Platelets Of Schizophrenic Patients Research Articles

Lipids and mental disorders: Evidence, uncertainties and perspectives

Brain is an organ with the highest lipid concentration in the body. Cellular membrane lipids can affect both the positioning and the functioning of membrane proteins, thus regulating several cell actions. Changes in the lipid composition of cell membrane can modulate the microenvironment and consequently the function of its proteins, e.g. neurotransmission. Some of the first studies on the subject have shown a negative correlation between serum cholesterol levels and depression, suicidality and behavioral disorders. Several studies -but not all- have found decreased concentrations of ω-3 polyunsaturated fatty acids (ω-3-PUFA) in plasma or erythrocyte membranes of patients with depression, bipolar disorder or after a suicide attempt. In some cases, positive results after their administration have been reported. The effect of ω-3-PUFA in affective disorders is attributed to their action on neurotransmission, neuroplasticity as well as to their anti-inflammatory and anti-oxidative properties. Besides, decreased levels of ω-3-PUFA have been found in erythrocytes or platelets of schizophrenic patients. Some studies have shown in schizophrenics an increased rate of membrane phospholipids breakdown and a decreased ratio of ω-3-PUFA incorporation in phospholipids, possibly because of increased activity of phospholipase A2, an enzyme with crucial role in signaling transduction. Deficient dietetic ingestion of ω-3-PUFA may increase the risk for development of schizophrenia, while a diet rich in ω-3-PUFA may have a preventive role for the disease or improve its course. Although there is no evidence for their action as a monotherapy, they may be useful as an add-on therapy to drug treatment. Some authors suggest that abnormal sphingolipid metabolism, leading to accumulation of ceramides, may be responsible for the development of mood and anxiety disorders, as well as for induction of inflammation or oxidative stress, mechanisms possibly responsible for the physical symptoms of depression. Some drugs seem to combine inhibition of sphingomyelinase (an enzyme catalyzing the production of ceramides) and antidepressant effect. Despite the multitude of related studies, many aspects of the subject remain obscure. Current research focuses on the validity of preventive (especially in the perinatal period) or therapeutic administration of ω-3-PUFA as well as to the pharmacological manipulation of enzymes involved in lipid metabolism (e.g. sphingomyelinase) for the treatment of psychiatric disorders.

A flow-cytometric method to investigate glutamate-receptor-sensitivity in whole blood platelets – Results from healthy controls and patients with schizophrenia

Hypofunction of glutamate receptors may contribute to the symptoms of schizophrenia. Human platelets express glutamate receptors and can serve as peripheral surrogate model for neuronal cells. Aim of this study was to establish a fast and sensitive flow-cytometric method to determine the glutamate-dependent kinetics of intracellular calcium ([Ca++]i) mobilization in platelets of schizophrenic patients. Glutamate stimulated [Ca++]i response was measured with a flow-cytometer in anti-CD-41a-labelled whole blood platelets of treated schizophrenic patients ( n = 18) and controls ( n = 18). In two control experiments the NMDA-receptor antagonist MK-801 and the dopamine antagonist amisulpride, respectively, were added to probes from healthy subjects. Stimulation with glutamate led dose-dependently to a mobilization of [Ca++]i in both healthy controls and patients. This effect was significantly reduced in patients. In vitro NMDA-antagonism inhibited the glutamate response, whereas dopamine-antagonism had no effect. Our flow-cytometric method allows to measure glutamate-receptor mediated [Ca++]i response in whole blood platelets, without requiring platelet rich preparations. The reduced glutamate-response in the patients was not explained by a direct inhibitory treatment effect. However, further studies with drug naive patients will be necessary to find out whether or not the observed hypoglutamergic function of platelets is endogenous to the disorder.

Effect of d-serine on the serotonin receptors of human platelets

Recent literature and our previous observations indicated the presence of both NMDA and serotonin type 3 receptors in human platelets with very similar ionic currents to that of cultured mammalian neuronal receptors. Baseline electrophysiological data shows similar profile for platelets from both normal and schizophrenic subjects, whereas serotonin receptor studies exhibited the presence of 5-hydroxytryptamine type-3 (5-HT3) currents in both normal and schizophrenic platelets significantly different from each other. The two major differences observed were: first, 5-HT3 receptors present in the platelets of schizophrenic patients were four times more sensitive to serotonin than those present in the platelets of normal subjects and, second, that D: -serine in micro molar concentrations dampens this effect in platelets from schizophrenic patients but increases the sensitivity of serotonin for platelet 5-HT3 receptors of normal subjects. Patch clamp technique was used to measure the whole cell currents passing through serotonin receptors in these two types of human platelets. The currents were found to be 5-HT3 receptor currents as they were abolished by 10 microM D-tubocurarine. Similarly, micromolar concentrations of D: -serine increased the sensitivity of 5HT3 receptor currents in the normal human platelets but decreased it in the platelets of the schizophrenic patients. This effect was reversed when D-amino acid oxidase (0.3 microM) was co applied with 100 microM of D-serine, raising the possibility that D-serine by itself may act as a modulator for platelet 5-HT3 receptor channel currents. These observations raised exciting new questions about the role of platelet serotonin receptors and their regulation by D-serine.

Phosphoinositide signalling system in platelets of schizophrenic patients and the effect of neuroleptic therapy

Alterations in the phosphoinositide signalling system have been proposed as a possible biological marker of schizophrenia. We studied the levels of inositol 1,4,5-trisphosphate (IP3), cytosolic Ca2+concentrations ([Ca2+]i), and the incorporation of [32P]-orthophosphate into inositol phospholipids and phosphatidic acid (PA) in blood platelets of neuroleptic-treated schizophrenics in comparison with controls. The [Ca2+]iwas significantly higher in platelets of one month neuroleptic-treated patients (155±5.8nM) in comparison with controls (95+5.4 nM). Neuroleptic therapy decreased the [Ca2+]i, but even after long-term therapy it remained significantly higher (114±5.7nM) than in controls. Differences were also found in the level of IP3between controls (30±4.0pmol /109platelets), drug-free schizophrenics (52±9.0pmol /109platelets) and treated patients (50±6.0pmol /109platelets). The increased turnover of PA was observed in platelets of neuroleptic-treated schizophrenic patients. The study suggests that the regulation of calcium homeostasis and pathways involved in the phosphoinositide signalling system are altered in the platelets of schizophrenics. Neuroleptic therapy did not remove the observed changes in [Ca2+]iand IP3levels.

What can the investigation of phosphoinositide signaling system in platelets of schizophrenic patients tell us?

Disturbances in the regulation of the phosphoinositide signaling system have been proposed as a possible biological marker of schizophrenia. This review considers the laboratory investigations of phosphoinositide metabolism in platelets of schizophrenic patients. We suggest that alterations in the inositol phosphate level and a disturbance of calcium homeostasis may be common denominators for the multiple factors implicated in the pathogenesis of schizophrenia. In addition, these abnormalities may account for the diverse clinical and biochemical manifestations of schizophrenia.

Platelet serotonin-2 receptors in schizophrenia: Effects of illness and neuroleptic treatment

To examine the role of serotonin 2 (5-hydroxytryptamine 2, 5-HT 2) receptors in schizophrenia, we determined the binding indices of 5-HT 2 receptors using 125I-lysergic acid diethylamide (LSD) as the radioligand in platelets obtained from 40 normal control subjects and 42 drug-free schizophrenic patients. We also examined the effect of neuroleptic drug treatment on the binding parameters ( B max and K d) of 5-HT 2 receptors in platelets of schizophrenic patients. We observed that the B max of 125I-LSD binding in platelets of schizophrenic patients was significantly higher than in platelets of normal subjects. There was no significant difference, however, between the K d of 125I-LSD binding in platelets of schizophrenic patients and normal control subjects. Furthermore, we found no correlation between Brief Psychiatric Rating Scale scores and either B max or K d of 125I-LSD binding at the end of the drug washout period. We also observed that neither treatment with haloperidol nor treatment with thiothixine caused significant changes in B max and K d of 125I-LSD binding in platelets of schizophrenic patients. However, both fluphenazine and trifluoperazine did significantly increase the B max of 125I-LSD binding without any significant change in the K d values in platelets of schizophrenic patients. Our results thus suggest that platelet 5-HT 2 receptors are increased in schizophrenia and that chronic treatment with fluphenazine and trifluoperazine, but not haloperidol or thiothixine, further increases the 5-HT 2 receptor binding sites in platelets of schizophrenic patients.

Increased turnover of platelet phosphatidylinositol in schizophrenia

The potential role of receptor-stimulated phosphatidylinositol (PI) hydrolysis in a signal transduction mechanism has been increasingly recognized. Earlier studies have suggested a defect in α-adrenergic receptor function in the platelets of schizophrenic patients. Little is known, however, about the mechanisms for PI synthesis, breakdown, and regulation in schizophrenia. The present study was undertaken to investigate the metabolic turnover of inositol phospholipids and inositol phosphates by incorporation of [ 3H]myoinositol or [ 32P]orthophosphate into resting and activated platelets of normal controls and schizophrenic patients with and without neuroleptic treatment. After 5 h incubation at 37°C, the majority of [ 3H]myoinositol was incorporated into platelet PI. Following thrombin-induced platelet activation, there was rapid formation of 3H-labeled inositol phosphates (IPs) with inositol monophosphate (IP 1) being the most abundant product. The thrombin-induced formation of platelet IPs was found significantly higher in both haloperidol-stabilized and drug-free schizophrenics than in normal control subjects. When platelets were prelabeled with [ 32P]orthophosphates, thrombin-induced formation of phosphatidic acid (PA) was also significantly higher in haloperidol-stabilized schizophrenics than in normal controls. It is thought that thrombin-induced platelet activation is mediated through hydrolysis of polyphosphoinositides (poly-PI). The present data thus may reflect an increased signal transduction in schizophrenia, which is mediated through neuroleptic-regulated inositol phospholipid hydrolysis.

Inositol phospholipid turnover in platelets of schizophrenic patients

Abnormalities in blood cell membrane phospholipid composition and metabolism from schizophrenic patients have been reported by many groups of investigators. Among membrane phospholipids, inositol phospholipids are of special importance as they are involved in transduction system that generates second messengers such as inositol trisphosphate and diacylglycerol. Our studies on platelet inositol phospholipid turnover suggest a significant increase in platelet phosphatidylinositol 4,5-bisphosphate levels, an increased production of inositol trisphosphate in neuroleptic-treated and neuroleptic-free schizophrenic patients platelets and a reduced calcium release by thrombin in neuroleptic-treated schizophrenic patients platelets. The enhanced production of inositol trisphosphate may be due to an increase in its precursor phosphatidylinositol 4,5-bisphosphate with an associated desensitisation of the intracellular inositol trisphosphate receptor by neuroleptics, which may explain the diminished calcium response to thrombin in schizophrenic patients platelets.

Serotonin-2 receptors in the platelets of schizophrenic patients

Serotonin-2 receptors in the platelets of schizophrenic patients

Kinetic values of active serotonin transport by platelets of bipolar, unipolar and schizophrenic patients at 2 and at 8 a.m. Preliminary report.

Serotonin active transport by platelets of psychiatric patients was determined at 2 and at 8 a.m. Kinetic values, Vmax and Km, of serotonin uptake by platelets of bipolar depressive patients at 2 a.m. were higher than those at 8 a.m. Contrary to that, the kinetic values, Vmax and Km, for unipolar patients at 2 a.m. were rather lower than the values at 8 a.m. Serotonin uptake kinetics by platelets of schizophrenic patients at 2 a.m. were similar to those at 8 a.m. The curves of serotonin uptake kinetics by platelets of bipolar patients at 2 and at 8 a.m. were different from those observed for platelets of unipolar and schizophrenic patients. The variability of the kinetics of serotonin uptake by platelets of the three groups of psychiatric patients may offer a clue to the heterogenicity of these disorders.

Sialic acid in platelets of schizophrenic patients

Sirota, Pinkhas, Hanna Bessler, David Allalouf, Meir Djaldetti and Haim Levinsky: Sialic acid in platelets of schizophrenic patients. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988, 12 : 103–107. 1. 1. Nerve cell membrane sialic acid is involved in the activity of nervous tissue by its capacity to bind Ca ions and positively charged biogenic amines. 2. 2. Blood platelets may serve as a model for amine-storing neurons. 3. 3. The purpose of the present study was to determine the sialic acid content of platelets of schizophrenic patients in view of reports showing a reduced serotonin uptake by their platelets. 4. 4. To this end platelets were isolated from the blood of 26 schizophrenic patients (13 males and 13 females) of various diagnostic subtypes and from 21 healthy subjects, and sialic acid was determined after hydrolysis at 80 ° for 1 h in 0.1 NHCl. 5. 5. The results showed significantly lower contents of sialic acid in the patients as compared to controls calculated both per 10 8 cells and per mg protein (18% and 25% lower, respectively) and appear to be in line with the reduced serotonin uptake in their cells in schizophrenia. 6. 6. There were no appreciable differences between sexes and between the various subtypes of this disease.

Kinetic constants of platelet monoamine oxidase in schizophrenia.

It has been reported that one or both of the kinetic constants (Km and Vmax) of monoamine oxidase (MAO) in the blood platelets of schizophrenic patients are significantly lower than those of normal controls. The authors found no significant differences in Km or Vmax of platelet MAO activity between schizophrenic patients, schizoaffective depressed, mainly schizophrenic patients, and normal control subjects of the same sex. There was also no relationship between paranoid symptoms, hallucinations, or a family history of schizophrenia and Vmax or Km of platelet MAO in the combined groups of schizophrenic and schizoaffective patients. Women had significantly higher Vmax values, but no sex difference in Km was noted.

Schizophrenia and reduced cyclic AMP production: Evidence for the role of receptor-linked events

Reduced cyclic AMP (cAMP) production has been found in platelets of schizophrenic patients. cAMP is generated physilogically as a result of a series of steps beginning with receptor activation by a ligand, progressing through activation of the enzyme protein, adenylate cyclase. The deficit of cAMP found in the schizophrenic population may occur at any one, or at multiple steps in this cascade. The present study attempts to discriminate whether impaired adenylate cyclase itself was responsible for the cAMP deficit or whether abnormalities in receptor events or linkage are present in schizophrenics. The production of cAMP following direct stimulation of adenylate cyclase by NaF was contrasted with receptor mediated activation of adenylate cyclase by prostaglandin E 1 (PGE 1) in disrupted platelet preparations from schizophrenics and normal controls. cAMP formation stimulated by NaF was not different in platelets of schizophrenics as compared to controls, however, platelets of schizophrenics showed reduced responsivity to PGE 1 stimulation. The authors interpret these findings as evidence for a membrane associated abnormality of either receptor or receptor-adenylate cyclase linkage in the schizophrenias.

The active uptake of serotonin by platelets of schizophrenic patients and their families: possibility of a genetic marker.

The active uptake of serotonin (5-HT) blood platelets of 20 schizophrenic patients and their families was studied. The uptake was studied over a wide range of 5-HT concentrations (0.1-20 microM), and Km and Vmax of the uptake process were calculated. Of 20 patients, 18 exhibited a lower rate of uptake than the family average at 5-HT concentrations lower than the Km value. At a 5-HT concentration of 0.1 microM, the average 5-HT uptake of patients was 2.15 pmol/10(8) platelets/min, while that of families was 2.99 pmol/10(8) platelets/min (33% difference). At a high 5-HT concentration, only the drug-treated patients had lower Vmax than the family average, and this might be attributed to the effect of the drugs. Km of patients and families were very similar. In eight families, one or more of the family members showed 5-HT uptake patterns very similar to that of the patient. We termed these healthy family members "schizophrenic risks". Our findings indicate the involvement of some genetic factors in this disease.

Serotonin uptake by blood platelets of schizophrenic patients

Active uptake of serotonin (5-hydroxytryptamine, 5-HT) by blood platelets of acute and chronic schizophrenic patients was compared with that of normal controls. Unlike previous reports, no significant difference in the kinetic parameters (Km and Vmax) of 5-HT uptake between schizophrenic patients and normal controls was observed, although a trend toward decreased Vmax in the acute schizophrenics was present. Since decreased Vmax of platelet 5-HT uptake has been found in patients with bipolar, unipolar, and schizoaffective depression, further study of the usefulness of platelet 5-HT uptake as a biological marker for major depressive illness is indicated. Abnormalities of 5-HT uptake do not appear to contribute significantly to the increased platelet 5-HT levels which have been reported in schizophrenic patients.

Correlation between serotonin uptake and imipramine binding in schizophrenic patients

1. The active uptake of serotonin by platelets of schizophrenic patients and a healthy control group was compared with imipramine binding to these platelets. 2. Significant correlation was observed between the V max of serotonin uptake and the imipramine binding. 3.Serotonin uptake by patients was much lower than that of control group.