetate Tryptophan metabolism 4.45 1.36 196.063 aminotransferase) 7 5.40 C12H8N2O 2 2-hydroxyphenazine Secondary Metabolism 4.24 1.62 145.052 8 5.54 C9H7NO 7 3-Methyleneoxindole N/A 3.73 1.3 Cofactors 1 is essential 250.062 4 9.31 C8H14N2O5S 2 Glu-Cys Peptide(di-) 3.45 1.38 (NAD+) 236.079 10.5 6 5 C11H12N2O4 2 L-Formylkynurenine Tryptophan metabolism 3.41 1.51 301.142 8 9.41 C16H19N3O3 3 Trp-Pro Peptide(di-) 0.33 0.74 264.153 18.1 Putative arginase Tryptophan metabolism: Putative arginase L-Tryptophan: possible enzyme Tryptophan 2,3-dioxygenase O2 L-Tryptophan L-Formylkynurenine 18000000 500000 16000000 450000 400000 14000000 350000 12000000 300000 10000000 250000 8000000 200000 6000000 150000 4000000 100000 2000000 50000 0 0 BYC1 BYC2 BYE1 BYE2 BYC1 BYC2 BYE1 BYE2 Putative arginase Tryptophan metabolism: Putative arginase L-Tryptophan: possible enzyme Tryptophan 2'-dioxygenase O2 NH3 CO2 L-Tryptophan 3-Indoleglycolaldehyde 18000000 140000 16000000 120000 14000000 100000 12000000 10000000 80000 8000000 60000 6000000 40000 4000000 2000000 20000 0 0 BYC1
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