The kynurenic acid hypothesis of schizophrenia.

In recent years progress in the field of schizophrenia research has led to the suggestion that dopamine only plays an intermediary role in the pathophysiology of the disease and that the main abnormalities lie elsewhere. In particular, deficits in brain glutamatergic systems are suggested to play a prominent role in the pathophysiology of the disease. Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl-D-aspartate-receptor. Mounting evidence indicates that the compound is significantly involved in basal neurophysiological processes in the brain. Thus, pharmacologically elevated levels of kynurenic acid, in similarity to systemic administration of phencyclidine or ketamine, were associated with increased firing rate and burst firing activity of midbrain dopamine neurons, indicating per se that elevated levels of brain kynurenic acid is associated with psychotomimetic effects. Indeed, cerebrospinal fluid level of kynurenic acid was elevated in schizophrenic patients as compared to healthy controls. The present paper also describes a prostaglandin-mediated regulation of kynurenic acid formation as well as a relationship between brain kynurenic acid concentration and the excitatory responses of ventral tegmental area dopamine neurons by clozapine and nicotine. Our results suggest that kynurenic acid contributes to the pathogenesis of schizophrenia and link the dopamine hypothesis of schizophrenia together with the idea of a deficiency in glutamatergic function in this disease.

A double-blind randomized clinical trial in amyotrophic lateral sclerosis using lamotrigine: effects on CSF glutamate, aspartate, branched-chain amino acid levels and clinical parameters.

OBJECTIVES: A study was conducted to examine the effect of lamotrigine (LTG) in amyotrophic lateral sclerosis (ALS). MATERIAL AND METHODS: Patients were entered in a double-blind, placebo-controlled, crossover study. None of the patients were treated with riluzole, which was not approved for treatment of ALS in Sweden when the study started. After randomization, each patient was treated with placebo or LTG 300 mg daily, followed by a washout period and a second treatment period. RESULTS: Thirty patients completed the study and were included in the analysis of the primary outcome, which was measured with clinical scales. The cerebrospinal fluid (CSF) levels of glutamate, aspartate, branched-chain amino acids and LTG were also measured. Changes for glutamate, valine and LTG were found during the progression of the disease. The clinical parameters and the levels of CSF amino acids were similar for the two treatment groups. CONCLUSION: No clinical effect of LTG on ALS progression could be found.

Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis.

OBJECTIVES: Excitotoxicity may play a role in neurodegeneration in amyotrophic lateral sclerosis (ALS). Kynurenic acid (KYNA), an endogenous antagonist of excitatory amino acid receptors, may inhibit excitotoxic lesions. The aim of this study was to determine the concentration of KYNA in ALS patients. MATERIAL AND METHODS: KYNA was measured by high-performance liquid chromatography in the serum and cerebrospinal fluid (CSF) from ALS and control patients. RESULTS: Our study revealed that CSF KYNA concentration was significantly higher in patients with bulbar onset of ALS compared to controls, and compared to patients with limb onset of the disease. CSF KYNA was also higher in patients with severe clinical status compared to controls. Serum KYNA was significantly lower in ALS patients with severe clinical status compared to controls, and compared to patients with mild clinical status. There were no significant differences in CSF and serum KYNA concentration between the whole ALS group of patients and controls. There was no difference in CSF KYNA concentration between males and females, and there was no correlation between KYNA concentration and age of patients, and duration of ALS. CONCLUSIONS: An increased CSF KYNA concentration in patients with bulbar onset of ALS and in patients with severe clinical status may indicate neuroprotective role of KYNA against excitotoxicity. The difference of KYNA concentration in CSF of patients with bulbar and limb onset of ALS suggests that these two variants of motor neuron disease may have different etiopathogenetic mechanisms.

Rapid quantification of the non-competitive NMDA antagonist MK-801 in canine cerebrospinal fluid and plasma by capillary gas chromatography-nitrogen phosphorus detection.

A facile and sensitive method utilizing solid-phase cartridge extraction and capillary gas chromatography (GC) with nitrogen phosphorus detection was validated for the determination of MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate], a non-competitive NMDA receptor antagonist, in dog cerebrospinal fluid (CSF) and plasma. Clonidine hydrochloride was used as the internal standard (ISTD), after evaluation of several ISTD candidates. Separations were performed with an intermediate polarity fused silica capillary column, yielding typical retention times of 3.20 min for MK-801 and 4.90 min for ISTD. Plasma and CSF samples were extracted with 100 mg Bond Elut C(18) TCA Copyright cartridges to yield methanolic eluates that were evaporatively enriched before reconstitution in anhydrous ethanol prior to injection. The standard curve was validated from 1 to 100,000 ng/ml for CSF, and from 0.1 to 1,000 ng/ml for plasma. Chromatograms from naive plasma and CSF exhibited no endogenous interfering peaks. The efficiency of extraction recovery was >94%, and the intra-assay and inter-assay precision was within 9% relative standard deviation (%R.S.D.) for both fluids. MK-801 and ISTD were stable in the injection solvent at 22 degrees C for at least 48 h. The assay was applied to the toxocologic study of intrathecal MK-801 administration in the dog.

Brain penetration and in vivo recovery of NMDA receptor antagonists amantadine and memantine: a quantitative microdialysis study.

PURPOSE: To determine free brain concentrations of the clinically used uncompetitive NMDA antagonists memantine and amantadine using microdialysis corrected for in vivo recovery in relations to serum, CSF and brain tissue levels and their in vitro potency at NMDA receptors. METHODS: Microdialysis corrected for in vivo recovery was used to determine brain ECF concentrations after steady-state administration of either memantine or amantadine. Additionally CSF, serum, and brain tissue were analyzed. RESULTS: Following 7 days of infusion of memantine or amantadine (20 and 100 mg/kg/day respectively) whole brain concentrations were 44-and 16-fold higher than free concentrations in serum respectively. The free brain ECF concentration of memantine (0.83 +/- 0.05 microM) was comparable to free serum and CSF concentrations. In case of amantadine, it was lower. A higher in vivo than in vitro recovery was found for memantine. CONCLUSIONS: At clinically relevant doses memantine reaches a brain ECF concentration in range of its affinity for the NMDA receptor and close to its free serum concentration. This is not the case for amantadine and different mechanisms of action may be operational.

Dose escalation safety and tolerance study of the competitive NMDA antagonist selfotel (CGS 19755) in neurosurgery patients.

Selfotel (CGS 19755), a competitive N-methyl-D-aspartate antagonist, is neuroprotective in experimental models of ischemic cerebral injury. We studied the safety and tolerability of a single intravenous dose (0.5 to 2.0 mg/kg) of selfotel in neurosurgery patients. Thirty-two neurosurgical patients undergoing intracranial surgery were given ascending doses of selfotel 2 to 14 h before surgery. Serum selfotel levels were measured over a period of 24 h. Cerebrospinal fluid (CSF) levels were measured 1.5 to 18 h after dosing. Frequent side effects included psychomimetic symptoms such as hallucinations, abnormal dreaming, agitation, and paranoia among 20 (66%) patients. Ataxia was seen among five (16%) and dizziness among eight (25%). Symptoms occurred 38 min to 40 h from administration and persisted 5 min to 4 days. Symptom severity worsened with increasing area under the curve measurements and doses above 1.0 mg/kg. All symptoms were reversible and easily treated with intravenous haloperidol. Modest elevations of hepatic enzymes were observed among four patients. No patient had severe adverse reactions. Maximum selfotel levels attained were 143 mumol (serum) and 4.76 mumol (CSF). Peak serum levels among six patients were within potentially neuroprotective ranges. CSF levels remained detectable up to 18 h after dosing. No obvious relationship was seen between CSF drug levels and symptoms. Selfotel in doses of 0.5 to 2.0 mg/kg can be administered safely to neurosurgical patients. Maximum serum levels attained were within the range shown to be neuroprotective in experimental studies. Side effects even at the highest levels are tolerable and reversible. Selfotel use in patients at risk for cerebral injury should be further explored.

Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats.

UNLABELLED: N-methyl-D-aspartate (NMDA) antagonists, such as MK801, delay the development of morphine tolerance. Magnesium, a noncompetitive NMDA antagonist, reduces postoperative morphine requirements. The present study was designed to evaluate the effects of intrathecal co-administration of magnesium sulfate with morphine on antinociceptive potentiation, tolerance, and naloxone-induced withdrawal signs. Magnesium sulfate (40-60 microg/h) co-administration for 7 days, similar to MK801 (10 nmol/h), prevented the decline in antinociceptive response compared with morphine (20 nmol/h). Magnesium sulfate (60 microg/h) produced no antinociception, but co-infused with morphine (1 nmol/h), it resulted in potentiated antinociception compared with morphine throughout the 7-day period. Probe morphine doses after 7-day infusions demonstrated a significantly greater 50% effective dose value for morphine 1 nmol/h (109.7 nmol) compared with saline (10.9 nmol), magnesium sulfate 60 microg/h (10.9 nmol), and magnesium sulfate 60 microg/h plus morphine 1 nmol/h (11.2 nmol), which indicates that magnesium had delayed morphine tolerance. Morphine withdrawal signs after naloxone administration were not altered by the co-infusion of magnesium sulfate. Cerebrospinal fluid magnesium levels after intrathecal magnesium sulfate (60 microg/h) for 2 days increased from 17.0 +/- 1.0 microg/mL to 41.4 +/- 23.6 microg/mL, although serum levels were unchanged. This study demonstrates antinociceptive potentiation and delay in the development of morphine tolerance by the intrathecal coinfusion of magnesium sulfate and morphine in the rat. IMPLICATIONS: The addition of magnesium sulfate, an N-methyl-D-aspartate antagonist, to morphine in an intrathecal infusion provided better analgesia than morphine alone in normal rats. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.

Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist.

1. The analgesic activity of CP-101,606, an NR2B subunit-selective N-methyl-D-aspartate (NMDA) receptor antagonist, was examined in carrageenan-induced hyperalgesia, capsaicin- and 4beta-phorbol-12-myristate-13-acetate (PMA)-induced nociceptive tests in the rat. 2. CP-101,606 30 mg kg(-1), s.c., at 0.5 and 2.5 h after carrageenan challenge suppressed mechanical hyperalgesia without any apparant alternations in motor coordination or behaviour in the rat. 3. CP-101,606 also inhibited capsaicin- and PMA-induced nociceptive responses (licking behaviour) with ED50 values of 7.5 and 5.7 mg kg(-1), s.c., respectively. 4. These results suggest that inhibition of the NR2B subunit of the NMDA receptor is effective in vivo at modulating nociception and hyperalgesia responses without causing the behavioural side effects often observed with currently available NMDA receptor antagonists.

On the nature of endogenous antiexcitatory factors in the cerebrospinal fluid of patients with demyelinating neurological disease.

The cerebrospinal fluid (CSF) of patients with demyelinating neurological disease, such as Guillain-Barré syndrome or multiple sclerosis, contains factors that inhibit the excitatory Na+ current. Such antiexcitatory factors are occasionally also detectable in CSF from patients with other neurological diseases but were absent from an artificial CSF containing all major CSF constituents (electrolytes, amino acids, vitamins, metabolites, albumin). In an attempt to characterize these factors, unphysiological pCa or pH values were excluded by the application of the Ca2+ chelator EGTA and the use of buffers. Heating the CSF for 10 min to 95 degrees C or digesting it with proteases did not destroy the antiexcitatory potency. Fractionation of the CSF contents according to molecular weight showed that the factors have a molecular weight < 3 kD. This excludes proteins, such as antibodies or cytokines, as candidates. Small peptides are known to be resistant to some proteases and heating.

Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man.

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with therapeutic potential in dementia, spasticity and Parkinson's disease. The Ki-value of memantine at the phencyclidine (PCP) binding site of the NMDA receptor is 0.5 microM in human frontal cortex. We investigated whether concentrations of memantine in cerebrospinal fluid (CSF) and serum samples under therapeutic conditions are in the range of its Ki-value at the PCP binding site. The serum levels ranged from 0.025 to 0.529 microM with daily doses between 5 and 30 mg. CSF levels were highly correlated to serum levels and were below serum levels in each patient with a mean CSF/serum ratio of 0.52. Serum and CSF levels were correlated to the daily dose, but not to the duration of treatment. At the concentrations reported here, memantine is expected to specifically interact with the PCP binding site of the NMDA receptor.