Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis

Iłżecka, Joanna; Kocki, Tomasz; Stelmasiak, Z; Turski, Waldemar A.

doi:10.1034/j.1600-0404.2003.00076.x

Cited by 68 publications

(58 citation statements)

References 51 publications

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“…As described above, KYNA is increased in the CSF of ALS patients [72] although as previously mentioned this is insuffi cient to counter the effects of QUIN. Intracerebral administration of KYN by increasing endogenous KYNA concentrations might exert neuroprotective effects through blockade of the NMDA receptor through a NO and cGMP pathway in the cerebellum and hippocampus of rats [102] .…”

Section: Direct Evidencementioning

confidence: 79%

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Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

2005

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The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of several neurobiologically active molecules. Among them is the excitotoxin quinolinic acid (QUIN) that is known to be involved in the pathogenesis of several major inflammatory neurological diseases. In amyotrophic lateral sclerosis (ALS) degeneration of motor neurons is associated with a chronic and local inflammation (presence of activated microglia and astrocytes). There is emerging evidence that the KP is important in ALS. Recently, we demonstrated that QUIN is significantly increased in serum and CSF of ALS patients. Moreover, most of the factors associated with QUIN toxicity are found in ALS, implying that QUIN may play a substantial role in the neuropathogenesis of ALS. This review details the potential role the KP has in ALS and advances a testable hypothetical model.

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Section: Direct Evidencementioning

confidence: 79%

“…KYNA, QUIN in CSF and Serum from ALS Patients Ilzecka et al [72] showed that KYNA ( fi g. 1 ) concentrations in CSF were signifi cantly higher in patients with bulbar onset of ALS compared to controls and to patients with limb onset. Levels of KYNA in CSF were also higher in patients with severe clinical status compared to controls.…”

Section: Direct Evidencementioning

confidence: 99%

Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

2005

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“…Recent studies have bridged a direct association between the KP and ALS (Guillemin et al 2005a). Ilzecka et al (2003) demonstrated that ALS patients with bulbar onset and severe clinical status had increased CSF KYNA levels. In contrast, serum KYNA levels were lower in patients with severe clinical status than in patients of mild clinical status or neurologically normal controls.…”

Section: Discussionmentioning

confidence: 97%

The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

et al. 2009

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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P < 0.0001), KYN (P < 0.0001) and QUIN (P < 0.05) and decreased levels of serum PIC (P < 0.05) in ALS samples. There was a significant increase in activated microglia expressing HLA-DR (P < 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP.

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“…Neurotoxicity in ALS is, at least for a part, mediated through a mechanism involving NMDA receptor activation (Urushitani et al, 2001;Spreux-Varoquaux et al, 2002;Kanki et al, 2004). The CSF of ALS patients induces neurotoxicity through NMDA receptor activation (Ilzecka et al, 2003). In vitro studies showed that QUIN depolarizes the spinal motoneurons of newborn rats by activating NMDA receptors (Martin and Lodge, 1987;Mizuno, 1998).…”

Section: Relevance Of the Model To Other Inflammatory Brain Diseasesmentioning

confidence: 98%

Involvement of quinolinic acid in aids dementia complex

2005

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Human immunodeficiency virus (HIV) infection is often complicated by the development of acquired immunodeficiency syndrome (AIDS) dementia complex (ADC). Quinolinic acid (QUIN) is an end product of tryptophan, metabolized through the kynurenine pathway (KP) that can act as an endogenous brain excitotoxin when produced and released by activated macrophages/microglia, the very cells that are prominent in the pathogenesis of ADC. This review examines QUIN's involvement in the features of ADC and its role in pathogenesis. We then synthesize these findings into a hypothetical model for the role played by QUIN in ADC, and discuss the implications of this model for ADC and other inflammatory brain diseases.

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Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis

Cited by 68 publications

References 51 publications

Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

Implications for the Kynurenine Pathway and Quinolinic Acid in Amyotrophic Lateral Sclerosis

The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

Involvement of quinolinic acid in aids dementia complex

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