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Biomedical subjects

H Q Wu

Publications and source records attributed to H Q Wu.

At least 19 recordsLinked to original sources
PubMed2001

Increased cortical kynurenate content in schizophrenia.

BACKGROUND: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of the key metabolites in this pathway, kynurenine, is either transaminated to form the glutamate receptor antagonist, kynurenate, or hydroxylated to 3-hydroxykynurenine, which in turn is further degraded to the excitotoxic N-methyl-D-aspartate receptor agonist quinolinate. Because a hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. METHODS: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. RESULTS: Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 +/- 2.2 vs. 1.9 +/- 1.3 pmol/mg protein, p <.05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 +/- 28.0 vs. 22.4 +/- 14.3 pmol/mg protein; p <.05) and 19 (40.3 +/- 23.4 vs. 30.9 +/- 10.8; p <.05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p <.05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p >.05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation observed in schizophrenia is not due to antipsychotic medication. CONCLUSIONS: The data demonstrate an impairment of brain kynurenine pathway metabolism in schizophrenia, resulting in elevated kynurenate levels and suggesting a possible concomitant reduction in glutamate receptor function.

Adult↗
PubMed2000

Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus.

The synthetic compound 4-chlorokynurenine has been shown to be enzymatically transaminated to the selective glycine(B) receptor antagonist 7-chlorokynurenate. Since 4-chlorokynurenine, in contrast to 7-chlorokynurenate, readily penetrates the blood-brain barrier, the present study evaluated its neuroprotective properties after systemic administration in rats. Intrahippocampal injection of the NMDA receptor agonist quinolinate (15 nmol/l microl) was used as the neurotoxic paradigm. Serum and hippocampal tissue measurements confirmed that 4-chlorokynurenine serves as an effective pro-drug of 7-chlorokynurenate both in the periphery and in the brain. These studies and complementary hippocampal microdialysis experiments compared the effects of single and repeated injections of 4-chlorokynurenine (50 or 200 mg/kg, intraperitoneal (i.p.), 10 min prior to an intrahippocampal quinolinate injection; or 50 mg/kg, i.p., 10 min before and 30, 120 and 360 min after quinolinate). With the multiple-dosing regimen, extracellular 7-chlorokynurenate levels in the hippocampus reached a maximum of approximately 750 nM 7 h after quinolinate and gradually decreased with a half-life of about 3 h. In contrast, a single injection of 200 mg/kg 4-chlorokynurenine resulted in a considerably shorter rise in extracellular 7-chlorokynurenate without yielding higher peak levels. In separate animals, repeated treatment with 50 mg/kg 4-chlorokynurenine, but not a single injection of 200 mg/kg of the pro-drug, provided total protection against quinolinate-induced excitotoxicity. These data suggest that a prolonged and functionally relevant blockade of hippocampal glycine(B) receptors can be achieved after the systemic administration of 4-chlorokynurenine.

Animals↗
PubMed2000

In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum.

Excitotoxic mechanisms may play a critical role in the pathophysiology of several neurological and psychiatric diseases. Excitatory amino acid receptor antagonists are therefore of great therapeutic interest, but untoward side effects often prevent their clinical use. Targeting the glycine coagonist site of the (NMDA) receptor may bypass these shortcomings. The present study was designed to evaluate the neuroprotective characteristics of l-4-chlorokynurenine (4-Cl-KYN), a synthetic compound which is enzymatically converted to the selective glycine/NMDA receptor antagonist 7-chlorokynurenate (7-Cl-KYNA). Using slow (2 h) intrastriatal infusions of the excitotoxins quinolinate (QUIN; 120 nmol) or malonate (6.8 micromol) as the experimental paradigm, the neuroprotective potency of 4-Cl-KYN was first compared with that of exogenous 7-Cl-KYNA, using glutamate decarboxylase activity as a lesion marker. One hundred and thirty-five nanomoles of the prodrug 4-Cl-KYN or 27 nmol 7-Cl-KYNA, the former used in a pre- and cotreatment regimen, were required to block QUIN or, less efficiently, malonate toxicity. In separate animals, the metabolic fate of this neuroprotective dose of 4-Cl-KYN was examined in vivo. In control striata, the treatment gave rise to 170 +/- 25 pmol 7-Cl-KYNA/mg protein, approximately six times less than an infusion of 27 nmol exogenous 7-Cl-KYNA, indicating greatly superior efficacy of the focally produced antagonist. Notably, the conversion of 4-Cl-KYN to 7-Cl-KYNA increased by 82% in the presence of QUIN. 4-Cl-KYN was also metabolized to 4-chloro-3-hydroxyanthranilate, an established, powerful inhibitor of QUIN synthesis. This unique pharmacological profile and the fact that the prodrug, unlike 7-Cl-KYNA, readily penetrates the blood-brain barrier suggest that 4-Cl-KYN may be exceptionally useful as an anti-excitotoxic agent.

3-Hydroxyanthranilic Acid↗
PubMed2000

Kynurenergic manipulations influence excitatory synaptic function and excitotoxic vulnerability in the rat hippocampus in vivo.

Competing enzymatic mechanisms degrade the tryptophan metabolite L-kynurenine to kynurenate, an inhibitory and neuroprotective compound, and to the neurotoxins 3-hydroxykynurenine and quinolinate. Kynurenine 3-hydroxylase inhibitors such as PNU 156561 shift metabolism towards enhanced kynurenate production, and this effect may underlie the recently discovered anticonvulsant and neuroprotective efficacy of these drugs. Using electrophysiological and neurotoxicological endpoints, we now used PNU 156561 as a tool to examine the functional interplay of kynurenate, 3-hydroxykynurenine and quinolinate in the rat hippocampus in vivo. First, population spike amplitude in area CA1 and the extent of quinolinate-induced excitotoxic neurodegeneration were studied in animals receiving acute or prolonged intravenous infusions of L-kynurenine, PNU 156561, (L-kynurenine+PNU 156561) or kynurenate. Only the latter two treatments, but not L-kynurenine or PNU 156561 alone, caused substantial inhibition of evoked responses in area CA1, and only prolonged (3h) infusion of (L-kynurenine+PNU 156561) or kynurenate was neuroprotective. Biochemical analyses in separate animals revealed that the levels of kynurenate attained in both blood and brain (hippocampus) were essentially identical in rats receiving extended infusions of L-kynurenine alone or (L-kynurenine+PNU 156561) (4 and 7microM, respectively, after an infusion of 90 or 180min). However, addition of the kynurenine 3-hydroxylase inhibitor resulted in a significant decrement in the formation of 3-hydroxykynurenine and quinolinate in both blood and brain. These data suggest that the ratio between kynurenate and 3-hydroxykynurenine and/or quinolinate in the brain is a critical determinant of neuronal excitability and viability. The anticonvulsant and neuroprotective potency of kynurenine 3-hydroxylase inhibitors may therefore be due to the drugs' dual action on both branches of the kynurenine pathway of tryptophan degradation.

3-Hydroxyanthranilic Acid↗
PubMed2000

Some metabotropic glutamate receptor ligands reduce kynurenate synthesis in rats by intracellular inhibition of kynurenine aminotransferase II.

Some metabotropic glutamate receptor (mGluR) ligands, such as quisqualate, L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), 4-carboxy-3-hydroxyphenylglycine (4C3HPG), and L-serine-O:-phosphate (L-SOP), reduced the formation of the endogenous excitatory amino acid receptor antagonist kynurenate in brain and liver slices. The use of novel, subtype-selective mGluR agonists and antagonists excluded a role for any known mGluR subtype in this effect. The reduction of kynurenate formation was no longer observed when slices were incubated with the active mGluR ligands in the absence of extracellular Na(+). trans-Pyrrolidine-2,4-dicarboxylate (trans-PDC), a broad-spectrum ligand of Na(+)-dependent glutamate transporters, was also able to reduce kynurenate formation. Quisqualate, 4C3HPG, L-AP4, and L-SOP did not further reduce kynurenate formation in the presence of trans-PDC, suggesting that the two classes of drugs may share the same mechanism of action. Hence, we hypothesized that the active mGluR ligands are transported inside the cell and act intracellularly to reduce kynurenate synthesis. We examined this possibility by assessing the direct effect of mGluR ligands on the activity of kynurenine aminotransferases (KATs) I and II, the enzymes that transaminate kynurenine to kynurenate. In brain tissue homogenates, KAT II (but not KAT I) activity was inhibited by quisqualate, 4C3HPG, L-AP4, L-SOP, and trans-PDC. Drugs that were unable to reduce kynurenate formation in tissue slices were inactive. We conclude that some mGluR ligands act intracellularly, inhibiting KAT II activity and therefore reducing kynurenate formation. This effect should be taken into consideration when novel mGluR ligands are developed for the treatment of neurological and psychiatric diseases.

Aminobutyrates↗
PubMed1999

Modulation and function of kynurenic acid in the immature rat brain.

Using in vivo and in vitro paradigms, the regulation and function of the brain metabolite kynurenic acid (KYNA) was examined in rats on postnatal days (PND) 7 and 14. As shown previously in adult rats, glucose removal and d-amphetamine (d-Amph) administration caused decreases in KYNA formation, while exposure to pyruvate up-regulated KYNA synthesis. The effect of glucose deprivation was substantially blunted in immature animals. In PND 14 rats, d-Amph pre-treatment exacerbated the excitotoxic effects of an intrastriatal N-methyl-D-aspartate (NMDA) injection. This potentiation was prevented by m-nitrobenzoylalanine, a kynurenine 3-hydroxylase inhibitor that also antagonized the KYNA reduction caused by d-Amph. These and additional experiments with the competitive NMDA receptor antagonist CGP 40116 indicate the existence of a functionally significant, novel high-affinity receptor for KYNA in the brain.

2-Amino-5-phosphonovalerate↗
PubMed1999

2-Oxoacids regulate kynurenic acid production in the rat brain: studies in vitro and in vivo.

This study was designed to examine the role of 2-oxoacids in the enzymatic transamination of L-kynurenine to the excitatory amino acid receptor antagonist, kynurenate, in the rat brain. In brain tissue slices incubated in Krebs-Ringer buffer with a physiological concentration of L-kynurenine, pyruvate, and several other straight- and branched-chain 2-oxoacids, substantially restored basal kynurenate production in a dose-dependent manner without increasing the intracellular concentration of L-kynurenine. All 2-oxoacids tested also reversed or attenuated the hypoglycemia-induced decrease in kynurenate synthesis, but only pyruvate and oxaloacetate also substantially restored intracellular L-kynurenine accumulation. Thus, 2-oxoacids increase kynurenate formation in the brain primarily by functioning as co-substrates of the transamination reaction. This was supported further by the fact that the nonspecific kynurenine aminotransferase inhibitors (aminooxy)acetic acid and dichlorovinylcysteine prevented the effect of pyruvate on kynurenate production in a dose-dependent manner. Moreover, all 2-oxoacids tested attenuated or prevented the effects of veratridine, quisqualate, or L-alpha-aminoadipate, which reduce the transamination of L-kynurenine to kynurenate. Finally, dose-dependent increases in extracellular kynurenate levels in response to an intracerebral perfusion with pyruvate or alpha-ketoisocaproate were demonstrated by in vivo microdialysis. Taken together, these data show that 2-oxoacids can directly augment the de novo production of kynurenate in several areas of the rat brain. 2-Oxoacids may therefore provide a novel pharmacological approach for the manipulation of excitatory amino acid receptor function and dysfunction.

2-Aminoadipic Acid↗
PubMed1998

Systemic d-amphetamine administration causes a reduction of kynurenic acid levels in rat brain.

Tissue levels of the endogenous excitatory amino acid receptor antagonist kynurenic acid (KYNA) and of its bioprecursor L-kynurenine were measured in rats of different ages after d-amphetamine administration. In adult animals, extracellular KYNA concentrations were also determined in vivo by hippocampal microdialysis. In the adult brain, d-amphetamine caused a transient, dose-dependent decrease in tissue content and extracellular levels of KYNA, reaching a nadir of approximately 70% of control values after 1 h at 5 mg/kg. Quantitatively similar decrements were observed in four different brain regions. Seven, 14 and 28-day-old pups were particularly sensitive to the drug, showing a reduction in forebrain KYNA levels to 25%, 40% and 35% of control values, respectively, 1 h after the administration of 5 mg/kg d-amphetamine. Notably, no changes in brain L-kynurenine levels and in liver L-kynurenine and KYNA concentrations were found after d-amphetamine administration. Thus, endogenous monoamines released by d-amphetamine may interfere with the transamination of L-kynurenine to KYNA specifically in the brain. These results suggest that d-amphetamine increases excitatory amino acid receptor function temporarily by reducing the levels of endogenous KYNA.

Animals↗
PubMed1998

Focal microinjection of gamma-acetylenic GABA into the rat entorhinal cortex: behavioral and electroencephalographic abnormalities and preferential neuron loss in layer III.

Neuron loss in layer III of the entorhinal cortex (EC) occurs in patients with temporal lobe epilepsy and in several animal models of the disease and may play a role in the development of spontaneously recurring seizures. This damage can be reproduced in rats by a focal microinjection of the indirect excitotoxin aminooxyacetic acid into the EC (Neurosci. Lett., 147: 185, 1992). We have now examined a similar but approximately 20 times more potent toxin, gamma-acetylenic GABA (GAG), for its ability to produce seizures and neurodegeneration in the rat EC. EEG activity was recorded continuously for 48 h after a focal injection of 4 micrograms GAG into the rat EC. Seizure episodes, spiking, and other irregularities occurred with a latency of 150 min. Behavioral abnormalities were observed in all animals and were always accompanied by EEG seizures. The behavioral changes subsided gradually, but EEG seizures continued up to 24 h after GAG treatment. Nissl and silver-stained tissue sections obtained 2-3 days after the injection of 4 micrograms GAG revealed neuron loss which preferentially affected the medial part of layer III of the EC, and caused a modest lesion in the hilar region of the ventral hippocampus. The neurodegenerative potency of GAG, in contrast to the effects of aminooxyacetic acid, was not influenced by the depth of anesthesia during surgery. A slight increase in the dose of GAG (to 5 micrograms) resulted in more severe behavioral seizures, causing generalized convulsions with salivation and loss of righting posture in 3 of 13 rats. These animals also showed a marked enlargement of the lesioned area, with substantial neuronal loss occurring in layer III of the EC, in the hilus of the dentate gyrus, and occasionally also in homotopic structures of the contralateral hemisphere. Seizure activity and lesions induced by 4 micrograms GAG were prevented by the NMDA receptor antagonist Dizolcipine (MK-801) (4 mg/kg, i.p., 10 min before and 12 h after GAG). These data support the notion of a close correlation between the occurrence of seizures and neuronal loss in layer III of the EC. Taken together, the study suggests that intraentorhinal injections of GAG may provide an advantageous model for the study of epileptogenic and epileptic mechanisms.

4-Aminobutyrate Transaminase↗
PubMed1998

Dopaminergic control of kynurenate levels and N-methyl-D-aspartate toxicity in the developing rat striatum.

This study was designed to examine the effects of d-amphetamine (D-AMPH) and D1- and D2-selective dopaminergic drugs on the concentration of the broad-spectrum excitatory amino acid receptor antagonist kynurenic acid (KYNA) in the striatum of developing and adult rats. At all ages, KYNA levels were significantly reduced 1 h after the systemic administration of D-AMPH (5 mg/kg). SKF 38393 (5 mg/kg) and quinpirole (2 mg/kg) also caused a rapid decrease in striatal KYNA, but only in postnatal day (PND) 7 and 14 rats. All these effects were readily prevented by specific dopamine receptor antagonists. The possible functional significance of the reduction in KYNA levels was tested in PND 14 animals. When pretreated with D-AMPH (5 mg/kg), these rats showed markedly increased vulnerability to an intrastriatal injection of the excitotoxin NMDA. These data suggest that KYNA plays a role as a mediator of dopamine-glutamate interactions in the rat striatum.

Aging↗
PubMed1997

Enzyme-catalyzed production of the neuroprotective NMDA receptor antagonist 7-chlorokynurenic acid in the rat brain in vivo.

NMDA receptors play a critical role in neurotransmission and are also involved in the occurrence of excitotoxic nerve cell death. Synthetic halogenated analogs of the endogenous broad spectrum excitatory amino acid receptor blocker kynurenic acid are among the most potent and selective antagonists of the glycine co-agonist site of the NMDA receptor complex. Pharmacological blockade of this site provides neuroprotection in animal models of cerebral ischemia, epilepsy and neurodegenerative disorders, and does not appear to be associated with some of the undesirable side effects linked to classic competitive and non-competitive NMDA receptor antagonists. Here we demonstrate the neuroprotective quantities of 7-chloro-kynurenic acid (7-Cl-KYNA), one of the most selective and well-studied glycine site antagonists, can be synthesized in the brain from its bioprecursor L-4-chlorokynurenine (4-Cl-KYN). Intracerebral infusion of 4-Cl-KYN dose-dependently reduced quinolinate neurotoxicity in the rat hippocampus after enzymatic conversion to 7-Cl-KYNA by kynurenine aminotransferase. In accordance with previous studies demonstrating that kynurenine aminotransferase is preferentially localized in astrocytes, both the enzymatic formation of 7-Cl-KYNA and the neuroprotective potency of 4-Cl-KYN were substantially reduced following an intrahippocampal injection of the gliotoxin fluorocitrate. In situ produced 7-Cl-KYNA offers a novel neuroprotective strategy for targeting the glycine/NMDA site while avoiding excessive receptor blockade and reducing the clinical risks associated with conventional NMDA receptor antagonism.

Animals↗
PubMed1997

[Gene expression and distribution in mouse abdominal cavity mediated by adenovirus].

Infection and expression of recombinant human adenovirus in mouse abdominal cavity was reported. After adenovirus vector Ad/RSV-beta-gal harboring the E. coli lacZ marker gene was injected into mice abdominal cavity, the peritoneal surface of jejunum, ileum, colon, uterus, liver, spleen, stomach, bladder, abdominal wall, diaphragm and testis was found large patches of lacZ-positive cells. But the adenovirus vector was not able to penetrate the peritoneum, as demonstrated by histochemical staining. Another adenovirus vector Ad/RSV-tk harboring the HSV-tk gene was injected into mouse abdominal cavity and the mouse was treated with ACV. No acute toxic reaction was observed. Based on these data, the feasibility of gene therapy of malignant tumor within abdominal cavity with adenovirus mediated TK/GCV system was discussed.

Abdomen↗
PubMed1996

Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid.

7-Chlorokynurenic acid (7-Cl-KYNA) and 5,7-dichlorokynurenic acid (5,7-Cl2-KYNA) are of therapeutic interest as potent glycine/N-methyl-D-aspartate NMDA) receptor antagonists, but are excluded from brain by the blood-brain barrier. We examined whether these compounds could be delivered to brain through their respective precursors, L-4-chlorokynurenine (4-Cl-KYN) and L-4,6-dichlorokynurenine (4,6-Cl2-KYN), which are amino acids. 4-Cl-KYN was shown to be rapidly shuttled into the brain by the large neutral amino acid transporter of the blood-brain barrier (K(m) = 105 +/- 14 microM, Vmax = 16.9 +/- 2.3 nmol min-1 g-1) and to be converted intracerebrally to 7-Cl-KYNA. 4,6-Cl2-KYN also expressed affinity for the transporter, but four-fold less than that of 4-Cl-KYN. In summary, the results show that because of their facilitated uptake 4-Cl-KYN and 4,6-Cl2KYN might be useful prodrugs for brain delivery of glycine-NMDA receptor antagonists.

Amino Acids↗
PubMed1996

(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats.

Kynurenic acid is an endogenous excitatory amino-acid receptor antagonist with neuroprotective and anticonvulsant properties. We demonstrate here that systemic administration of the new and potent kynurenine 3-hydroxylase inhibitor (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a dose-dependent elevation in endogenous kynurenine and kynurenic acid levels in rat brain tissue. In hippocampal microdialysates, peak increases of 10- and 80-fold above basal kynurenic acid concentrations, respectively, were obtained after a single oral or intraperitoneal administration of 400 mg/kg FCE 28833A. After intraperitoneal treatment with FCE 28833A, extracellular brain kynurenic acid levels remained significantly elevated for at least 22 h, rendering this compound a far more effective enhancer of kynurenic acid levels than the previously described kynurenine 3-hydroxylase blocker m-nitrobenzoylalanine. FCE 28833A and similar molecules may have therapeutic value in diseases which are linked to a hyperfunction of excitatory amino-acid receptors.

Animals↗
PubMed1996

Seizure activity causes elevation of endogenous extracellular kynurenic acid in the rat brain.

This study was designed to examine the effects of several classic convulsants on the extracellular concentration of the anticonvulsant and neuroprotective brain metabolite kynurenic acid (KYNA) in the rat brain. Drug effects were investigated in vivo, mostly by unilateral microdialysis in the dorsal hippocampus. Systemic administration of pentylenetetrazole (60 mg/kg, SC), pilocarpine (325 mg/kg, SC), bicuculline (6 mg/kg, SC), or kainic acid (10 mg/kg, SC) caused characteristic clonic and/or tonic convulsions. In all seizure paradigms, KYNA levels in the dialysate began to rise within 1 h and gradually reached a plateau approximately 4 h after administration of the convulsants. Peak increases were 1.5-3-fold over basal levels. The duration of the elevation in KYNA levels was significantly prolonged following kainic acid application. In the kainic acid model, extracellular KYNA was also measured and found to be increased in the ventral hippocampus, piriform cortex, and striatum. Moreover, temporary intrahippocampal infusion of the KYN synthesis inhibitor aminooxyacetic acid (1 mM) in the kainic acid- and pentylenetetrazole models attenuated the increase in extracellular KYNA levels, demonstrating that de novo production of KYNA in the brain accounts for the seizure-induced KYNA overflow. A separate group of animals received a unilateral intrahippocampal injection of the endogenous convulsant excitotoxin quinolinic acid (120 nmol) and showed long-lasting (> 24 h) bilateral increases in extracellular KYNA levels. Taken together, these data indicate that an increase in extracellular KYNA may constitute a common occurrence in response to seizures and that KYNA elevations may signify the brain's attempt to counteract seizure activity.

Animals↗