Kynurenic Acid Metabolism in Various Types of Brain Pathology in HIV-1 Infected Patients.

Kynurenic acid, an intermediate metabolite of L-kynurenine, is a competitive antagonist of inotropic excitatory amino acid (EAA) receptors as well as a non competitive antagonist of 7 alpha nicotine cholinergic receptors and its involvement in memory deficit and cognition impairment has been suggested. Alterations of kynurenic acid metabolism in the brain after HIV-1 (human immunodeficiency virus type-1) infection have been demonstrated. The present study evaluates the biosynthetic machinery of kynurenic acid e.g. the content of L-kynurenine and kynurenic acid, as well as the activity of enzymes synthesizing kynurenic acid, kynurenine aminotransferase I (KAT I) and kynurenine aminotransferase II (KAT II) in the frontal cortex and cerebellum of HIV-1 infected patients in relation to different types of pathology classified as follows: HIV in brain (HIV); opportunistic infection (OPP); infarction of brain (INF); malignant lymphoma of brain (LY); and glial dystrophy (GD) and of control (CO) subjects. Of all investigated pathologies the most frequent was OPP (65%), followed by HIV (26%), LY, INF, and GD (each 22%, respectively). Further, 68% of HIV-1 patients had bronchopneumonia, the highest incidence of which, at 60%, was seen in the OPP and LY group. Kynurenic acid was increased significantly in the frontal cortex of LY (392% of CO, P < 0.001), HIV (231% of CO, P < 0.01) and GD (193% of CO, P < 0.05), as well as in the cerebellum of GD (261% of CO, P < 0.01). A significant increase of L-kynurenine was observed in the frontal cortex of LY (385% of CO, P < 0.001) and INF (206% of CO, P < 0.01), and in the cerebellum of GD, LY, OPP and HIV (between 177% and 147% of CO). The KAT I activity increased significantly in the frontal cortex of all pathological subgroups, ie OPP = 420% > INF > LY > HIV > GD = 192% of CO. In the cerebellum, too, all pathological subgroups showed marked increase of KAT I activity (OPP = 320% > LY, HIV > GD > INF = 176% of CO). On contrary, the activity of KAT II was moderately, but significantly, higher in the frontal cortex of INF and OPP; in the cerebellum of HIV, OPP and LY it was comparable to the control, while mildly reduced in INF and GD. Interestingly, normal subjects with the diagnosis of bronchopneumonia were characterized by high kynurenic acid metabolism in the brain, too. Correlation analyses between kynurenine parameters revealed association between high ratio KAT I/KAT II and increased kynurenic acid level and lower L-kynurenine in the frontal cortex and cerebellum of HIV and LY subgroups. The present study revealed a different pattern of alteration of kynurenic acid metabolism in frontal cortex and cerebellum among investigated pathological subgroups of HIV-1 infected patients. Interestingly, a marked enhancement of kynurenic acid metabolism in the brain has been found with occurrence of bronchopneumonia. This finding indicates a notable association between impaired conditions of oxygen availability and enhancement of kynurenic acid formation in the human brain. These observation(s) might have an impact on the understanding of pathological processes in the brain after HIV-1 infection involving the development of neuropsychiatric and neurological symptoms, including memory and cognition impairment.

Kynurenines and the respiratory parameters on rat heart mitochondria.

It has been shown recently that the L-kynurenine metabolite kynurenic acid lowers the efficacy of mitochondria ATP synthesis by significantly increasing state IV, and reducing respiratory control index and ADP/oxygen ratio of glutamate/malate-consuming heart mitochondria. In the present study we investigated the effect of L-tryptophan (1.25 microM to 5 mM) and other metabolites of L-kynurenine as 3-hydroxykynurenine (1.25 microM to 2.5 mM), anthranilic acid (1.25 microM to 5 mM) and 3-hydroxyanthranilic acid (1.25 microM to 5 mM) on the heart mitochondria function. Mitochondria were incubated with saturating concentrations of respiratory substrates glutamate/malate (5 mM), succinate (10 mM) or NADH (1 mM) in the presence or absence of L-tryptophan metabolites. Among tested substances, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and anthranilic acid but not tryptophan affected the respiratory parameters dose-dependently, however at a high concentration, of a micro molar range. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid lowered respiratory control index and ADP/oxygen ratio in the presence of glutamate/malate and succinate but not with NADH. While, anthranilic acid reduced state III oxygen consumption rate and lowered the respiratory control index only of glutamate/malate-consuming heart mitochondria. Co-application of anthranilic acid and kynurenic acid (125 or 625 microM each) to glutamate/malate-consuming heart mitochondria caused a non-additive deterioration of the respiratory parameters determined predominantly by kynurenic acid. Accumulated data indicate that within L-tryptophan metabolites kynurenic acid is the most effective, followed by anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid to influence the respiratory parameters of heart mitochondria. Present data allow to speculate that changes of kynurenic acid and/or anthranilic acid formation in heart tissue mitochondria due to fluctuation of L-kynurenine metabolism may be of functional importance for cardiovascular processes. On the other hand, beside the effect of 3-hydroxyanthranilic acid and 3-hydroxykynurenine on respiratory parameters, their oxidative reactivity may contribute to impairment of mitochondria function, too.

Increased kynurenic acid in the brain after neonatal asphyxia.

In the brain, L-kynurenine is an intermediate for the formation of kynurenic acid, a metabolite with neuroprotective activities, and a substrate for the synthesis of 3-hydroxy-kynurenine, a metabolite with neurotoxic properties. In the present study, alterations of L-kynurenine, 3-hydroxy-kynurenine and kynurenic acid levels were examined in the brain of neonatal (10 minutes old) rats after 5, 10, 15 or 20 minutes of asphyxia, and in the brain of the corresponding caesarean-delivered controls, using sensitive high-performance liquid chromatographic methods. Among kynurenines we found a marked time-dependent increase of kynurenic acid levels, a moderately delayed increase of 3-hydroxy-kynurenine, and a trend for a decrease of L-kynurenine content. Thus, the brain reacted rapidly to the oxygen deficit by increasing kynurenic acid levels by 44% already after 5 minutes of asphyxia, and the most prominent elevation of kynurenic acid (302% of control) was found after 20 minutes of asphyxia--the critical time limit of survival.

Kynurenic acid influences the respiratory parameters of rat heart mitochondria.

In the present study the effect of L-kynurenine, kynurenic acid and quinolinic acid on the heart mitochondrial function were investigated. Mitochondria were incubated with saturating concentrations of respiratory substrates glutamate/malate (5 mmol/l), succinate (10 mmol/l) or NADH (1 mmol/l), with and without kynurenines. The concentration of kynurenines varied between 1.25 micromol/l and 10 mmol/l. From all investigated kynurenines, only kynurenic acid affected dose-dependently the respiratory parameters of heart mitochondria. Respiratory control and P/O values were reduced significantly with glutamate/malate and moderately with succinate as substrates in the presence of 125 micromol/l to 10 mmol/l kynurenic acid. A known elevation of L-kynurenine in the blood of patients with ischemic heart disease or essential hypertension may suggest the involvement of L-kynurenine metabolites in the impairment of heart mitochondrial function, for example in cardiomyopathy.

Kynurenic acid metabolism in the brain of HIV-1 infected patients.

Patients who are infected with human immunodeficiency virus type 1 (HIV-1) frequently present with neurological and psychiatric symptoms. Kynurenic acid (KYNA), an intermediate metabolite of L-kynurenine (L-KYN), is a neuroprotectant and a broad-spectrum antagonist at excitatory amino acid (EAA) receptors. The present study examines the biosynthetic machinery of KYNA in the frontal cortex and cerebellum of 25 HIV-1 and 16 control (CO) patients. We measured the contents of L-KYN and KYNA and the activity of enzymes synthesizing KYNA, kynurenine aminotransferases I and II (KAT I and KAT II). The KYNA level was significantly increased in the frontal cortex (209 +/- 38% of CO; p < 0.05) and moderately increased in the cerebellum (164 +/- 31% of CO) of HIV-1 brains as compared with controls. The bioprecursor of KYNA, L-KYN, was increased in frontal cortex (188 +/- 45% of CO) and cerebellum (151 +/- 16% of CO; p < 0.05). The elevated KYNA in frontal cortex correlated with significant increases of KAT I (341 +/- 95% of CO; p < 0.05) and KAT II (141 +/- 8% of CO; p < 0.05). In the cerebellum, a high KYNA content was in the line with increased KAT I (262 +/- 52% of CO; p < 0.05) activity, while KAT II was in a control range (85 +/- 12% of CO). This study demonstrates that HIV-1 infection associates with elevated KYNA synthesis in the brain. In contrast to KAT II, KAT I was prominently increased in both brain regions investigated. Differences in neurochemical parameters of KYNA metabolism between frontal cortex and cerebellum suggests selective tissue damage. Drugs which influence the synthesis of the endogenous neuroprotectant KYNA may become useful in the therapy of neuropsychiatric manifestations of HIV-1 infected patients.

Clonidine modulates BAY K 8644-induced rat behavior and neurotransmitter changes in the brain.

BAY K 8644 (methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4[2-trifluoromethyl-phenyl]-pyridine-5-carboxylate), an activator of dihydropyridine-sensitive Ca(2+) channels, injected in rats [2 mg/kg intraperitoneally (i.p.)], induces behavioral changes including ataxia, increased sensitivity to auditory stimulation, stiff tail, arched back, limb tonus and clonus, and rolling over. Neurochemical changes in the brain 45 min after application of 2 mg/kg were characterized by a significant decrease of noradrenaline in the amygdala (-27.8%, P<0.02) and piriform cortex (-16.3%, P<0.02). No significant changes of catecholamines were found in the hippocampal subregions CA1, CA3 and dentate gyrus or in the septum as compared to controls. The dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the amygdala were elevated by 60% (P<0.02) and 66.7% (P<0.02), respectively. In the septum, a 52.6% (P<0.02) increase of HVA was observed. Analysis of amino acids revealed a marked increase of gamma-aminobutyric acid (GABA) content (+50.4%, P<0.001) in the septum. Pretreatment of the rats with the alpha(2)-adrenoceptor agonist, clonidine (0.1 mg/kg i.p.), 30 min before BAY K 8644 (2 mg/kg i.p.) injection completely abolished the behavioral and neurochemical changes. The data suggest that the Ca(2+)-dependent neurotransmitter release provoked by BAY K 8644 can be modulated by stimulation of presynaptic alpha(2)-adrenoceptors. The effect of clonidine on the GABAergic system may represent an important mechanism involved in the prevention of BAY K 8644-induced behavior.

Long-term intraspinal infusions of opioids with a new implantable medication pump.

Experiences with long-term intraspinal infusion of opioid drugs using the new implantable medication pump VIP 30 in patients with chronic non-malignant pain are reported. During a 19-month period 10 patients with chronic pain--mainly mixed nociceptive-neuropathic pain--underwent implantation of the medication pump for long-term treatment. The mean follow-up period was 9.5 months. Pain relief was classified as very good in 22.2%, good in 44.4%, moderate in 22.2% and poor in 11.1%. In 88.9% of the cases the patients stated they would undergo the same procedure again. Technical problems (catheter dislocation) developed in 1/10 patients could be surgically corrected. One pump including catheter was explanted because of an infected seroma within the pocket area. Long-term intrathecal application of opioids with the VIP 30 pumps is an effective and safe treatment in patients with chronic non-malignant pain.

Percutaneous radiofrequency thermolesion of the sympathetic chain in the treatment of peripheral vascular disease.

Percutaneous radiofrequency thermal lesion of the lumbar sympathetic chain (PRFS) was performed in 30 patients with diabetes mellitus suffering from unreconstractable endstage peripheral vascular disease. All of the patients had the feeling of warmth after PRFS, 45% were free of further complaints and 63% changed to stage II according fontaine. The reported data demonstrate a good comparability concerning amputation after a period of two years to the results obtained by surgical sympathectomy. As there is no need of general anesthesia PRFS turned out to be a good alternative to the surgical sympathectomy.

[Percutaneous radio-frequency sympathetic block in peripheral circulatory disorders]. / Die perkutane Radiofrequenz-Sympathikussausschaltung (PRFS) bei peripheren Durchblutungsstörungen.

Thirty patients with inoperable diabetic angiopathies (degree III and IV concerning to Fontaine) were treated by means of percutanous radiofrequency thermolesion of the lumbar sympathetic chain (PRFS). All patients reported immediately after this procedure a distinct feeling of warmth in the treated leg. After a period of 6 month to two years 22 patients were re-examined clinically: Fifteen patients changed to Fontaine IIa and ten patients were free of further complaints. Also an improved wound healing and ulcer demarcation following amputation or skin transplantation was observed. The advantage of PRFS in comparison to the surgical sympathectomy is the fact that there is no general anesthesia necessary, which too minimizes the risk especially for the aged vascular patient. Moreover the patient can be mobilised immediately after the procedure. There were no complications like lesion of the ureter or the genitofemoral nerve as well as bleading into the psoas muscle as reported in percutanous chemical lesion of the sympathetic chain.

[Differential behavior of skin temperature in vascular patients vs. pain patients in lumbar radicular stimulation and nerve block]. / Unterschiedliches Hauttemperaturverhalten vaskulärer Patienten vs. Schmerzpatienten bei der lumbalen Grenzstrangstimulation und -Ausschaltung.

Plantar skin temperature monitoring during the procedure of percutaneous radiofrequency-thermolesion of the sympathetic chain (PRFS) in patients with vascular diseases and patients with lumbar radicular pain and signs of sympathetic irritation showed a distinct difference. A significant decrease of skin temperature was observed during stimulation of the sympathetic chain by means of canula placement and contrast medium instillation only in the group of "vascular" patients, while "radicular pain" patients showed a significant increase of skin temperature after PRFS. This observation leads to the conclusion that the effect of sympathectomy more or less is to prevent physiological hyperactivity of the sympathetic system.

Quantification of the effect of epidural spinal electrostimulation (ESES) in central motor disorders.

The importance of film documentation for objective and quantitative assessment of the results of epidural spinal electrical stimulation (ESES) was shown. Our experience is based on 25 patients with central motor disorders, predominantly of spinal origin. 17 were selected for internalization of a receiver system. By means of description and clinical registration of spasticity, reduced mobility, motor strength, dexterity, etc., or by means of electrophysiological tests, complex motor performance such as standing, sitting, dressing and undressing, eating and writing cannot be sufficiently evaluated. Short scenes of these activities when demonstrated by motion picture enable the therapist to compare better the condition of the patient before and with ESES, and thereby facilitate the selection of patients for internalization of receiver systems.

[Epidural spinal electrostimulation (ESES) in patients with chronic pain and central motor disturbances (author's transl)]. / Die epidurale spinale Elektrostimulation (ESES) bei chronischen Schmerzzuständen und zentralen motorischen Störungen.

Epidural spinal electrostimulation (ESES), as method in the treatment of patients with chronic pain or severe central motor disturbances, especially spastic paresis of spinal origin and bladder dysfunction, is indicated when conservative measures prove ineffectual and before surgical intervention is considered. The biochemical and innervation processes which are brought about by ESES are discussed, as well as the literature on the efficacy and possible complications of the method. Twenty cases were subjected to a test stimulation and in twelve of these the stimulation system was implanted. Spinal spasticity and the range of mobility were improved by 20 to 30% in 8 patients with multiple sclerosis and 3 other patients with myelopathy of varied aetiology. In addition, spastic cramps of abrupt onset, with or without pain, disappeared almost completely following ESES in all cases. Three cases with chronic pain, two after a caudal lesion and one with cervical radicular damage, were markedly improved.