[Clinical and psychopathological characteristics of patients with late-onset schizophrenia and schizophrenia-like psychoses in clusters identified by biological parameters]. / Kliniko-psikhopatologicheskie kharakteristiki bol'nykh s pozdno manifestiruyushchimi shizofreniei i shizofrenopodobnymi psikhozami v klasterakh, vydelennykh po biologicheskim parametram.

OBJECTIVE: To assess clinical and psychopathological characteristics of late-aged female patients with late-onset psychoses in clusters formed on the basis of biochemical and immunological blood parameters. MATERIAL AND METHODS: We examined 59 women with schizophrenia and schizophrenia-like psychoses with onset after 40 years (ICD-10 F20, F22.8, F25, F23, F06.2), including 34 women with late-onset (40-60 years) and 25 with very late onset psychoses (after 60 years). At the time of hospitalization, a clinical/ psychopathological study was carried out using CGI-S, PANSS, CDSS, and HAMD-17, as well as the activities of glutathione reductase (GR) and glutathione-S-transferase (GT) have been determined in erythrocyte hemolysates, and the activities of leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) have been assessed in blood plasma. Biochemical and immunological parameters have been also determined in 34 age-matched mentally healthy women. RESULTS: Clustering by signs such as GR, GT, LE and α1-PI has yielded two clusters of objects (patients) significantly different in GT (p<0.0001), LE (p<0.0001), and α1-PI (p<0.001) activities. Relatively to the controls, in the cluster 1 patients, the activities of GST and α1-PI are increased, the activity of LE is decreased, whereas, in the cluster 2 patients, the activity of GR is decreased, and the activities of LE and α1-PI are increased. Cluster 1 patients differ from cluster 2 patients in greater severity of the condition (CGI-S, p=0.04) and higher total scores on PANSS subscales' items. Cluster 1 includes 76% of patients with very late onset. Different correlations between clinical and biological signs are found in two clusters. CONCLUSION: The identified clusters have different clinical and psychopathological characteristics. Dividing patients into subgroups according to biochemical and immunological parameters is promising for the search for differentiated therapeutic approaches.

[Activity of enzymes of glutamate, energy and glutathione metabolism in the first juvenile depression with attenuated symptoms of schizophrenia]. / Aktivnost' fermentov glutamatnogo, energeticheskogo i glutationovogo obmena pri pervykh yunosheskikh depressiyakh s attenuirovannymi simptomami shizofrenii.

OBJECTIVE: To reveal clinical and biological correlations in patients with attenuated symptoms of schizophrenia in the first juvenile depression, namely, the correlation between SOPS and HDRS-21 scores and the levels of activities of glutathione, glutamate and energy metabolism enzymes in the blood of patients. MATERIAL AND METHODS: The study included 81 young men, aged 16-25 years, with the first depressive episode (ICD-10 items F32.1, F32.2, F32.38, F32.8), from which the groups with predominantly attenuated positive symptoms (group 1, n=36) and predominantly attenuated negative symptoms (group 2, n=24), and a group without attenuated schizophrenia symptoms (group 3, n=21) were selected. The control group consisted of 20 mentally healthy men aged 19-25 years. Psychometric methods (SOPS and HDRS-21) and psychopathological methods were used. Activities of cytochrome c oxidase (COX), glutamate dehydrogenase (GDH), glutathione reductase (GR), and glutathione S-transferase (GST) enzymes were determined spectrophotometrically in blood cells. RESULTS: When compared with the control group, activities of platelet GDH, GR, and GST (before and after treatment) were significantly reduced in groups 1, 2, 3 (Mann-Whitney U-test, p<0.0002, p<0.001 and p<0.0001, respectively); the activity of erythrocyte GST was reduced in group 1, and the activities of erythrocyte GR and GST were reduced in group 3 (p<0.05). In group 1, baseline COX (before treatment) was positively correlated with post-treatment SOPS-N scores (R=0.580, p=0.0003), while baseline erythrocyte GR was negatively correlated with post-treatment HDRS-21 scores (R=-0.591, p=0.0004). In group 2, baseline GDH levels were positively correlated with post-treatment scores on SOPS-P (R=0.425, p=0.0384), SOPS-N (R=0.500, p=0.0129), SOPS total (R=0.526, p=0.0083) and HDRS-21 (R=0.479, p=0.0180). CONCLUSION: The discovery of clinical and biological correlations in groups of patients with attenuated symptoms of schizophrenia in the structure of juvenile depression contributes to understanding the pathogenetic mechanisms of the formation of a high clinical risk of psychosis and contributes to the search for markers of the initial stages of schizophrenia.

[New approaches to the typology and prediction of the effectiveness of therapy for late-life depression]. / Novye podkhody k tipologii i prediktsii effektivnosti terapii depressii pozdnego vozrasta.

OBJECTIVE: To analyze clinical parameters and effectiveness of therapy in depressed patients of late age with different activity of enzymes of energy, glutamate metabolism and antioxidant glutathione system in platelets and red blood cells. MATERIAL AND METHODS: The study included 53 hospitalized patients (41 women and 12 men), aged 60 to 86 years (median - 66 years), with a depressive episode of mild to marked severity within the framework of recurrent depressive disorder, bipolar affective disorder or a single depressive episode according to ICD-10. The patients were examined using clinical, psychometric, biochemical and statistical methods. Psychometric assessment of patients' condition was performed before the start of therapy and on the 28th day of treatment using HAMD-17 and HARS. Blood sampling was carried out to determine the activity of cytochrome c-oxidase (COX), glutathione reductase (GR), glutathione S-transferase (GST) and glutamate dehydrogenase (GDH). RESULTS: Cluster analysis revealed 3 clusters (Cl.1, Cl.2, Cl.3), which differed in biochemical indicators. In Cl.1 (n=24, 45.2%), there was a decrease in the activity of COX (p<0.05) and a decrease of GR activity in red blood cells and GST activity in platelets (p<0.001). Patients of Cl.2 (n=11, 20.8%) had increased COX activity (p<0.001) and decreased GDH activity (p<0.001). In patients of Cl.3 (n=18, 34%) the enzyme activity was similar to that in the controls. Later age at disease onset was observed in Cl.1 compared to Cl.2 (51 years [40; 60.5] and 32 years [19; 59], p=0.052). Compared with Cl.2 and Cl.3, patients of Cl.1 significantly more often (p<0.05) had apathetic depressions (41.7%), while complex depressions were observed almost 2 times less often than in Cl.2 (50% and 91.9%, p<0.05). The effectiveness and tolerability of psychopharmacotherapy was higher in Cl.3. CONCLUSION: There is a relationship between the nature of changes in metabolic parameters and differences in the phenomenology and course of late-age depression. The results of the study open up new directions in the field of predicting the effectiveness of therapy and the development of personalized therapeutic approaches to improve the effectiveness and safety of treatment of depressed elderly patients.

[Platelet glutathione reductase and glutathione-S-transferase in elderly patients with depression]. / Trombotsitarnye glutationreduktaza i glutation-S-transferaza u bol'nykh s depressiyami v pozhilom vozraste.

OBJECTIVE: To compare the activity of platelet glutathione reductase (GR) and glutathione-S-transferase (GST) in elderly patients with depression and in the control group, and to identify a possible relationship between the activity of these enzymes and clinical parameters of the disease. MATERIAL AND METHODS: We examined 42 elderly patients (60-86 years old) with depressive episodes of various nosological categories according to ICD-10: a single depressive episode (F32.0, F32.1), a depressive episode in recurrent depressive disorder (RDR - F33.0, F33.1), and a depressive episode in bipolar disorder (BD - F31.3). The GR, GST activity and the severity of depression were assessed twice: before the beginning of the course of 28-day antidepressant therapy (day 0) and on the 28th day of the course of therapy, using the Hamilton Depressive Scale (HAMD-17) and the Hamilton Anxiety Scale (HARS). RESULTS: As compared with the control group, a significant decrease in GST activity was found in patients before and after the course of therapy (p<0.0001 and p<0.0003, respectively), no significant difference in GR activity was found. Significant correlations of the platelet GR activity in patients before thetreatment course with the age of disease manifestation (R= -0.44; p=0.004, inverse correlation) and with its duration (R=0.43, p=0.004, direct correlation), estimated after a 28-day course of therapy. A significant inverse correlation of the baseline (before treatment) GR activity with the HAMD score estimated after the course of therapy (R=-0.440; p=0.009) was found only in women subgroup (n=33). CONCLUSION: A pilot study has revealed a decrease in platelet GST activity, and a link between platelet GR activity and the severity of depression after a course of therapy. The results obtained indicate the promise of further study of glutathione metabolism enzymes as a biomarker for assessing the state.

[The link of platelet cytochrome C-oxidase activity with some clinical parameters of depression in elderly patients]. / Svyaz' aktivnosti trombotsitarnoi tsitokhrom s s-oksidazy s otdel'nymi klinicheskimi parametrami depressii u bol'nykh pozhilogo vozrasta.

OBJECTIVE: To search for correlations between platelet cytochrome c-oxidase (COX) activity and the quality of therapeutic outcomes and other clinical parameters of depression in elderly patients. MATERIAL AND METHODS: Twenty elderly women, aged 55-78 years, with depressive episodes in recurrent depressive disorder (RDD) or bipolar affective disorder (BD) were studied. COX activity and severity of depression were evaluated twice: before the beginning of antidepressant treatment and at the 28-th day of the therapy, using the Hamilton Depression Rating Scale (HAMD-17) and the Hamilton Anxiety Rating Scale (HAM-A). RESULTS: Significant correlations were revealed between platelet COX activity and some clinical parameters of the disease and the severity of depression in patients after treatment. The baseline level of the platelet COX activity was correlated with the age of disease onset (R= -0.63, p=0.003) and its duration (R=0.55, p=0.010). Significant negative correlations were also found between the baseline level of COX activity and depression severity (HAMD-17 total score) (R= -0.48, p=0.032) and the severity of anxiety (HARSHAM-A total score) (R= -0.54, p=0.010) after 28-day treatment. CONCLUSION: This pilot study has revealed a link between platelet COX activity and the severity of depression and anxiety after a 28-day antidepressant therapy. The results indicate the prospects for further study of COX as a biomarker of therapeutic outcomes in elderly patients with depression.

Neurotropic peptide HLDF-6-amide reduces age-related decline in sexual activity in old male rats.

Aging is associated with a decline in the erectile capacity and sexual motivation. Emerging new therapy for the treatment of these age-related pathologies in men is the use of the regulatory peptides. We validated the use of HLDF-6-amide (Thr-Gly-Glu-Hse-His-Arg-NH2) as a potential modulator of sexual performance in aged male rats. Behavioral tests, including the standard parameters of sexual behavior, were performed longitudinally at 20 and 26 months of age. The effects of HLDF-6-amide administered daily at 300 µg/kg for 3 week on the levels of sex hormones and the activity of antioxidant enzymes and indicators of inflammation were evaluated. HLDF-6-amide administration increased the copulative activity of the 20-month-old male rats. This effect of HLDF-6-amide was more pronounced in the 26-month-old rats. Although HLDF-6-amide did not have the effect on the levels of circulating testosterone and estradiol, it reduced the activity of leukocyte elastase and glutathione-S-peroxidase, suggesting that the peptide has anti-inflammatory and antioxidant properties. Therefore, this study shows that HLDF-6-amide has the positive impact on sexual activity in this rodent model, representing a new therapeutic approach for improving sexual performance in older men.

Decrease in 130 kDa- amyloid protein precursor protein (APP) and APP protein ratio in schizophrenia platelets.

Cognitive dysfunction is common among people with schizophrenia. The molecular substrates underlying this remain poorly understood. To address this, we analyzed changes in amyloid precursor protein (APP) in platelets of people with acute schizophrenia (n=24) and control subjects (n=20) by ECL-immunoblotting. APP bands corresponding to molecular masses of ∼130, ∼110 and ∼100 kDa, and the APP ratio (APPr: highest APP molecular mass vs lowest APP molecular mass bands) were quantified. The intensity of 130 kDa-APP and the APPr were significantly reduced in schizophrenia patients compared to control subjects. The age-associated decreases in the 130 kDa, ∼110 kDa proteins and APPr were present in patients, but not controls. Our results confirm peripheral APP metabolism is altered in people with schizophrenia. Further work is now warranted on a larger sample of diseased subjects with detailed cognitive assessment to determine the APP role in cognitive processing in schizophrenia, how it is related to severity and disease progression, as well as outcomes.

Haloperidol Reduces the Activity of Complement and Induces the Anti-Inflammatory Transformation of Peritoneal Macrophages in Rats.

It is known that psychotropic substances affect the immune system. Unfortunately, chronic antipsychotic administration causes side toxicological effects, associated with oxidative stress. The mechanisms of these effects are still unclear. We investigated the impact of sub-chronic administration of haloperidol (Hal) on parameters of innate immunity and related systems in healthy rats and compared them with Hal content. Hal administration (0.5 mg/kg, 3 weeks) resulted in two-fold decrease of the activity of the complement system and hemostasis. Hal content correlated with the activity of the complement (r = -0.71), phagocytic activity of peritoneal macrophages (r = 0.78), leukocyte elastase (r = -0.71) and glutathione-S-transferase activity (r = -0.67). Hal fully blocked in vitro PMA-induced iNOS expression in macrophages and changed their morphology to "anti-inflammatory" phenotype. The comparison of in vivo and in vitro data showed that Hal has a direct effect on phagocytic component of innate immunity and an indirect effect on leukocyte elastase and antioxidant enzymes. The results obtained in the present study indicated that Hal significantly affects homeostasis and causes a number of complex biological transformations. Graphical Abstract.

[The activity of enzymes of glutathione metabolism in blood cells of patients with a high risk of manifestation of endogenous psychoses and patients with the first psychotic episode]. / Aktivnost' fermentov glutationovogo obmena v formennykh élementakh krovi u patsientov s vysokim riskom manifestatsii éndogennykh psikhozov i bol'nykh s pervym psikhoticheskim pristupom.

AIM: To assess the activity of glutathione reductase (GR) and glutathione-S-transferase (GST) in blood cells of patients at clinical high-risk (HR) state for psychosis, in first-episode patients with schizophrenia and schizoaffective disorder (SD), and control group, and to seek correlations of these biochemical parameters with clinical assessments in patients. MATERIAL AND METHODS: The study included male patients at HR (n=21, 16-25 years old), first-episode patients with schizophrenia (F20, n=14, 18-25 years old) and SD (F25, n=20, 16-25 years old), and 12 people of the control group (19-25 years old). Psychometric scales (SOPS, HDRS, and PANSS) and psychopathological methods were employed. GR and GST enzymatic activities were determined spectrophotometrically. RESULTS: The activities of platelet GR and GST in all groups of patients both before and after treatment were lower than in controls (p<0.01). The platelet GST activity was lower in patients at HR compared to patients with schizophrenia before treatment and lower than in patients with SD after treatment (p<0.05), it was higher in patients with schizophrenia than in patients with SD before treatment (p<0.05). Erythrocyte GST activity in patients with HR was lower than in patients with SD after treatment, and in the latter it exceeded that in patients with schizophrenia and controls (p<0.05). Complex and different patterns of changes in the activities of erythrocyte and platelet GR and GST in patients with schizophrenia spectrum disorders, occurring both before the first psychotic episode in the initial stage of disease, and in the first-episode patients, were detected. CONCLUSION: The activity of glutathione-converting enzymes in endogenous psychoses of the schizophrenic spectrum, including its early stages, can be used as a biomarker for predicting the development of psychosis, the course of disease, and as criteria for evaluation of therapeutic response to antipsychotic treatment.

[Glutathione reductase and glutathione-S-transferase in blood cells in schizophrenia and schizophrenia spectrum disorders]. / Glutationreduktaza i glutation-S-transferaza v formennykh élementakh krovi pri shizofrenii i rasstroistvakh shizofrenicheskogo spektra.

AIM: To compare glutathione reductase (GR) and glutathione-S-transferase (GST) enzymatic activities in blood cells (erythrocytes and platelets) of patients with schizophrenia spectrum disorders and in the control group and to search for correlations of these biochemical parameters with clinical psychiatric assessments of the patient. MATERIAL AND METHODS: The study included patients (97 men) with schizophrenia spectrum disorder (schizophrenia and schizoaffective disorders) in an acute state of exacerbation of psychotic symptoms and 33 men without mental pathology. Symptom severity was measured with the PANSS before and after antipsychotic therapy. GR and GST activities were determined spectrophotometrically. RESULTS: There were no significant between-group differences in the activities of erythrocyte GR and GST. In platelets, the GR activity was lower in all patients' groups than in controls, whereas the GST activity in patients with schizophrenia relapses and in patients with schizoaffective disorder (SD) was lower than in controls (p<0.05) both before and after treatment. Differences between subgroups of first-episode patients (schizophrenia and SD) and patients with schizophrenia relapses were found not only in the levels of erythrocyte and platelet GR and GST activities, but also in the changes of these enzymatic activity levels under antipsychotic treatment, as well as in links binding these enzymatic activities and PANSS scores. CONCLUSION: The decreased level of GR and GST, the glutathione-dependent enzymes, contributes to the reduction of antioxidant defense in schizophrenia spectrum disorders. The correlations linking the basal levels of GR and GST activities with the results of clinical assessments after treatment allow us to consider these parameters as potential biomarkers for predicting treatment response.

[α-Klotho protein in neurodegenerative and mental diseases]. / Belok α-kloto pri neirodegenerativnykh i psikhicheskikh zabolevaniiakh.

The review aims to attract attention of psychiatrists and neurologists to a role of α-Klotho protein in biochemical mechanisms that counteract pathogenic processes of neurodegenerative and psychiatric diseases and to possible therapeutic potential of the protein. Basing on the analysis of contemporary literature, the authors summarized the results of model experiments and a few clinical trials (in psychiatry and neurology) indicating the role of α-Klotho protein in the brain processes of neurogenesis, dendrite growth, myelination (oligodendroglia differentiation and activity), regulation of antioxidant system, and synthesis of glutamate neurotransmitter system components, regulation of the activity and synthesis of ion channel protein components and membrane transporters, synaptic plasticity. It is concluded that α-Klotho protein can be used for therapeutic purposes in diseases associated with pathological brain aging, and/or in diseases associated with insufficient synthesis of this protein.

[The activity of erythrocyte and platelet glutathione reductase and glutathione-S-transferase in paranoid schizophrenia]. / Aktivnost' éritrotsitarnykh i trombotsitarnykh glutationreduktazy i glutation-S-transferazy pri paranoidnoi shizofrenii.

AIM: A comparative evaluation of glutathione reductase (GR) and glutathione-S-transferase (GST) activities in erythrocytes and platelets of patients with schizophrenia. MATERIAL AND METHODS: Fifty patients, 47 men and 3 women, aged 25-56 years (medium 34) with acute paranoid schizophrenia (F20.0 ICD-10) with hallucinatory-paranoid or paranoid syndrome were studied. The control group consisted of 48 healthy people, 45 men and 3 women, aged 21-59 years (medium 38). GR activity was determined by the oxidation of NADP-H in the reduction reaction of oxidized glutathione. GST activity was determined by the rate of chromogenic conjugate formation between glutathione and 1-chloro-2.4-dinitrobenzene. RESULTS: No differences in the erythrocyte GR and GST activities between the control group and patients with schizophrenia were found. The platelet activity of GR and GST was significantly lower in patients compared to the control group (Mann-Whitney U test, p<0.01). Spearman rank correlation analysis showed that the erythrocyte GST activity was significantly correlated with PANSSneg scores when measured at the beginning of the study, GST was higher in those patients who had less PANSSneg scores after treatment (R=-0.41, p<0.05). The activity of platelet GST in patients with schizophrenia was correlated with the severity of positive symptoms (PANSSpos score) at the beginning of the study before taking therapy (R=-0.31, p<0.05), i.e. the more prominent psychotic symptoms were expressed in patients with lower GST activity. Upon completion of therapy, this association disappeared. CONCLUSION: The activity of glutathione-dependent enzymes in the blood cells of schizophrenic patients determined before the beginning of antipsychotic pharmacotherapy may be important for objective assessment of this metabolic system status and the degree of its impairment in patients.

[Comparative study of glutamate dehydrogenase in the brain of patients with schizophrenia and mentally healthy people]. / Glutamatdegidrogenaza v mozge bol'nykh shizofreniei i psikhicheski zdorovykh lits.

AIM: To compare the glutamate dehydrogenase (GDH) activity and amounts of GDHI, GDHII, and GDHIII immunoreactive forms in prefrontal, anterior and posterior cingulate cortex and cerebellar cortex of patients with schizophrenia and control subjects. MATERIAL AND METHODS: GDH enzymatic activity was measured and levels of GDH immunoreactive forms were determined in extracts of autopsied samples of prefrontal, anterior and posterior cingulate cortex (areas 10, 24, and 23 by Brodmann), and cerebellar cortex of patients with schizophrenia (n=8) and controls (n=9). RESULTS AND CONCLUSION: GDH enzymatic activity was significantly increased in the prefrontal cortex (area 10) (p<0.004), the posterior cingulate cortex (area 23) (p<0.05) and the cerebellar cortex (p<0.002) and was unchanged in the anterior cingulate cortex (area 24) in patients with schizophrenia compared to controls. The levels of immunoreactive GDH I, GDH II and GDH III were significantly higher in the prefrontal cortex of patients with schizophrenia than in controls (p<0.008, p<0.003, and p<0.0001, respectively). Levels of all three immunoreactive GDH forms were unchanged in the anterior cingulate cortex (area 24), but they were increased in the posterior cingulate cortex (area 23) (p<0.004, p<0.001 and p<0.02, respectively). The levels of immunoreactive GDH II and GDH III, but not GDH I, were significantly increased in the cerebellar cortex of patients with schizophrenia compared with the control group (p<0.02 and p<0.001, respectively). The alteration in the levels of GDH immunoreactive forms in the brain of patients with schizophrenia is one of the causes of impaired brain glutamate metabolism and an important aspect of schizophrenia pathogenesis.

Klotho Protein: Its Role in Aging and Central Nervous System Pathology.

This review is devoted to Klotho protein and recent evidences for its functions in the brain. Information on transcriptional regulation of the klotho gene and posttranslational modifications of the protein resulting in multiple forms of Klotho is reviewed. Evidence is summarized that Klotho regulates the activity of protein factors, enzymes, and receptors, including data suggesting the importance of its glycosidase activity. Effects of Klotho on components of the glutamatergic neurotransmitter system, signal cascades involving protein kinases and protein phosphorylation, as well as oligodendrocyte differentiation and myelination are discussed. A possible contribution is proposed for Klotho levels in the development of central nervous system pathologies including mental disorders.

[Creatine kinase isoform B distribution in the brain in schizophrenia]. / Raspredelenie izoformy V kreatinkinazy v mozge pri shizofrenii.

AIM: To compare patterns of brain isoform creatine phosphokinase (CPK B) distributions in post-mortem brain from patients with schizophrenia (Sch) and patients with somatic diseases (controls). MATERIAL AND METHODS: Extracts of readily soluble and membrane-associated proteins were prepared from post-mortem samples of prefrontal cortex (Brodmann area 10), anterior (area 24) and posterior (area 23) cingulate cortex, hippocampus and cerebellum cortex from patients with Sch and control group (the samples were matched by age and postmortem interval). CPK enzymatic activity was measured by determination of inorganic phosphate, amounts of immunoreative CPK В were estimated by ECL-Western blotting using monoclonal antibodies. RESULTS: A significant decrease in CPK activity and amounts of immunoreative CPK В was observed in fractions of readily soluble proteins in all studied brain structures of patients with Sch compared to controls (p<0.01). Significant differences in CPK activity were found in membrane-associated protein fractions from the hippocampus (p<0.01), but not from the cingulate cortex (areas 23 and 24), of Sch patients compared with controls, whereas no difference between groups was found in levels of immunoreactive CPK B in membrane-associated protein fractions from the cingulate cortex (areas 23 and 24) and hippocampus. The decrease in the amount of CPK B in the frontal cortex of patients with Sch was confirmed by purification of CPK B active dimer from brain samples of patients with Sch and controls. CONCLUSION: Changes in the levels of CPK brain isoform in the brain of patients with Sch (the decrease in CPK activity and amounts in various brain structures at different extents) lead to the substantial alteration of CPK distribution pattern among the brain areas studied, result in the disturbance of the brain energy metabolism and contribute to Sch pathogenesis.

Glutamate and GABA-metabolizing enzymes in post-mortem cerebellum in Alzheimer's disease: phosphate-activated glutaminase and glutamic acid decarboxylase.

Enzymes of glutamate and GABA metabolism in postmortem cerebellum from patients with Alzheimer's disease (AD) have not been comprehensively studied. The present work reports results of original comparative study on levels of phosphate-activated glutaminase (PAG) and glutamic acid decarboxylase isoenzymes (GAD65/67) in autopsied cerebellum samples from AD patients and matched controls (13 cases in each group) as well as summarizes published evidence for altered levels of PAG and GAD65/67 in AD brain. Altered (decreased) levels of these enzymes and changes in links between amounts of these enzymes and other glutamate-metabolizing enzymes (such as glutamate dehydrogenase and glutamine synthetase-like protein) in AD cerebella suggest significantly impaired glutamate and GABA metabolism in this brain region, which was previously regarded as not substantially involved in AD pathogenesis.

[A role of glutamate decarboxylase in Alzheimer's disease].

OBJECTIVE: To evaluate the levels of the main GABA synthetic enzyme, glutamate decarboxylase (represented by two isoforms, GAD65 and GAD67) in the cerebellum cortex of patients with Alzheimer's disease (AD) and mentally healthy subjects. MATERIALS AND METHODS: Samples of the cerebellum cortex from 13 mentally healthy subjects (the control group) and 13 patients with AD were studied. Samples obtained after autopsy were frozen and stored at -80 °C. The groups are matched by sex, age, postmortem interval and cause of death. Protein extracts from cerebellum tissues were obtained after removing of nuclei and cell debris by centrifugation and treatment of the obtained fractions with detergent (SDS). Relative amounts of GAD65 and GAD67 were determined using SDS-PAAG-electrophoresis with the following semi-quantitative ECL-Western-immunoblotting with chemiluminescence detection. RESULTS: The amounts of both isoenzymes (GAD65 and GAD67) were significantly reduced in AD samples. CONCLUSION: The decreased amount of both glutamate decarboxylase isoenzymes suggests the decreased synthesis of neurotransmitter and basic GABA pools that indicates insufficient functioning of the GABA system in the cerebellar cortex of AD patients.

[Glutaminase in the cerebellum of patients with Alzheimer's disease: a postmortem brain study].

Phosphate activated glutaminase (PAG) was quantified in human cerebellar cortex extracts in 13 patients with Alzheimer's disease (AD) and 13 controls by Western immunoblotting using antibody to C-terminus of PAG kidney isoform. The majority of samples from the AD group contained less amount of PAG in comparison with control samples. Although medians in these groups were slightly different (21 and 28 arbitrary units in AD patients and controls, respectively), the Mann Whitney U-test demonstrated a significant between-group difference (U= 28.5, Z= -2.87, p=0.004). Since the both groups were matched for gender, age and postmortem interval, the difference in the PAG level was probably due to the presence of AD. The alteration in the PAG level observed in the cerebellum of patients with AD results in the disturbance of probably not only glutamate metabolism but also many other pathways involving PAG and leads to crucial consequences, particularly, to neurodegeneration.

[Glutamine synthetase-like protein, glutamate dehydrogenase, and cytochrome c-oxidase in platelets of patients with the first episode psychosis in the course of treatment].

The authors searched for correlations between amounts of platelet proteins and results of psychometric tests in patients with the first episode psychosis (schizophrenia, schizoaffective psychosis) in the course of their combined antipsychotic treatment with haloperidol and clozapine. Psychometric evaluations (PANSS, BPRS) and analyses of platelet enzymes - glutamine synthetase-like protein (GSLP), glutamate dehydrogenase (GDH), and cytochrome c-oxidase (COX) - were carried out before, during, and after the treatment. These proteins were also analyzed in matched controls. All the parameters comprised a database, followed by statistical data processing using Statistica 6.0 (StatSoft) software, nonparametric statistics module. The patients before the treatment, when compared with controls, demonstrated significantly decreased COX activity (p=0,0000001) and increased GSLP amount (p=0,006) with a positive correlation between GSLP amount and PANSSneg (R=0,34, p<0,01). Those patients who displayed initially low COX activity (below median) demonstrated significant increase in COX activity after the treatment. Negative correlations were revealed between COX activity and PANSS, PANSSpsy scores during the treatment, i.e. the lower was COX activity, the more severe syndromes were observed. Negative correlations were found between the initial COX activity and PANSS, PANSSpsy, BPRS scores after the treatment, i.e., the higher was COX before the treatment, the less prominent syndromes were observed after the treatment. Significantly more "non-responders" by PANSSneg were found among the patients with low GSLP level (below median) than their calculated expected amount. The COX activity measured before the treatment was significantly lower in patients with schizophrenia than in patients with schizoaffective disorder (SAD) (p=0,038). In SAD patients, the initial COX activity was negatively correlated with PANSSpsy and BPRS scores after the treatment (R=-0,5, p=0,02), i.e. the lower was the COX the activity before the treatment, the more prominent syndromes were observed after the treatment.

[Glutamate dysmetabolism in patients with schizophrenia].

The glutamate-ergic hypothesis of schizophrenia pathogenesis has been substantially expanded due to recent data on changes in glutamate metabolizing enzymes (GME) in the brain of patients with schizophrenia. Significant changes in the amounts of glutamate synthetase (GS), glutamate synthetase-like protein (GSLP), and glutamate dehydrogenase (GDH) have been found. Alterations in the cerebral metabolism of glutamate (together with disturbances in glutamate receptors and transporters) apparently play an important role in the pathogenesis of schizophrenia. Glutamate dysmetabolism has been shown to be of systemic nature, i.e. the amounts of GME (GDH and GSLP) are elevated in platelets of patients with chronic schizophrenia, and these enzymes may be vital markers of glutamate system status. The amounts of GDH and GSLP were monitored in platelets of chronic patients during treatment with olanzapine, an atypical neuroleptic modulating glutamate concentration in the brain and blood of patients. GSLP amount can serve as a predictor of the duration of treatment to achieve a positive outcome. Further studies of GME in blood may result in elaboration of prognostically valuable biological tests not only for schizophrenia treatments, but also for other mental and nervous system diseases in which the glutamate system is substantially implicated.