Phospholipase A2 activity in first episode schizophrenia: associations with symptom severity and outcome at week 12.

OBJECTIVES: Intracellular phospholipases A2 (inPLA2) are activated during monoaminergic neurotranismision and act as key enzymes in cell membrane repair and remodelling, neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes and neuroinflammation. Several independent studies found increased inPLA2 activity in drug-naïve first episode and chronic schizophrenia. This study investigates if inPLA2 activity is associated with symptoms severity and treatment response in first episode schizophrenia (FES). METHODS: InPLA2 activity was measured in serum of 35 young FES patients (mean age: 19.36 ± 3.32, mean duration of illness: 7.53 ± 6.28 months, 16 neuroleptic-naïve) before and after 12 weeks of treatment with second-generation antipsychotic medications (olanzapine, quetiapine or risperidone), as well as in 22 healthy controls matched for age. Psychopathology and social functioning were assessed at the same time points. RESULTS: Baseline inPLA2 activity was significantly increased in drug-naïve and treated FES patients compared to healthy controls. Baseline inPLA2 activity was also associated with severity of negative symptoms and lower functioning at baseline. Furthermore, baseline inPLA2 activity was associated with improvement in negative symptoms and functioning within the first 12 weeks of treatment. CONCLUSIONS: Intracellular PLA2 activity is increased in first episode schizophrenia and associated with symptom severity and outcome after 12 weeks of treatment. Future studies should investigate the implications of inPLA2 activity as a potential predictor of treatment response for different antipsychotic agents.

Phospholipase A2 activity is associated with structural brain changes in schizophrenia.

Regional structural brain changes are among the most robust biological findings in schizophrenia, yet the underlying pathophysiological changes remain poorly understood. Recent evidence suggests that abnormal neuronal/dendritic plasticity is related to alterations in membrane lipids. We examined whether serum activity of membrane lipid remodelling/repairing cytosolic phospholipase A(2) (PLA(2)) were related to regional brain structure in magnetic resonance images (MRI). The study involved 24 schizophrenia patients, who were either drug-naïve or off antipsychotic medication, and 25 healthy controls. Using voxel-based morphometry (VBM) analysis of T1-high-resolution MRI-images, we correlated both gray matter and white matter changes with serum PLA(2)-activity. PLA(2) activity was increased in patients, consistent with previous findings. VBM group comparison of patients vs. controls showed abnormalities of frontal and medial temporal cortices/hippocampus, and left middle/superior temporal gyrus in first-episode patients. Group comparison of VBM/PLA(2)-correlations revealed a distinct pattern of disease-related interactions between gray/white matter changes in patients and PLA(2)-activity: in first-episode patients (n=13), PLA(2)-activity was associated with structural alterations in the left prefrontal cortex and the bilateral thalamus. Recurrent-episode patients (n=11) showed a wide-spread pattern of associations between PLA(2)-activity and structural changes in the left (less right) prefrontal and inferior parietal cortex, the left (less right) thalamus and caudate nucleus, the left medial temporal and orbitofrontal cortex and anterior cingulum, and the cerebellum. Our findings demonstrate a potential association between membrane lipid biochemistry and focal brain structural abnormalities in schizophrenia. Differential patterns in first-episode vs. chronic patients might be related to PLA(2)-increase at disease-onset reflecting localized regenerative activity, whereas correlations in recurrent-episode patients might point to less specific neurodegenerative aspects of disease progression.

Decreased phospholipase A2 activity in cerebrospinal fluid of patients with dementia.

Phospholipase A2 (PLA2) is involved in important aspects of dementia, for example neurotransmission and memory processing, membrane function, choline availability, and antioxidative defense. Reduced PLA2-activity has been reported so far in blood samples and postmortem neuronal tissue in Alzheimer disease. For the first time, we studied PLA2 in cerebrospinal fluid (CSF) in Alzheimer disease (AD), vascular (VD), and mixed Alzheimer/vascular dementia (MD). Intracellular PLA2 was assessed in CSF of 16 AD, 12 VD, 15 MD patients, and 19 healthy control subjects. A fluorometric assay was applied using the PLA2-specific substrate NBDC6-HPC. Significantly reduced PLA2 activity was not only found in AD, but also in VD and MD. This finding was independent of demographic co-variates and medication. PLA2 results in CSF corroborate previous findings of impaired PLA2 function in Alzheimer's disease and extend these to patients with VD. They are likely to reflect an involvement of PLA2 impairment in a variety of pathomechanisms crucial in different dementia subtypes, in which disruption of cholinergic neurotransmission and disturbance of intact membrane function appear to be the key mechanisms.

Increased calcium-independent phospholipase A2 activity in first but not in multiepisode chronic schizophrenia.

BACKGROUND: Increased activity of calcium independent phospholipase A2 (iPLA2) has repeatedly been found in the serum of unmedicated first-episode schizophrenia patients and assumed to reflect a pertubation of phospholipid metabolism. Previous studies in chronic schizophrenia were less conclusive. To explore whether iPLA2 changes are stage dependent, we investigated serum iPLA2 activity in various stages of schizophrenia. METHODS: iPLA2 activity was assessed in the serum of 30 first-episode and 23 multiepisode schizophrenia patients and 53 healthy control subjects matched for age and gender. A fluorimetric assay was applied using the PLA2 specific substrate NBDC6-HPC, thin-layer chromatography of reaction products, and digital image scanning for signal detection. RESULTS: Group comparison between first-episode and multiepisode patients and corresponding control groups revealed significantly increased iPLA2 activity only in first-episode patients. Enzyme activity in first-episode patients was also markedly increased, compared with chronic patients. iPLA2 changes observed were irrespective of neuroleptic medication, age, or gender. CONCLUSIONS: Our results suggest increased lipid turnover in the acute early phase of schizophrenia that is less obvious in chronic stages. Future longitudinal studies involving iPLA2 activity and phosphorous magnetic resonance spectroscopy need to address the relation between perturbed brain lipid metabolism and iPLA2 increment in the course of schizophrenia.

Fluorometric assays of phospholipase A2 activity with three different substrates in biological samples of patients with schizophrenia.

The rationale of this study was to understand the complexity of kinetics of fluorogenic phospholipid substrates as well as contradictory findings of clinical papers measuring phospholipase A2 (PLA2) activity using different methodologies. The aim was to recommend to clinicians and researchers what substrate in conjunction with what assay should be used. Two methods, (i) continuous fluorometric assay and (ii) high performance thin layer chromatography (HPTLC) on microplates combined with quantitative image scanning, were studied with three different substrates (bis-BODIPY FL C11-PC, NBDC6-HPC, PED6). The study demonstrates that NBD-PC is not a suitable substrate to measure PLA2 activity using a spectrofluorometer. On the other hand, NBD-PC gives the highest and most reproducible integrated light intensities (ILls) in HPTLC studies. Slow time-dependent increases in fluorescence intensities recorded with biological samples in fluorometers, but not caused by substrate splitting, had to be classified as "perturbation kinetics". PLA2 activities in blood samples of 26 unmedicated schizophrenia patients and 26 age-matched healthy controls were measured by the spectrofluorometric method and then compared with the activity data obtained with the HPTLC method. A significant group difference was found only with the HPTLC. In order to get more reliable results, we recommend that clinicians and researchers use NBD-phosphatidylcholines as PLA2 substrates in biological samples and start with an analytical separation of reaction products followed by image analysis of the fluorescent spots.