Regional changes in kynurenic acid, quinolinic acid, and glial fibrillary acidic protein concentrations in the fetal sheep brain after experimentally induced placental insufficiency

Nicholls, Trisha Anne; Lacey, Brendan; Nitsos, Ilias; Smythe, George A.; Walker, David

doi:10.1067/mob.2001.108862

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…Furthermore, impaired cerebral KYNA formation might adversely affect glutamatergic or cholinergic neurotransmission in the metabolically challenged fetal brain (Nicholls et al, 2001), during neonatal asphyxia (CeresoliBorroni and Schwarcz, 2001) and in aged individuals (Gramsbergen et al, 1992). Staining of KAT II-ir cells in the brain may show anomalies under some or all of these diverse conditions, as recently observed in rats following kainate-induced convulsive seizures (unpublished data).…”

Section: Discussionmentioning

confidence: 87%

Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry

Guidetti

Hoffman

Meléndez-Ferro

et al. 2006

Glia

129

111

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Kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation, is a neuroinhibitory agent present in the mammalian brain. Endogenous KYNA preferentially affects the alpha7 nicotinic acetylcholine (alpha7nACh) receptor and, possibly, the glycine co-agonist (glycineB) site of the NMDA receptor. Functionally relevant fluctuations in brain KYNA occur under both physiological and pathological conditions, affecting cholinergic and glutamatergic neurotransmission. Kynurenine aminotransferase II (KAT II), the major biosynthetic enzyme of KYNA in the rat brain, catalyzes the irreversible formation of KYNA from its immediate bioprecursor, kynurenine. We now purified rat kidney KAT II to homogeneity, generated a polyclonal rabbit anti-rat KAT II antibody, and purified the antibody using routine biochemical methods. The antibody selectively recognized KAT II by Western blot analysis and in immunotitration experiments. Used for immunocytochemistry, the antibody revealed discrete, specific staining of KAT II-positive astrocyte-like cells throughout the adult rat brain. The presence of KAT II in astrocytes was confirmed by double fluorescence immunostaining with an antibody against the astrocyte-specific marker glial fibrillary acidic protein (GFAP). No specific labeling was detected in neurons or microglia. However, KAT II-positive astrocytes were intimately associated with select neuron populations, supporting a neuromodulatory role of KYNA. Intense staining was frequently seen around brain capillaries, with astrocytic end feet contacting the capillary wall. This may explain the rapid access of blood-derived kynurenine to KAT II-containing astrocytes. The new anti-KAT II antibody should be useful in the further elucidation of the presumed role of KYNA in brain physiology and pathology.

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Section: Discussionmentioning

confidence: 87%

Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry

Guidetti

Hoffman

Meléndez-Ferro

et al. 2006

Glia

129

111

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“…After QUIN injection into the rat brain, a reduction in the density of GFAP-immunoreactivity of astrocytes occurs early (within 6 hours of injection) suggesting astrocytic death; which could be associated with necrosis rather than apoptosis [28,29]. Another in vivo study using fetuses derived from ewes and damaged by hypoxia and hypoglycemia showed a significant increase in QUIN concentration associated with reduction in GFAP in fetal brain [30]. However, whether QUIN is able to induce astrogliosis and/or astrocytosis is still controversial [28,29].…”

Section: Resultsmentioning

confidence: 99%

Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex

Guillemin

Wang

Brew

2005

J Neuroinflammation

122

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There is evidence that the kynurenine pathway (KP) and particularly one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neuroinflammatory diseases, and more particularly AIDS dementia complex (ADC). We hypothesized that QUIN may be involved in astrocyte apoptosis because: 1) apoptotic astrocytes have been observed in the brains of ADC patients, 2) ADC patients have elevated cerebrospinal fluid QUIN concentrations, and 3) QUIN can induce astrocyte death. Primary cultures of human fetal astrocytes were treated with three pathophysiological concentrations of QUIN. Numeration of apoptotic cells was assessed using double immunocytochemistry for expression of active caspase 3 and for nucleus condensation. We found that treatment of human astrocytes with QUIN induced morphological (cell body shrinking) and biochemical changes (nucleus condensation and over-expression of active caspase 3) of apoptosis. After 24 hours of treatment with QUIN 500 nM and 1200 nM respectively 10 and 14% of astrocytes were undergoing apoptosis. This would be expected to lead to a relative lack of trophic support factors with consequent neuronal dysfunction and possibly death. Astroglial apoptosis induced by QUIN provides another potential mechanism for the neurotoxicity of QUIN during ADC. FindingsThe kynurenine pathway (KP) is a major route of L-tryptophan catabolism, resulting in the production of nicotinamide adenine dinucleotide and other neuroactive intermediates [1]. Of the metabolites, the N-methyl-Daspartate (NMDA) receptor agonist and neurotoxin quinolinic acid (QUIN) is likely to be one of the most important. There is evidence that QUIN is involved in the neurocytotoxicity associated with several major inflammatory brain diseases [2,3] such as AIDS dementia complex (ADC) [4,5] and other viral brain infections [2]. In the central nervous system (CNS), astrocytes play essential roles including metabolic homeostasis especially providing neurotrophic support, detoxification, maintenance of the blood brain barrier and immune response. During the brain inflammation associated with ADC, many mediators are released and astrocytes are activated leading to their cellular hypertrophy and/or proliferation [6]. For some astrocytes, this prolonged activation may induce apoptosis and the death of these reactive astrocytes can

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“…CXCR4 has been shown to be involved in brain development, in neuronal cell migration and patterning (Zou et al, 1998). There is preliminary evidence (Nicholls et al, 2001b) that QUIN concentrations are increased in pregnancy, raising the possibility that QUIN upregulation of CXCR4 expression may be important in fetal brain development.…”

Section: Discussionmentioning

confidence: 98%

“…Increased L-TRP catabolism through the kynurenine pathway (KP) has been detected during inflammatory states and pregnancy (Kudo and Boyd, 2000;Nicholls et al, 2001a). L-TRP degradation leads to production of a number of biologically active molecules (Stone, 2001).…”

Section: Introductionmentioning

confidence: 99%

Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes

Guillemin

Croitoru-Lamoury

Dormont

et al. 2003

Glia

147

102

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Within the brain, quinolinic acid (QUIN) is an important neurotoxin, especially in AIDS dementia complex (ADC). Its production by monocytic lineage cells is increased in the context of inflammation. However, it is not known whether QUIN promotes inflammation. Astrocytes are important in immunoregulation within the brain and so we chose to examine the effects of QUIN on the astrocyte. Using purified primary human fetal astrocyte cultures, we determined chemokine production using ELISA assays and RT-PCR and chemokine receptor expression using immunocytochemistry and RT-PCR with QUIN in comparison to TNFalpha, IL-1beta, and IFNgamma. We found that QUIN induces astrocytes to produce large quantities of MCP-1 (CCL2) and lesser amounts of RANTES (CCL5) and IL-8 (CXCL8). QUIN also increases SDF-1alpha (CXCL12), HuMIG (CXCL9), and fractalkine (CX(3)CL1) mRNA expression. Moreover, QUIN leads to upregulation of the chemokine receptor expression of CXCR4, CCR5, and CCR3 in human fetal astrocytes. Most of these effects were comparable to those induced by TNFalpha, IL-1beta, and IFNgamma. The present work represents the first evidence that QUIN induces chemokine and chemokine receptor expression in astrocytes and is at least as potent as classical mediators such as inflammatory cytokines. These results suggest that QUIN may be critical in the amplification of brain inflammation, particularly in ADC.

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Regional changes in kynurenic acid, quinolinic acid, and glial fibrillary acidic protein concentrations in the fetal sheep brain after experimentally induced placental insufficiency

Cited by 19 publications

References 32 publications

Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry

Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry

Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex

Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes

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