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.

STUDY DESIGN: Blinded, placebo-controlled, parallel treatment group studies of the effects of methylprednisolone (MP) or 4-chloro-3-hydroxyanthranilate (4-Cl-3-HAA) on behavioral outcome and quinolinic acid tissue levels from experimental thoracic spinal cord injury in adult guinea pigs. OBJECTIVES: To compare the effects of treatment with high-dose MP, a corticosteroid, and 4-Cl-3-HAA, a compound that inhibits synthesis of the neurotoxin quinolinic acid (QUIN) by activated macrophages. To explore the effect of different times of treatment using these two approaches to ameliorating secondary tissue damage. SETTING: Laboratory animal studies at the University of North Carolina, Chapel Hill, NC, USA. METHODS: Standardized spinal cord injuries were produced in anesthetized guinea pigs, using lateral compression of the spinal cord. Behavioral impairment and recovery were measured by placing and toe-spread responses (motor function), cutaneus trunci muscle reflex receptive field areas and somatosensory-evoked potentials (sensory function). Tissue quinolinic acid levels were measured by gas chromatograph/mass spectrometry. RESULTS: The current experiments showed a reduction in delayed loss of motor and sensory function in the guinea pig with MP (150 mg kg(-1), intraperitoneally in split doses between 0.5 and 6 h), but no significant reduction in tissue QUIN. Improved sensory function was seen with a single dose of 60 mg kg(-1) MP intraperitoneally at 5 h after injury, but not at 10 h after injury. A single dose of 4-Cl-3-HAA at 5 h in the guinea pig did not produce the sensory and motor improvements seen in previous studies with 12 days of dosing, beginning at 5 h. CONCLUSION: These studies, together with earlier findings, indicate that both drugs can attenuate secondary pathologic damage after SCI, but through separate mechanisms. These are most likely an acute reduction by MP of oxidative processes and reduction by 4-Cl-3-HAA of QUIN synthesis.

Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains.

HIV encephalitis is unusual in that neurologic damage occurs in the absence of significant infection of neuronal or glial cells. Because the predominant infected cell in the brain is the macrophage, it has been proposed that release of viral or immune activation factors from macrophages may mediate neurologic damage. Numerous studies have examined the concentration of immune activation factors in the cerebrospinal fluid (CSF), however, there has been no correlation between these CSF measurements and severity of HIV encephalitis (Wiley, C.A., C.L. Achim, R.D. Schrier, M.P. Heyes, J.A. McCutchen, and I. Grant. 1992. AIDS (Phila.). 6:1299-1307. Because CSF measurements may not represent tissue concentrations of these factors, we examined the concentrations of HIV p24, quinolinic acid (QUIN), IL-1, IL-3, IL-6, TNF-alpha, and GMCSF within the brains of 10 AIDS autopsies. Homogenization and extraction of cortical gray, cortical white and deep gray matter showed a good correlation between the amount of HIV gp41 immunostaining and extracted HIV gag protein p24. The concentrations of cytokines were low in the tissue extracts and showed no correlation with severity of HIV encephalitis. Brain extracts from mild cases of HIV encephalitis showed elevated levels of TNF-alpha in deep gray matter, while in more severe cases, elevated TNF-alpha levels were also found within cortical white and cortical gray matter. Brain tissue and CSF QUIN concentrations were substantially increased compared to control values. QUIN concentrations were not correlated with the severity of HIV encephalitis. We conclude that increased tissue levels of TNF-alpha and QUIN may have a role in the etiology of HIV-related neurologic dysfunction.

A murine model of the eosinophilia-myalgia syndrome induced by 1,1'-ethylidenebis (L-tryptophan).

The eosinophilia-myalgia syndrome (EMS) is a recently described disease that has been associated with the ingestion of L-tryptophan containing trace amounts of several impurities. The first such contaminant to be identified and linked epidemiologically to the EMS epidemic was 1,1'-ethylidenebis(L-tryptophan) (EBT), but its role in the etiology and pathogenesis of the syndrome has been controversial. We report the development of inflammation and fibrosis affecting the dermis and subcutis, including the fascia and perimyseal tissues, after the daily intraperitoneal administration of EBT to female C57BL/6 mice. Such changes are accompanied by increased numbers of mast cells, many of which appear to be degranulating. Plasma levels of quinolinic acid, a metabolic product of L-tryptophan via the kynurenine pathway, are reduced initially, and then become elevated when inflammation and fibrosis are more pronounced. The nature and location of the inflammatory cell infiltrate and fibrosis, as well as the presence of mast cells and alterations of L-tryptophan metabolism, are consistent with findings reported in patients with EMS. This murine model suggests that EBT may have been one of the mediators of EMS and should facilitate studies of the pathogenesis of EMS.

L-tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat.

Tryptophan-associated eosinophilia-myalgia syndrome (L-TRP-EMS) is a newly described syndrome which occurred in epidemic fashion in the United States in the summer and fall of 1989. Epidemiologic data has linked the syndrome to intake of L-tryptophan (L-TRP) from one specific manufacturer, but the precise etiologic compound(s) must be established by replication of the syndrome in an appropriate animal model. In this study, implicated L-TRP, United States Pharmacopeia (USP) grade L-TRP, or vehicle was administered by gavage in a blinded fashion for 38 d to female Lewis rats at doses comparable with those ingested by patients who developed the eosinophilia-myalgia syndrome. Animals receiving implicated L-TRP, but not those receiving USP grade L-TRP or vehicle, developed histologic signs consistent with fasciitis and perimyositis, specific pathologic features of human L-TRP-EMS. Peripheral blood eosinophilia was not observed. Hypothalamic corticotropin releasing hormone mRNA levels were lower and plasma corticosterone levels tended to be lower in the animals that received implicated L-TRP. Plasma L-kynurenine was higher in both L-TRP-treated groups compared to the vehicle-treated animals. The female Lewis rat is known to be susceptible to a wide variety of inflammatory diseases. Identification of specific inflammatory changes in this rat following exposure to implicated L-TRP indicates that this animal model will be important in subsequent investigations into the etiology, pathogenesis, and treatment of human L-TRP-EMS.

Virus isolation and quinolinic acid in primary and chronic simian immunodeficiency virus infection.

OBJECTIVE: In this 2.5-year study of simian immunodeficiency virus (SIVsm) infection in rhesus monkeys, quinolinic acid (QUIN) levels and virus isolation determinations were made in serial cerebrospinal fluid (CSF) and blood samples to evaluate the relationship between these parameters over the course of infection. METHODS: Eight rhesus monkeys were inoculated in the saphenous vein with SIVsm. Four animals were maintained as uninoculated controls. CSF and blood samples were obtained every 1-4 weeks over the course of study. SIV isolation was determined in H9 cells for the CSF and in primary rhesus lymphocyte co-cultures for peripheral blood mononuclear cells (PBMC). QUIN was quantitated in CSF and serum by electron-capture negative chemical ionization gas chromatography mass spectrometry. RESULTS: All SIV-inoculated animals became CSF and PBMC isolation-positive by 1-3 weeks post-inoculation. Control animals remained SIV-negative. One SIV-positive animal was humanely euthanized at 2 weeks post-inoculation. The three SIV-inoculated animals that were CSF isolation-negative after the fifth week post-inoculation maintained CSF QUIN values < 100 nM, remained CSF and PBMC isolation-negative, and clinically healthy in the chronic course of disease. In contrast, the four SIV-inoculated animals that were CSF isolation-positive 6-8 weeks post-inoculation had CSF QUIN levels as high as 153-565 nM during the second month post-inoculation and remained CSF virus isolation-negative, persistently PBMC isolation-positive, and experienced clinical symptoms of SIV in the chronic course of disease. Three of these four animals have succumbed to SIV infection. DISCUSSION: Initial QUIN responses and viral isolation status in the first month post-inoculation were consistent among SIV-inoculated animals with CSF and serum QUIN values significantly higher than those of controls. A divergence within the SIV-inoculated group of animals became apparent within the second month of primary SIV infection and was maintained throughout the course of infection. Persistent PBMC viral isolation and marked elevations of QUIN were linked to symptomatic disease and a poor prognosis for survival. Predominantly negative PBMC viral isolation and slight, but significant, elevations of QUIN were linked to asymptomatic disease with a favorable prognosis for survival.

Cerebrospinal fluid and serum neopterin and biopterin in D-retrovirus-infected rhesus macaques (Macaca mulatta): relationship to clinical and viral status.

Increases in serum and cerebrospinal fluid (CSF) neopterin concentrations accompany many inflammatory diseases, including infection with HIV-1 and may reflect activation of guanosine triphosphate (GTP) cyclohydrolase 1 by gamma-interferon and other cytokines. In the present study, macaques with clinical simian AIDS (SAIDS) infected with the immunosuppressive type-D retrovirus D/1/California had increased concentrations of CSF neopterin but not of biopterin beginning soon after seroconversion. Normal neopterin concentrations in the CSF were found in macaques with SAIDS-related complex as well as asymptomatic, viremic macaques. CSF biopterin, serum neopterin and serum biopterin concentrations of D/1/California-infected macaques were not different from the levels in control animals. The increase in CSF neopterin may reflect local inflammatory responses and paralleled previously documented changes in L-tryptophan metabolism in these macaques. However, the absence of macrophage infiltrates in the brain of the infected macaques suggests a non-macrophage source of both increased CSF neopterin and tryptophan metabolites in the SAIDS macaques.

Relationship of cerebrospinal fluid immune activation associated factors to HIV encephalitis.

OBJECTIVES AND DESIGN: Because macrophages are the predominant immune cell and the predominant infected cell in the brains of patients with HIV encephalitis, we studied macrophage and immune activation-associated factors in the cerebrospinal fluid (CSF) from 39 autopsied AIDS cases for whom complete neuropathologic evaluation of the brain was available. RESULTS: CSF HIV p24 antigen was present in less than one-third of cases (11 out of 39). Less than half of the autopsies with moderate to severe parenchymal infection by HIV had high levels of CSF p24, although all autopsies with elevated levels of HIV p24 had moderate to severe HIV encephalitis. Elevated levels of cytokines, beta 2-microglobulin, neopterin, and quinolinic acid were observed. CONCLUSIONS: Although many of the CSF findings showed a strong correlation with each other, none showed a strong correlation with the severity of HIV infection of the brain itself. The absence of a close association between CSF abnormalities and HIV encephalitis could reflect the abundance of complicating opportunistic infections in these terminally ill patients or the inadequacy of CSF as a marker of basal ganglia involvement in HIV encephalitis. These findings complicate interpretation of clinical studies of CSF in patients with AIDS where neuropathologic evaluation is unavailable.

Cytopathologic and neurochemical correlates of progression to motor/cognitive impairment in SIV-infected rhesus monkeys.

Neurochemical, pathologic, virologic, and histochemical correlates of simian immunodeficiency virus (SIV)-associated central nervous system (CNS) dysfunction were assessed serially or at necropsy in rhesus monkeys that exhibited motor and cognitive deficits after SIV infection. Some infected monkeys presented with signs of acquired immunodeficiency disease (AIDS) at the time of sacrifice. Seven of eight animals exhibited motor skill impairment which was associated with elevated quinolinic acid in cerebrospinal fluid (CSF). Examination of the brains revealed diffuse increases in glial fibrillary acidic protein immunoreactivity in cerebral cortex in all animals, regardless of evidence of immunodeficiency disease. Reactive astrogliosis preceded or was coincident with the onset of neuropsychological impairments. Virus rescue from CSF of six of eight infected animals showed that one of three animals with AIDS and none of three animals without AIDS at necropsy had virus rescue-positive CSF. Multinucleated giant cells were seen in the brain of only one animal with end-stage AIDS and high systemic virus burden at death. Neither systemic nor CNS virus burden was associated with the onset of CNS dysfunction. SIV-associated motor/cognitive impairment is associated with subtle, widespread changes in CNS cytology and neurochemistry, rather than with large increases in brain virus burden or widespread virus-associated brain lesions.

Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: relation to clinical and biochemical variable.

In brain, most L-tryptophan is metabolized to indoleamines, whereas in systemic tissues L-tryptophan is catabolized to kynurenine pathway metabolites. Among these latter compounds are: quinolinic acid, an N-methyl-D-aspartate receptor agonist; kynurenic acid, an antagonist of excitatory amino acid receptors that also reduces quinolinic acid-mediated neurotoxicity; and L-kynurenine, a possible convulsant. Because the metabolism of L-tryptophan through the kynurenine pathway is dependent upon adequate nutrition, we sought to determine whether the impaired nutrition characteristic of eating-disordered patients might be associated with specific disturbances in this metabolic pathway. Cerebrospinal fluid levels of L-tryptophan, quinolinic acid, kynurenic acid, L-kynurenine, and 5-hydroxyindoleacetic acid were measured in medication-free female patients meeting DSM-III-R criteria for either anorexia nervosa (n = 10) or normal-weight bulimia nervosa (n = 22), studied at varying stages of nutritional recovery. Eight healthy, normal-weight females served as a comparison group. Cerebrospinal fluid levels of kynurenic acid were significantly reduced in underweight anorectics, compared to normal females, but returned to normal values with restoration of normal body weight. Although cerebrospinal fluid quinolinic acid levels were not different from controls, the ratio of quinolinic acid to kynurenic acid was significantly increased during the underweight phase of anorexia nervosa. Furthermore, in the eating-disordered patients, kynurenic acid levels in cerebrospinal fluid correlated positively with percent-of-population average body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed increases in regional brain quinolinic acid follow transient ischemia in the gerbil.

Excessive activity or release of excitatory amino acids has been implicated in the neuronal injury that follows transient cerebral ischemia. To investigate the metabolism of the endogenous excitotoxin, quinolinic acid, and its potential for mediating cell loss following ischemia, the concentrations of quinolinic acid, L-tryptophan, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were quantified in gerbil brain regions at different times after 5 or 15 min of ischemia induced by bilateral carotid artery occlusion. Significant elevation of brain tryptophan levels, accompanied by increased 5-hydroxyindoleacetic acid concentrations, occurred during the first several hours of recirculation, but regional brain quinolinic acid concentrations were found either to decrease or remain unchanged during the first 24 h after the ischemic insult. However, significant increases in quinolinic acid concentrations occurred in striatum and hippocampus at 2 days of recirculation after 5 min of ischemia. After a further 4 and 7 days, strikingly large increases in quinolinic acid concentrations were observed in all regions examined, with the highest levels observed in the hippocampus and striatum, regions that also show the most severe ischemic injury. These delayed increases in brain quinolinic acid concentrations are suggested to reflect the presence of activated macrophages, reactive astrocytes, and/or microglia in vulnerable regions during and subsequent to ischemic injury. While the results do not support a role for increased quinolinic acid concentrations in early excitotoxic neuronal damage, the role of the delayed increases in brain quinolinic acid in the progression of postischemic injury and its relevance to postischemic brain function remain to be established.

Brain eicosanoid formation following acute penetration injury as studied by in vivo microdialysis.

Formation of eicosanoids has been implicated in the pathological changes that follow brain injuries. In the present study, we used a microdialysis probe to both induce acute penetration injury and also sample extracellular fluid concentrations of eicosanoids. Formation of prostaglandin (PG) D2, PGF2 alpha, and thromboxane B2 was highest in the first hour following introduction of the probe into rat striatum. In contrast, the level of PGE2 was highest during the sixth hour of collection, while 6-keto-PGF1 alpha remained stable throughout the sampling period. We conclude that in vivo microdialysis may be useful in the evaluation of the time course of the effects of acute penetration injury of the brain on the local production of eicosanoids.

Quinolinic acid is increased in CSF and associated with mortality after traumatic brain injury in humans.

We tested the hypothesis that quinolinic acid, a tryptophan-derived N-methyl-D-aspartate agonist produced by macrophages and microglia, would be increased in CSF after severe traumatic brain injury (TBI) in humans, and that this increase would be associated with outcome. We also sought to determine whether therapeutic hypothermia reduced CSF quinolinic acid after injury. Samples of CSF (n = 230) were collected from ventricular catheters in 39 patients (16 to 73 years old) during the first week after TBI, (Glasgow Coma Scale [GCS] < 8). As part of an ongoing study, patients were randomized within 6 hours after injury to either hypothermia (32 degrees C) or normothermia (37 degrees C) treatments for 24 hours. Otherwise, patients received standard neurointensive care. Quinolinic acid was measured by mass spectrometry. Univariate and multivariate analyses were used to compare CSF quinolinic acid concentrations with age, gender, GCS, time after injury, mortality, and treatment (hypothermia versus normothermia). Quinolinic acid concentration in CSF increased maximally to 463 +/- 128 nmol/L (mean +/- SEM) at 72 to 83 hours after TBI. Normal values for quinolinic acid concentration in CSF are less than 50 nmol/L. Quinolinic acid concentration was increased 5- to 50-fold in many patients. There was a powerful association between time after TBI and increased quinolinic acid (P < 0.00001), and quinolinic acid was higher in patients who died than in survivors (P = 0.003). Age, gender, GCS, and treatment (32 degrees C versus 37 degrees C) did not correlate with CSF quinolinic acid. These data reveal a large increase in quinolinic acid concentration in CSF after TBI in humans and raise the possibility that this macrophage-derived excitotoxin may contribute to secondary damage.

Neuroactive metabolites of L-tryptophan, serotonin and quinolinic acid, in striatal extracellular fluid. Effect of tryptophan loading.

Extracellular fluid levels of the neurotoxin quinolinic acid in the corpus striatum of rats, measured by in vivo microdialysis, were increased in a dose-dependent manner following the intraperitoneal administration of tryptophan. The lowest dose of tryptophan (12.5 mg/kg), equivalent to about 5% of the normal daily intake, increased peak quinolinic acid levels nearly 3-fold. At higher doses of tryptophan (up to 250 mg/kg), concentrations of quinolinic acid increased over 200-fold and exceeded potentially neurotoxic levels (10 microM). In contrast, the increase in extracellular serotonin following even the highest tryptophan dose was small (less than 2-fold). These data indicate that quinolinic acid is present in the extracellular fluid where it may function as a neuromodulator and that it is very responsive to physiological changes in precursor availability.

Effect of antiretroviral therapy on the cerebrospinal fluid of patients seropositive for the human immunodeficiency virus.

Elevated levels of beta 2-microglobulin and neopterin in cerebrospinal fluid (CSF) have been associated with neurologic complications of infection with the human immunodeficiency virus (HIV). The effect of zidovudine (ZDV) on these markers was assessed by studying the effect of ZDV treatment duration on CSF levels in a cohort of 145 HIV-positive men who were receiving ZDV. CSF beta 2-microglobulin and neopterin levels were significantly lower in those who had been taking ZDV for an intermediate period of time (46-365 days) than in those who had received ZDV either long term (> 365 days) or short term (1-45 days). CSF quinolinic acid levels were independent of duration of ZDV administration. A second CSF evaluation was available after 1 year for 54 HIV-positive men (19 of whom were also in the first cohort) and 11 HIV-negative controls. Patients who had started ZDV between lumbar punctures showed a significant decrease in CSF beta 2-microglobulin, but in those who had been receiving ZDV for > 1 year beta 2-microglobulin increased (p = 0.001). The effect was not observed with neopterin (p = 0.14). (Quinolinic acid levels were not studied longitudinally.) Finally, we observed that CSF levels of beta 2-microglobulin, neopterin, and quinolinic acid correlated strongly with each other in HIV-positive individuals (r = 0.7, p < 0.0001), even though ZDV might have different effects on these markers. In conclusion, we report that initiation of ZDV therapy is associated with a transient decrease in CSF levels of beta 2-microglobulin and neopterin.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroactive kynurenines in Lyme borreliosis.

Although neurologic dysfunction occurs frequently in patients with Lyme borreliosis, it is rarely possible to demonstrate the causative organism within the neuraxis. This discordance could arise if neurologic symptoms were actually due to soluble neuromodulators produced in response to infection. Since immune stimulation is associated with the production of quinolinic acid (QUIN), an excitotoxin and N-methyl-D-aspartate (NMDA) agonist, we measured levels of CSF and serum QUIN, and lymphokines. Samples were obtained from 16 patients with CNS Borrelia burgdorferi infection, eight patients with Lyme encephalopathy (confusion without intra-CNS inflammation), and 45 controls. CSF QUIN was substantially elevated in patients with CNS Lyme and correlated strongly with CSF leukocytosis. In patients with encephalopathy, serum QUIN was elevated with corresponding increments in CSF QUIN. Lymphokine concentrations were not consistently elevated. We conclude that CSF QUIN is significantly elevated in B burgdorferi infection--dramatically in patients with CNS inflammation, less in encephalopathy. The presence of this known agonist of NMDA synaptic function--a receptor involved in learning, memory, and synaptic plasticity--may contribute to the neurologic and cognitive deficits seen in many Lyme disease patients.

Brain extracellular quinolinic acid in chronic experimental hepatic encephalopathy as assessed by in vivo microdialysis: acute effects of L-tryptophan.

Increased brain quinolinic acid (QUIN) levels have been suggested to play a role in hepatic encephalopathy (HE). Previous brain tissue studies have been unable to confirm this hypothesis. Because QUIn is a potent NMDA-receptor agonist, it also is relevant to determine brain extracellular QUIN levels in HE. For this purpose, we assessed frontal neocortical extracellular QUIN levels by in vivo microdialysis in rats subjected to a portacaval shunt (PCS). We also evaluated the acute effects of altered L-tryptophan (L-TRP) availability on brain extracellular QUIN levels. The basal extracellular L-TRP levels were significantly (p < .001) higher in the PCS rats than in the sham-operated controls. However, the QUIN level (p < .05) and the QUIN to L-TRP ratio (p < .01) were significantly lower in the PCS rats. Elevated L-TRP availability increased the QUIN levels to a similar degree in both sham and PCS rats. This study, in conjunction with our previous results, does thereby not support a major involvement of QUIN in the pathogenesis of HE.

U50,488 protection against HIV-1-related neurotoxicity: involvement of quinolinic acid suppression.

The pathogenesis of human immunodeficiency virus type 1 (HIV-1) encephalopathy has been associated with multiple factors including the neurotoxin quinolinate (an endogenous N-methyl-D-aspartate [NMDA] receptor ligand) and viral proteins. The kappa opioid receptor (KOR) agonist U50,488 recently has been shown to inhibit HIV-1 p24 antigen production in acutely infected microglial cell cultures. Using primary human brain cell cultures in the present study, we found that U50,488 also suppressed in a dose-dependent manner the neurotoxicity mediated by supernatants derived from HIV-1-infected microglia. This neuroprotective effect of U50,488 was blocked by the KOR selective antagonist nor-binaltorphimine. The neurotoxic activity of the supernatants from HIV-1-infected microglia was blocked by the NMDA receptor antagonists 2-amino-5-phosphonovalerate and MK-801. HIV-1 infection of microglial cell cultures induced the release of quinolinate, and U50,488 dose-dependently suppressed quinolinate release by infected microglial cell cultures with a corresponding inhibition of HIV-1 p24 antigen levels. These findings suggest that the kappa opioid ligand U50,488 may have therapeutic potential in HIV-1 encephalopathy by attenuating microglial cell production of the neurotoxin quinolinate and viral proteins.

Increased biogenic amine release in mouse hypothalamus following immunological challenge: antagonism by indomethacin.

Stimulation of the acute-phase response in mice by lipopolysaccharide, pokeweed mitogen, concanavalin A or interleukin-1 was associated with increased release of biogenic amines, serotonin and norepinephrine in the hypothalamus as indexed by their primary metabolites, 5-hydroxyindoleacetic acid and 3-methoxy-4-hydroxyphenylglycol, respectively. The increases in norepinephrine and serotonin turnover observed 4 h following systemic administration of interleukin-1 were antagonized by concurrent administration of indomethacin, a potent inhibitor of cyclooxygenase. These data suggest that the increase in norepinephrine and serotonin release in mouse hypothalamus during the acute-phase response to infection is partially mediated by the actions of arachidonic acid metabolites.

Glutamate is a mediator of neurotoxicity in secretions of activated HIV-1-infected macrophages.

We sought to identify neurotoxin(s) secreted by HIV-1-infected mononuclear phagocytes that could contribute to the pathophysiology of HIV-1-associated dementia (HAD). Neurotoxic factors were characterized in batches of conditioned media (CM) from human monocyte-derived macrophages (MDM) infected with HIV-1(ADA) and/or activated with lipopolysaccharide (LPS). All of the neurotoxicity was: present in the <3000-Da fraction; blocked by 5 microM MK801; and not trypsin sensitive or extractable into polar organic solvents. Glutamate measured in CM accounted for all neurotoxic effects observed from HIV/LPS CM in astrocyte-poor neuronal cultures and may contribute to the pathophysiology of HIV-1-associated dementia.

Inter-relationships between quinolinic acid, neuroactive kynurenines, neopterin and beta 2-microglobulin in cerebrospinal fluid and serum of HIV-1-infected patients.

Quinolinic acid (QUIN) is an neurotoxic N-methyl-D-aspartate receptor agonist and an L-tryptophan metabolite of the kynurenine pathway. Increased concentrations of QUIN occur in both cerebrospinal fluid (CSF) and blood of patients infected with human immunodeficiency virus (HIV)-1, particularly those with neurologic disturbances. In the present study of HIV-1 infected patients in Walter Reed stages 4, 5 and 6, reductions in L-tryptophan accompanied proportional increases in L-kynurenine and QUIN in both serum and CSF. Further, close inter-correlations exist between QUIN kynurenic acid and L-kynurenine with both beta 2-microglobulin and neopterin in CSF and serum. These correlations support the hypotheses that the kynurenine pathway is activated in association with inflammation and induction of indoleamine-2,3-dioxygenase. There were no relationships between CSF QUIN, L-kynurenine or kynurenic acid with the ratio of serum:CSF albumin concentrations, which indicates that the increases in CSF QUIN, L-kynurenine or kynurenic acid were not dependent on a breakdown of the blood-brain barrier. Kynurenic acid is also a kynurenine pathway metabolite that can attenuate the excitotoxic effects of QUIN when present in higher molar concentrations. While CSF kynurenic acid levels were increased in HIV-1-infected patients, the magnitude of the increases were smaller than those of QUIN and the molar concentrations of kynurenic acid were consistently lower than QUIN by at least one order of magnitude. We conclude that immune activation increases the levels of neuroactive kynurenines within the central nervous system of HIV-1-infected patients secondary to activation of indoleamine-2,3-dioxygenase.