Inhibiting the kynurenine pathway in spinal cord injury: multiple therapeutic potentials?
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摘要
Chronic induction of the kynurenine pathway(KP) contributes to neuroinflammation by producing the excitotoxin quinolinic acid(QUIN). This has led to significant interest in the development of inhibitors of this pathway, particularly in the context of neurodegenerative disease. However, acute spinal cord injury(SCI) also results in deleterious increases in QUIN, as secondary inflammatory processes mediated largely by infiltrating macrophages, become predominant. QUIN mediates significant neurotoxicity primarily by excitotoxic stimulation of the N-methyl-D-aspartate receptor, but other mechanisms of QUIN toxicity are known. More recent focus has assessed the contribution that neuroinflammation and modulations in the KP make in mood and psychiatric disorders with recent studies linking inflammation and modulations in the KP, to impaired cognitive performance and depressed mood in SCI patients. We hypothesize that these findings suggest that in SCI, inhibition of QUIN production and other metabolites, may have multiple therapeutic modalities and further studies investigating this are warranted. However, for central nervous system-based conditions, achieving good blood-brain-barrier permeability continues to be a limitation of current KP inhibitors.
Chronic induction of the kynurenine pathway(KP) contributes to neuroinflammation by producing the excitotoxin quinolinic acid(QUIN). This has led to significant interest in the development of inhibitors of this pathway, particularly in the context of neurodegenerative disease. However, acute spinal cord injury(SCI) also results in deleterious increases in QUIN, as secondary inflammatory processes mediated largely by infiltrating macrophages, become predominant. QUIN mediates significant neurotoxicity primarily by excitotoxic stimulation of the N-methyl-D-aspartate receptor, but other mechanisms of QUIN toxicity are known. More recent focus has assessed the contribution that neuroinflammation and modulations in the KP make in mood and psychiatric disorders with recent studies linking inflammation and modulations in the KP, to impaired cognitive performance and depressed mood in SCI patients. We hypothesize that these findings suggest that in SCI, inhibition of QUIN production and other metabolites, may have multiple therapeutic modalities and further studies investigating this are warranted. However, for central nervous system-based conditions, achieving good blood-brain-barrier permeability continues to be a limitation of current KP inhibitors.
Chronic induction of the kynurenine pathway(KP) contributes to neuroinflammation by producing the excitotoxin quinolinic acid(QUIN). This has led to significant interest in the development of inhibitors of this pathway, particularly in the context of neurodegenerative disease. However, acute spinal cord injury(SCI) also results in deleterious increases in QUIN, as secondary inflammatory processes mediated largely by infiltrating macrophages, become predominant. QUIN mediates significant neurotoxicity primarily by excitotoxic stimulation of the N-methyl-D-aspartate receptor, but other mechanisms of QUIN toxicity are known. More recent focus has assessed the contribution that neuroinflammation and modulations in the KP make in mood and psychiatric disorders with recent studies linking inflammation and modulations in the KP, to impaired cognitive performance and depressed mood in SCI patients. We hypothesize that these findings suggest that in SCI, inhibition of QUIN production and other metabolites, may have multiple therapeutic modalities and further studies investigating this are warranted. However, for central nervous system-based conditions, achieving good blood-brain-barrier permeability continues to be a limitation of current KP inhibitors.
引文
Allison DJ,Ditor DS(2015)Targeting inflammation to influence mood following spinal cord injury:a randomized clinical trial.J Neuroinflammation 12:204.
Allison DJ,Josse AR,Gabriel DA,Klentrou P,Ditor DS(2017)Targeting inflammation to influence cognitive function following spinal cord injury:a randomized clinical trial.Spinal cord 55:26-32.
Blight AR,Saito K,Heyes MP(1993)Increased levels of the excitotoxin quinolinic acid in spinal cord following contusion injury.Brain Res632:314-316.
Blight AR,Cohen TI,Saito K,Heyes MP(1995)Quinolinic acid accumulation and functional deficits following experimental spinal cord injury.Brain 118:735-752.
Bryleva EY,Brundin L(2017)Kynurenine pathway metabolites and suicidality.Neuropharmacology 112:324-330.
Chobot V,Hadacek F,Weckwerth W,Kubicova L(2015)Iron chelation and redox chemistry of anthranilic acid and 3-hydroxyanthranilic acid:A comparison of two structurally related kynurenine pathway metabolites to obtain improved insights into their potential role in neurological disease development.J Organomet Chem 782:103-110.
Colín-González AL,Maya-López M,Pedraza-ChaverríJ,Ali SF,Chavarría A,Santamaría A(2014b)The Janus faces of 3-hydroxykynurenine:Dual redox modulatory activity and lack of neurotoxicity in the rat striatum.Brain Res 1589:1-14.
Colin-Gonzalez AL,Luna-Lopez A,Konigsberg M,Ali SF,Pedraza-Chaverri J,Santamaria A(2014a)Early modulation of the transcription factor Nrf2 in rodent striatal slices by quinolinic acid,a toxic metabolite of the kynurenine pathway.Neuroscience 260:130-139.
Darlington LG,Forrest CM,Mackay GM,Smith RA,Smith AJ,Stoy N,Stone TW(2010)On the biological importance of the 3-hydroxyanthranilic acid:anthranilic acid ratio.Int J Tryptophan Res 3:51-59.
Erhardt S,Lim CK,Linderholm KR,Janelidze S,Lindqvist D,Samuelsson M,Lundberg K,Postolache TT,Traskman-Bendz L,Guillemin GJ,Brundin L(2013)Connecting inflammation with glutamate agonism in suicidality.Neuropsychopharmacology 38:743-752.
Gensel JC,Zhang B(2015)Macrophage activation and its role in repair and pathology after spinal cord injury.Brain Res 1619:1-11.
Guerrero AR,Uchida K,Nakajima H,Watanabe S,Nakamura M,Johnson WEB,Baba H(2012)Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice.J Neuroinflammation 9:40.
Guillemin GJ,Smythe G,Takikawa O,Brew BJ(2004)Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia,astrocytes,and neurons.Glia 49:15-23.
Hagen EM,Rekand T(2015)Management of neuropathic pain associated with spinal cord injury.Pain Ther 4:51-65.
Jacobs KR,Guillemin GJ,Lovejoy DB(2018)Development of a rapid fluorescence-based high-throughput screening assay to identify novel kynurenine 3-monooxygenase inhibitor scaffolds.SLAS Discov23:554-560.
Jacobs KR,Castellano-Gonzalez G,Guillemin GJ,Lovejoy DB(2017)Major developments in the design of inhibitors along the kynurenine pathway.Curr Med Chem 24:2471-2495.
Jia C,Yoshimura N,Liao L(2014)Herpes simplex virus vector-mediated gene transfer of kynurenine aminotransferase improves detrusor overactivity in spinal cord-injured rats.Gene Ther 21:484-489.
KorimováA,Cí?kováD,Toldi J,Vécsei L,VanickyI(2012)Protective effects of glucosamine-kynurenic acid after compression-induced spinal cord injury in the rat.Cent Eur J Biol 7:996-1004.
Krause D,Suh HS,Tarassishin L,Cui QL,Durafourt BA,Choi N,Bauman A,Cosenza-Nashat M,Antel JP,Zhao ML,Lee SC(2011)The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation:role of hemeoxygenase-1.Am J Pathol 179:1360-1372.
Lim CK,Essa MM,de Paula Martins R,Lovejoy DB,Bilgin AA,Waly MI,Al-Farsi YM,Al-Sharbati M,Al-Shaffae MA,Guillemin GJ(2016)Altered kynurenine pathway metabolism in autism:Implication for immune-induced glutamatergic activity.Autism Res 9:621-631.
Liu Y,Tachibana T,Dai Y,Kondo E,Fukuoka T,Yamanaka H,Noguchi K(2002)Heme oxygenase-1 expression after spinal cord injury:the induction in activated neutrophils.J Neurotrauma 19:479-490.
Niesters M,Dahan A(2012)Pharmacokinetic and pharmacodynamic considerations for NMDA receptor antagonists in the treatment of chronic neuropathic pain.Expert Opin Drug Metab Toxicol 8:1409-1417.
Plitman E,Iwata Y,Caravaggio F,Nakajima S,Chung JK,Gerretsen P,Kim J,Takeuchi H,Chakravarty MM,Remington G,Graff-Guerrero A(2017)Kynurenic acid in schizophrenia:a systematic review and meta-analysis.Schizophr Bull 43:764-777.
Rojewska E,Piotrowska A,Makuch W,Przewlocka B,Mika J(2016)Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.Neuropharmacology 102:80-91.
Rojewska E,Ciapala K,Piotrowska A,Makuch W,Mika J(2018)Pharmacological inhibition of indoleamine 2,3-dioxygenase-2 and kynurenine 3-monooxygenase,enzymes of the kynurenine pathway,significantly diminishes neuropathic pain in a rat model.Front Pharmacol 9:724.
Steiner J,Walter M,Gos T,Guillemin GJ,Bernstein HG,Sarnyai Z,Mawrin C,Brisch R,Bielau H,zu Schwabedissen LM,Bogerts B,Myint AM(2011)Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus:Evidence for an immune-modulated glutamatergic neurotransmission?J Neuroinflammation 8:94.
Wrathall JR,Bouzoukis J,Choiniere D(1992)Effect of kynurenate on functional deficits resulting from traumatic spinal cord injury.Eur JPharmacol 218:273-281.
Yates JR,Heyes MP,Blight AR(2006)4-Chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis,improves functional recovery,and preserves white matter after spinal cord injury.J Neurotrauma 23:866-881.
Yates JR,Gay EA,Heyes MP,Blight AR(2014)Effects of methylprednisolone and 4-chloro-3-hydroxyanthranilic acid in experimental spinal cord injury in the guinea pig appear to be mediated by different and potentially complementary mechanisms.Spinal Cord 52:662-666.
Zwilling D,Huang SY,Sathyasaikumar KV,Notarangelo FM,Guidetti P,Wu HQ,Lee J,Truong J,Andrews-Zwilling Y,Hsieh EW,Louie JY,Wu T,Scearce-Levie K,Patrick C,Adame A,Giorgini F,Moussaoui S,Laue G,Rassoulpour A,Flik G,et al.(2011)Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.Cell145:863-874.
Allison DJ,Josse AR,Gabriel DA,Klentrou P,Ditor DS(2017)Targeting inflammation to influence cognitive function following spinal cord injury:a randomized clinical trial.Spinal cord 55:26-32.
Blight AR,Saito K,Heyes MP(1993)Increased levels of the excitotoxin quinolinic acid in spinal cord following contusion injury.Brain Res632:314-316.
Blight AR,Cohen TI,Saito K,Heyes MP(1995)Quinolinic acid accumulation and functional deficits following experimental spinal cord injury.Brain 118:735-752.
Bryleva EY,Brundin L(2017)Kynurenine pathway metabolites and suicidality.Neuropharmacology 112:324-330.
Chobot V,Hadacek F,Weckwerth W,Kubicova L(2015)Iron chelation and redox chemistry of anthranilic acid and 3-hydroxyanthranilic acid:A comparison of two structurally related kynurenine pathway metabolites to obtain improved insights into their potential role in neurological disease development.J Organomet Chem 782:103-110.
Colín-González AL,Maya-López M,Pedraza-ChaverríJ,Ali SF,Chavarría A,Santamaría A(2014b)The Janus faces of 3-hydroxykynurenine:Dual redox modulatory activity and lack of neurotoxicity in the rat striatum.Brain Res 1589:1-14.
Colin-Gonzalez AL,Luna-Lopez A,Konigsberg M,Ali SF,Pedraza-Chaverri J,Santamaria A(2014a)Early modulation of the transcription factor Nrf2 in rodent striatal slices by quinolinic acid,a toxic metabolite of the kynurenine pathway.Neuroscience 260:130-139.
Darlington LG,Forrest CM,Mackay GM,Smith RA,Smith AJ,Stoy N,Stone TW(2010)On the biological importance of the 3-hydroxyanthranilic acid:anthranilic acid ratio.Int J Tryptophan Res 3:51-59.
Erhardt S,Lim CK,Linderholm KR,Janelidze S,Lindqvist D,Samuelsson M,Lundberg K,Postolache TT,Traskman-Bendz L,Guillemin GJ,Brundin L(2013)Connecting inflammation with glutamate agonism in suicidality.Neuropsychopharmacology 38:743-752.
Gensel JC,Zhang B(2015)Macrophage activation and its role in repair and pathology after spinal cord injury.Brain Res 1619:1-11.
Guerrero AR,Uchida K,Nakajima H,Watanabe S,Nakamura M,Johnson WEB,Baba H(2012)Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice.J Neuroinflammation 9:40.
Guillemin GJ,Smythe G,Takikawa O,Brew BJ(2004)Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia,astrocytes,and neurons.Glia 49:15-23.
Hagen EM,Rekand T(2015)Management of neuropathic pain associated with spinal cord injury.Pain Ther 4:51-65.
Jacobs KR,Guillemin GJ,Lovejoy DB(2018)Development of a rapid fluorescence-based high-throughput screening assay to identify novel kynurenine 3-monooxygenase inhibitor scaffolds.SLAS Discov23:554-560.
Jacobs KR,Castellano-Gonzalez G,Guillemin GJ,Lovejoy DB(2017)Major developments in the design of inhibitors along the kynurenine pathway.Curr Med Chem 24:2471-2495.
Jia C,Yoshimura N,Liao L(2014)Herpes simplex virus vector-mediated gene transfer of kynurenine aminotransferase improves detrusor overactivity in spinal cord-injured rats.Gene Ther 21:484-489.
KorimováA,Cí?kováD,Toldi J,Vécsei L,VanickyI(2012)Protective effects of glucosamine-kynurenic acid after compression-induced spinal cord injury in the rat.Cent Eur J Biol 7:996-1004.
Krause D,Suh HS,Tarassishin L,Cui QL,Durafourt BA,Choi N,Bauman A,Cosenza-Nashat M,Antel JP,Zhao ML,Lee SC(2011)The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation:role of hemeoxygenase-1.Am J Pathol 179:1360-1372.
Lim CK,Essa MM,de Paula Martins R,Lovejoy DB,Bilgin AA,Waly MI,Al-Farsi YM,Al-Sharbati M,Al-Shaffae MA,Guillemin GJ(2016)Altered kynurenine pathway metabolism in autism:Implication for immune-induced glutamatergic activity.Autism Res 9:621-631.
Liu Y,Tachibana T,Dai Y,Kondo E,Fukuoka T,Yamanaka H,Noguchi K(2002)Heme oxygenase-1 expression after spinal cord injury:the induction in activated neutrophils.J Neurotrauma 19:479-490.
Niesters M,Dahan A(2012)Pharmacokinetic and pharmacodynamic considerations for NMDA receptor antagonists in the treatment of chronic neuropathic pain.Expert Opin Drug Metab Toxicol 8:1409-1417.
Plitman E,Iwata Y,Caravaggio F,Nakajima S,Chung JK,Gerretsen P,Kim J,Takeuchi H,Chakravarty MM,Remington G,Graff-Guerrero A(2017)Kynurenic acid in schizophrenia:a systematic review and meta-analysis.Schizophr Bull 43:764-777.
Rojewska E,Piotrowska A,Makuch W,Przewlocka B,Mika J(2016)Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.Neuropharmacology 102:80-91.
Rojewska E,Ciapala K,Piotrowska A,Makuch W,Mika J(2018)Pharmacological inhibition of indoleamine 2,3-dioxygenase-2 and kynurenine 3-monooxygenase,enzymes of the kynurenine pathway,significantly diminishes neuropathic pain in a rat model.Front Pharmacol 9:724.
Steiner J,Walter M,Gos T,Guillemin GJ,Bernstein HG,Sarnyai Z,Mawrin C,Brisch R,Bielau H,zu Schwabedissen LM,Bogerts B,Myint AM(2011)Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus:Evidence for an immune-modulated glutamatergic neurotransmission?J Neuroinflammation 8:94.
Wrathall JR,Bouzoukis J,Choiniere D(1992)Effect of kynurenate on functional deficits resulting from traumatic spinal cord injury.Eur JPharmacol 218:273-281.
Yates JR,Heyes MP,Blight AR(2006)4-Chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis,improves functional recovery,and preserves white matter after spinal cord injury.J Neurotrauma 23:866-881.
Yates JR,Gay EA,Heyes MP,Blight AR(2014)Effects of methylprednisolone and 4-chloro-3-hydroxyanthranilic acid in experimental spinal cord injury in the guinea pig appear to be mediated by different and potentially complementary mechanisms.Spinal Cord 52:662-666.
Zwilling D,Huang SY,Sathyasaikumar KV,Notarangelo FM,Guidetti P,Wu HQ,Lee J,Truong J,Andrews-Zwilling Y,Hsieh EW,Louie JY,Wu T,Scearce-Levie K,Patrick C,Adame A,Giorgini F,Moussaoui S,Laue G,Rassoulpour A,Flik G,et al.(2011)Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration.Cell145:863-874.