EEG power spectra differentiate positive and negative subgroups in neuroleptic-naive schizophrenia patients.

Electroencephalogram spectral power was estimated at 30 scalp locations in 28 neuroleptic-naive, recent-onset schizophrenia (NRS) patients and 25 healthy comparison subjects in the resting eyes closed condition. Weighted relative power values in the various bandwidths were initially compared between NRS subjects and comparison subjects and subsequently between the positive symptom subgroup, negative symptom subgroup, and comparison subjects, to look for characteristic spectral power profiles of the homogeneous symptom subgroups. Significant differences were noted especially in alpha2, delta, and theta bands between NRS patients and healthy comparison subjects, while the positive symptom and negative symptom subgroups showed characteristic spectral power profiles in alpha1, alpha2, delta, and theta bands.

The effects of chronic administration of ethosuximide on learning and memory: a behavioral and biochemical study on nonepileptic rats.

Long-term use of antiepileptic drugs is common in the treatment of epilepsy. Clinical reports exist of cognitive impairment attributed to antiepileptic drugs. Hence, this study evaluates the effect of chronic administration of one antiepileptic drug, ethosuximide, on spatial and fear learning and memory in nonepileptic rats. High performance liquid chromatography with electrochemical detection was used for quantification of glutamate, glycine, taurine, gamma-aminobutyric acid, dopamine, and serotonin in the frontal cortex and hippocampus to elucidate the neurobiological basis of the effect of ethosuximide on learning and memory. We found that 21 days of ethosuximide treatment produced negative effects on fear memory (passive avoidance) at all doses (100, 200 and 250 mg/kg body weight), but had no effect on spatial learning (T-maze). Fear memory impairment was associated with decreased hippocampal dopamine levels. Ethosuximide (at all doses) had a minimal effect on the GABAergic and glutamatergic systems in all brain regions studied, with the exception of elevated levels of gamma-aminobutyric acid in the frontal cortex with the 250 mg/kg body weight dose. We have shown that long-term administration of ethosuximide adversely affects fear memory, but does not affect spatial learning and memory.

Comparative analysis of different competitive antagonists interaction with NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor.

The antagonist-bound conformation of the NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor are modeled using the crystal structure of the DCKA (5,7-dichloro-kynurenic acid)-bound form of the NR1 subunit ligand-binding core (S1S2). Five different competitive NMDA receptor antagonists [(1) DL-AP5; (2) DL-AP7; (3) CGP-37847; (4) CGP 39551; (5) (RS)-CPP] have been docked into both NR2A and NR2B subunits. Experimental studies report NR2A and NR2B subunits having dissimilar interactions and affinities towards the antagonists. However, the molecular mechanism of this difference remains unexplored. The distinctive features in the antagonist's interaction with these two different but closely related (approximately 80% sequence identity at this region) subunits are analyzed from the patterns of their hydrogen bonding. The regions directly involved in the antagonist binding have been classified into seven different interaction sites. Two conserved hydrophilic pockets located at both the S1 and S2 domains are found to be crucial for antagonist binding. The positively charged (Lys) residues present at the second interaction site and the invariant residue (Arg) located at the fourth interaction site are seen to influence ligand binding. The geometry of the binding pockets of NR2A and NR2B subunits have been determined from the distance between the C-alpha atoms in the residues interacting with the ligands. The binding pockets are found to be different for NR2A and NR2B. There are gross dissimilarities in competitive antagonist binding between these two subunits. The binding pocket geometry identified in this study may have the potential for future development of selective antagonists for the NR2A or NR2B subunit.

Evolutionary trace analysis of ionotropic glutamate receptor sequences and modeling the interactions of agonists with different NMDA receptor subunits.

The ionotropic N-methyl- d-aspartate (NMDA) receptor is of importance in neuronal development, functioning, and degeneration in the mammalian central nervous system. The functional NMDA receptor is a heterotetramer comprising two NR1 and two NR2 or NR3 subunits. We have carried out evolutionary trace (ET) analysis of forty ionotropic glutamate receptor (IGRs) sequences to identify and characterize the residues forming the binding socket. We have also modeled the ligand binding core (S1S2) of NMDA receptor subunits using the recently available crystal structure of NR1 subunit ligand binding core which shares approximately 40% homology with other NMDA receptor subunits. A short molecular dynamics simulation of the glycine-bound form of wild-type and double-mutated (D481N; K483Q) NR1 subunit structure shows considerable RMSD at the hinge region of S1S2 segment, where pore forming transmembrane helices are located in the native receptor. It is suggested that the disruption of domain closure could affect ion-channel activation and thereby lead to perturbations in normal animal behavior. In conclusion, we identified the amino acids that form the ligand-binding pocket in many ionotropic glutamate receptors and studied their hydrogen bonded and nonbonded interaction patterns. Finally, the disruption in the S1S2 domain conformation (of NR1 subunit- crystal structure) has been studied with a short molecular dynamics simulation and correlated with some experimental observations. [figure: see text]. The figure shows the binding mechanism of glutamate with NR2B subunit of the NMDA receptor. Glutamate is shown in cpk, hydrogen bonds in dotted lines and amino acids in blue. The amino acids shown here are within a 4-A radius of the ligand (glutamate).

Heart rate variability and outcome in acute severe stroke: role of power spectral analysis.

INTRODUCTION: Heart rate variability (HRV) is a predictor of outcome in acute myocardial infarction and head trauma. Its efficacy in predicting outcome in stroke has not been well documented. MATERIALS AND METHODS: Twenty-five patients (mean age 39 years) with acute stroke treated in a stroke intensive care unit were studied. Continuous echocardiogram recorded for a 1-hour period was digitized and stored for off-line analysis. Time and frequency domain HRV measures were derived for the filtered and rectified ECG data for each patient. Clinical and HRV profiles were compared among patients who died or survived. RESULTS: At admission, 16 patients were comatose (Glasgow Coma score<9 at admission), 16 had focal weakness, and all had abnormal brain computed tomography. Of the 25 patients,11 died, 10 had a poor outcome, and 4 had good outcome. Two variables low-frequency (LF) spectral power and very low-frequency (VLF) spectral power correlated with mortality. After adjustment for mechanical ventilation and vasopressor administration, LF, VLF, and Triangular index of RR interval (TINN) correlated with mortality. On multiple regression analysis weighed for mechanical ventilation and vasopressor administration, the eye-opening score on Glasgow Coma Scale and LF spectral power were factors that were independently predictive of mortality. CONCLUSION: HRV measurements are independent predictors of outcome in acute severe stroke.