European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2012
Preclinical studies indicate that brain-derived neurotrophic factor (BDNF) is involved in neuropl... more Preclinical studies indicate that brain-derived neurotrophic factor (BDNF) is involved in neuroplastic changes underlying enduring cocaine-seeking following withdrawal. However, little is known about temporal changes in serum BDNF levels or the involvement of BDNF in craving and abstinence in early-abstinent cocaine-dependent patients. Twenty-three cocaine-dependent individuals (aged 33.6576.85 years) completed a two-week detoxification program at an inpatient facility. Two serum samples were collected for each patient at baseline and at the end of the protocol. Serum samples were also collected for 46 healthy controls (aged 35.5279.37 years). Demographic, consumption and clinical data were recorded for all patients. Significantly lower serum BDNF levels (po.0001) were observed for cocaine-dependent patients at baseline compared to healthy controls. Serum BDNF levels increased significantly across 12 days of early abstinence (p=.030). Baseline BDNF levels correlated with craving (p=.034). Post-detoxification BDNF levels correlated with craving (p=.018), loss of control (po.000), abstinence measures (p=0.031), depression (p=0.036), and anxiety (p=0.036). Post-detoxification BDNF levels also had predictive value for the loss of control measure of craving. Chronic cocaine use is associated with decreased serum BDNF. A progressive increase in serum BDNF levels during early abstinence Please cite this article as: Corominas-Roso, M., et al., Brain-derived neurotrophic factor serum levels in cocaine-dependent patients during early abstinence. European Neuropsychopharmacology (2012), http://dx.
Background: There is evidence of decreased neurotrophic support in Alzheimer's disease (AD), ... more Background: There is evidence of decreased neurotrophic support in Alzheimer's disease (AD), including its prodromal stages, but it is not clear whether this abnormality represents a marker of this process. Objective: To determine serum concentrations of a panel of neurotrophic factors (BDNF, NGF, and GDNF) in a cross-section of elderly patients with mild cognitive impairment (MCI) and AD compared to cognitively healthy controls, and to evaluate whether abnormal levels of these factors at baseline predict the transition from MCI to dementia. Methods: A total of 134 older adults were enrolled in this study. Twenty-six patients with mild to moderate AD, 62 with MCI, and 46 cognitively healthy older adults (controls) were subjected to a clinical evaluation including several cognitive tests. Peripheral blood was drawn and serum levels of BDNF, NGF, and GDNF were measured by enzyme-linked immunosorbent assay. APOE genotyping was performed by PCR assays. Results: Serum concentrations ...
Prostaglandins, leukotrienes, and essential fatty acids
Phospholipases A(2) (PLA(2)) are ubiquitous enzymes involved in membrane fatty acid metabolism an... more Phospholipases A(2) (PLA(2)) are ubiquitous enzymes involved in membrane fatty acid metabolism and intracellular signalling. Recent studies have shown that PLA(2) subtypes are implicated in the modulation of pathways related to memory acquisition and retrieval. We investigated the effects of cognitive training on platelet PLA(2) activity in healthy elderly individuals. Twenty-three cognitively unimpaired older adults were randomly assigned to receive memory training or standard outpatient care only. Both groups were cognitively assessed by the same protocol, and the experimental group (EG) underwent a four-session memory training intervention. Pre- and post-test measures included prose and list recall, WAIS-III digit symbol, strategy use measures and platelet PLA(2) group activity. After cognitive training, patients in the EG group had significant increase in cytosolic, calcium-dependent PLA(2) (cPLA(2)), extracellular (or secreted), calcium-dependent PLA(2) (sPLA(2)), total platele...
both size and color represented percent differences in metabolite levels were easily distinguishe... more both size and color represented percent differences in metabolite levels were easily distinguished across study groups. Edges were directional and displayed as arrows where size represented percent difference in flux and color the difference in expression level across study groups. Colors ranged from green for decreases to brown for zero and orange to red for increases. Pathways had to be mapped separately and some split in order to allow visual analyses. shows the cholesterol pathway comparing the aged with youngest group; note how easily one can assess the extent of decrease in all metabolites and fluxes. Also note how even in cases of increased gene expression (red arrows) flux was low because the substrates were low. Export of maps into image files allowed assembly of Powerpoint slides for film-strip inspections of pathway changes. Conclusions: These results demonstrate the value of flux and metabolite pathway mapping, especially with integrating gene expression changes. Such complete pathway mapping is only.
The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) lev... more The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) levels and cognitive functioning have been reported in the literature. However, the variability of individual responses may be linked to genetic differences. BDNF is considered one of the most plausible factors involved in the cognitive benefits associated with physical activity practice. A single nucleotide polymorphism localized in the gene that codes BDNF results in a missense mutation that promotes an amino acid substitution (Val66Met) in the protein. This process has been associated with decreased levels of BDNF secretion, with corresponding impairments in specific cognitive functions. Therefore, the objective of this study was to analyze the effects of a multimodal physical exercise program on peripheral BDNF levels and cognitive functions in elderly individuals with mild cognitive impairment (MCI). The participants were genotyped for the BDNF Val66Met polymorphism. Cognitive function...
Objective: Previous studies suggest that concentration of serotonin ) plays a pathogenic role in ... more Objective: Previous studies suggest that concentration of serotonin ) plays a pathogenic role in various types of epilepsy inhibiting seizures. However, most have not considered the clinical variables of epilepsy, and all of these studies included small and heterogeneous samples with refractory epilepsy, regardless of etiology. In this work, we measured [5-HT]s in hippocampal tissues from a large series of patients with refractory temporal lobe epilepsy caused by hippocampal sclerosis who underwent epilepsy surgery and evaluated the relationship between [5HT] and epilepsy-related clinical variables and psychiatric disorders. Methods: We included 44 patients with refractory unilateral TLE-HS who underwent surgical treatment for epilepsy. Hippocampal samples were collected, and serotonin concentrations were measured with high-pressure liquid chromatography (HPLC). Results: Lower [5-HT]s were correlated with a history of GTC seizures (Student's t-test: p 0.041). There were no differences in [5-HT]s according to the other clinical variables and the presence of psychiatric disorders. Hippocampal serotonin depletion is related to the presence of generalized tonic-clonic seizures 19
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 2010
To assess the serum levels of interleukin 1beta (IL-1beta) in elderly depressed patients in compa... more To assess the serum levels of interleukin 1beta (IL-1beta) in elderly depressed patients in comparison with nondepressed healthy elderly subjects. Cross-sectional study. Tertiary memory clinic. Twenty-three antidepressant-free elderly depressed patients and 44 nondepressed healthy elderly comparison group were enrolled to this study. Serum IL-1beta levels were determined with highly sensitive colorimetric sandwich enzyme-linked immunosorbent assay. Severity of the depressive episode was determined by scores on the Hamilton Depression Scale-21 item and cognitive performance by the scores on the Cambridge Cognition Examination, Mini Mental State Examination clock drawing test, and verbal fluency. IL-1beta serum levels were increased in elderly patients versus nondepressed elderly (t = 2.21, df = 65, p = 0.04). After categorizing elderly depressed subjects into late onset (LOD) versus early onset (EOD), patients with EOD had the highest IL-1beta levels, when compared with nondepressed ...
The journals of gerontology. Series B, Psychological sciences and social sciences, 2014
Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in n... more Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in neurodegenerative cascades. The aim of the present study is to determine the concentrations of brain-derived neurotrophic factor (BDNF), amyloid-β42, total Tau, and phosphorylated Tau in the cerebrospinal fluid (CSF) of patients with LLD and cognitive impairment compared to healthy older adults. We included 25 antidepressant-free patients with LLD (10 with mild cognitive impairment [LLD + MCI] and 15 with no cognitive decline [LLD + NCD]) and 25 healthy older adults as a comparison group. Depressive symptoms were assessed by the 21-item Hamilton Depression Rating Scale (HDRS-21) and cognitive performance by a comprehensive cognitive battery. Patients with LLD + MCI showed significantly lower CSF BDNF levels compared to LLD + NCD and healthy controls (p = .003). There were no significant differences in Alzheimer's disease-related CSF biomarkers between groups. CSF BDNF concentrations w...
association by genotyping an additional 38 SNPs including all coding and tagging SNPs in VDR usin... more association by genotyping an additional 38 SNPs including all coding and tagging SNPs in VDR using 492 cases and 496 controls. Results: We found a novel SNP with nominally significant association (Pϭ0.04) in intron 2. Furthermore, we found multiple significant associations with LOAD with SNPs in intron1, intron 2, and promoter region in VDR (PϽ0.001). Conclusions: These results suggest that VDR is a strong candidate for a genetic risk factor for LOAD.
Background: Glycogen synthase kinase-3 b (GSK3b) is an intracellular enzyme directly implicated i... more Background: Glycogen synthase kinase-3 b (GSK3b) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3b is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3b becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3b (phospho-GSK3b) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3b has never been studied in humans. Methods: In 27 patients with bipolar depression, total GSK3b and phospho-GSK3b were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n ¼ 22) were used as a control group. Results: No differences in phospho-GSK3b or total GSK3b were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho-GSK3b and total GSK3b levels. From baseline to endpoint, lithium treatment inactivated GSK3b by significantly increasing phospho-GSK3b levels (p ¼ 0.010). Clinical improvement (baseline HAM-D d endpoint HAM-D) negatively correlated with the increase in phospho-GSK3b (p ¼ 0.03). Conclusion: The present results show that lithium inactivates platelet GSK3b in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3b as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3b in other neuropsychiatric disorders and as a new therapeutic target per se.
Background: Recent studies evaluated the disease-modifying properties of lithium in mild cognitiv... more Background: Recent studies evaluated the disease-modifying properties of lithium in mild cognitive impairment and dementia. Although potentially effective for these purposes, chronic lithium use in regard to safety in the elderly needs to be better explored.
The search for diagnostic and prognostic markers in Alzheimer&amp... more The search for diagnostic and prognostic markers in Alzheimer's disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.
levels and the allelic-dose of ApoE4 gene in the brains of subjects with Alzheimer's disease (AD)... more levels and the allelic-dose of ApoE4 gene in the brains of subjects with Alzheimer's disease (AD). Methods: We examined the post-mortem brain tissue of AD subjects with different ApoE genotypes (n ¼ 12 ApoE 3/3, 13 ApoE 3/4, and 11 ApoE 4/4; average death age 82 6 11 years) by using a newly developed BACE1 ELISA and by Western blotting. Measurements were performed in the mid-temporal gyrus (MTG) and mid-frontal gyrus (MFG), two cortical areas displaying amyloid beta pathology in AD subjects. Results: BACE1 ELISA and Western blot revealed that BACE1 levels were decreased by 60% in ApoE 4/4 subjects when compared to ApoE 3/3 subjects in both the MTG (p ¼ 0.007) and MFG (p ¼ 0.008) areas. Moreover a 50% decrease in BACE1 levels was observed in ApoE 3/4 subjects when compared to ApoE3/3 (MTG p ¼ 0.017; MFG p ¼ 0.025). Conclusions: These data point in the direction of differential levels of BACE1 expression in the brain of AD subjects with different ApoE genotypes, potentially explaining the large inter-individual variations noted in earlier studies measuring BACE1 levels in AD and control subjects. This suggests that the reported increase in amyloid plaque load in ApoE4 allele carriers may result from clearance defects rather than increased Aß production, and that the molecular mechanisms of AD pathogenesis may be different between ApoE3 and ApoE4 carriers.
Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer's disease (AD),... more Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer's disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE * E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2210.5; 581.9379.4; and 777.5467.8 pg/l respectively; P0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8463.0; stable MCI, 724.0343.4; P0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR3.0 CI 95% [1.2-7.8], P0.02). We also found a significant interaction between the APOE * E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR4.4 CI 95% [1.6-12.1], P0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE * E4, may predict a worse cognitive outcome in patients with MCI.
A¤r›l› Sendromlarda serum beyin-türevli nörotrofik faktör düzeyleri: Major depresyon ile kontroll... more A¤r›l› Sendromlarda serum beyin-türevli nörotrofik faktör düzeyleri: Major depresyon ile kontrollü bir çal›flma Amaç: Bu çal›flmada, a¤r›l› semdromlar›n ortaya ç›kmas›nda stresin rolünün araflt›r›lmas› amac›yla migren ve fibromiyalji tan›l› hastalar›n serum Beyin-türevli Nörotrofik Faktör (BDNF) düzeyleri depresif hastalar›n ve sa¤l›kl› kontrollerin düzeyleri ile karfl›laflt›r›lm›flt›r. Yöntem: Önceden herhangi bir psikiyatrik tan›s› olmayan ve antidepresan tedavi kullanmam›fl olan 27 migren tan›l› hasta ve 19 fibromiyalji tan›l› hasta çal›flmaya al›nm›flt›r. Depresyon grubuna ise en az sekiz haftad›r antidepresan tedavi kullanmayan major depresif bozukluk tan›l› 24 hasta dahil edilmifltir. Bu grupta da depresyona efllik eden baflka bir birinci eksen tan›s› olan hasta yoktur. Herhangi bir psikiyatrik tan›s› bulunmayan ve psikiyatrik tedavi kullanmam›fl olan 26 sa¤l›kl› denek kontrol grubunu oluflturmufltur. Tüm gruplardaki deneklerin depresyon ve di¤er eksen I tan›lar›n›n de¤erlendirlmesi için DSM-IV için Yap›land›-r›lm›fl Klinik Görüflme K›lavuzu (SCID-I) kullan›larak tan›sal görüflme yap›lm›flt›r. Deneklerin depresyon fliddetinin belirlenmesi için Hamilton Depresyon Derecelendirme Ölçe¤i (HAM-D) kullan›lm›flt›r. Migren tan›s› için Uluslararas› Bafla¤r›s› Birli¤i'nin belirledi¤i ölçütlere göre konmufltur. Fibromiyalj› tan›s› için ise American College of Rheumatology ölçütleri kullan›lm›flt›r. Fibromiyalji ve migren has-talar›nda a¤r› fliddeti visual analogue scale (VAS) ile de¤erlendirilmifltir. BDNF ölçümü için serum örne¤i -70°C derecede saklanm›fl ve kit ile beraber verilen Block ve Sample solüsyon ile dilüe edildikten sonra ELISA Kit (Promega; Madison, WI, ABD) ile çal›fl›lm›flt›r. Verilerin de¤erlendirilmesinde, serum BDNF de¤erlerinin ortalamalar›n›n k›yaslanmas› için Kruskal Wallis testi uygulanm›flt›r. Serum BDNF düzeylerinin yaflla iliflkisinin de¤erlendirilmesinde Spearman s›ral› korelasyon testi, cinsiyetle iliflkisinin de¤erlendirilmesinde Bonferroni düzeltmeli Mann Whitney U testi kullan›lm›flt›r. Serum BDNF düzeylerinin HAM-D ve VAS puanlar› ara-s›ndaki iliflkinin test edilmesi için Spearman s›ral› korelasyon testi uygulanm›flt›r. Bulgular: Depresyon grubunun serum BDNF düzeyleri (21.2±11.3 ng/ml), migren grubunun (32.2±10.1 ng/ml), fibromiyalji grubunun (30.7±8.9 ng/ml) ve kontrol grubunun (31.4±8.8 ng/ml) düzeylerinden istatistiksel olarak anlaml› düzeyde düflük bulunmufltur (p<0.0001). Migren, fibromiyalji ve kontrol gruplar› aras›nda serum BDNF düzeyleri aç›s›ndan istatistiksel olarak anlaml› bir farkl›l›k bulunma-m›flt›r. Serum BDNF düzeyleri ile, yafl ve cinsiyet aras›nda istatistiksel olarak an-laml› bir iliflki yoktur. A¤r›l› sendromlarda HAM-D ve VAS puanlar› ile serum BDNF düzeyleri aras›nda istatistiksel olarak anlaml› bir korelasyon olmad›¤› görülmüfltür (s›ras› ile r= 0.085; p= 0.579 ve r= 0.191; p= 0.204). benzer flekilde depresyon grubunda da serum BDNF düzeyleri ile HAM-D puanlar› aras›nda anlaml› bir iliflki yoktur (r= 0.122; p= 0.579). Sonuçlar: A¤r›l› sendromlar stres ile iliflkilendirilse bile, bu çal›flmada, stresin bir belirteci olan serum BDNF düzeyi bu görüflü desteklememifltir. Bu durumun nedeni fibromiyalji veya migren gibi a¤r›l› sendromlarda serum BDNF düzeylerinin periferik trombosit ifllevlerindeki de¤iflimlerden etkilenmesi olabilir. Öte yandan belli bir düzeyde kalan kronik stres durumlar›ndan serum BDNF düzeylerinin etkilenmiyor olmas› da bu durumda rol oynam›fl olabilir. Anahtar sözcükler: BDNF, depresyon, fibromyalji, migren Klinik Psikofarmakoloji Bülteni 2008;18:259-265 ABSTRACT:
An absent response to the niacin skin test has been reported to occur in about 80% of schizophren... more An absent response to the niacin skin test has been reported to occur in about 80% of schizophrenic patients, as compared to 20% of healthy individuals. Niacin provokes redness in skin caused by a capillary vasodilatation mediated by prostaglandins. The metabolism of prostaglandins is regulated by the enzyme phospholipase A2 (PLA2). Several studies have reported increased PLA2 activity in schizophrenia. In this study we investigated the relationship between niacin response and PLA2 activity in 38 drug-free schizophrenic patients and in 28 healthy controls. Twenty-two of these patients were reevaluated after 8 weeks under treatment with new generation antipsychotic drugs. Niacin response was absent in 23% of the schizophrenic patients and in 14% in controls (n.s.). PLA2 activity was higher in schizophrenics than in controls (344+/-115 vs. 290+/-71 pmol/ml/min; p=0.03). Patients with absent response to niacin had the highest PLA2 activity as compared to those with positive response (426+/-155 vs. 319+/-111; p=0.02). After 8 weeks on antipsychotic treatment, PLA2 activity was reduced (355+/-115 before, 267+/-39 after, p=0.001) and 4 out of 13 patients with absent response to niacin converted to positive. The reduction of PLA2 activity in these patients was higher than in patients who remained with absent response (36% vs. 23%). Our data support the findings that absent response to niacin is more frequent in schizophrenic than in healthy individuals although the magnitude of the difference was smaller than that reported in the literature. The relationship between absent response to niacin in schizophrenia and increased PLA2 activity suggests further that the skin test may be useful to easily identify a subgroup of patients with a disordered phospholipid metabolism.
Objective: It has been postulated that mood stabilizers inhibit glycogen synthase kinase 3-beta (... more Objective: It has been postulated that mood stabilizers inhibit glycogen synthase kinase 3-beta (Gsk3b) activity, mainly through its phosphorylation on serine-9 (Ser9). However, in vivo studies addressing Gsk3b activity in patients with bipolar disorder are scarce. Here, we compare Gsk3b inactivation (as indicated by Ser9-phosphorylation) in platelets of elderly patients with bipolar disorder undergoing clinical treatment and healthy elderly adults not taking medication. Methods: Platelet samples were obtained from 37 elderly adults (bipolar disorder = 19, controls = 18). Relative changes in Gsk3b inactivation was estimated by comparing the ratios of phosphorylated Gsk3b to total Gsk3b (p-Gsk3b Ser9/Gsk3b) between the disease and control groups. Results: Phosphorylated-Gsk3b (p , 0.001) and the p-Gsk3b Ser9/Gsk3b ratio (p = 0.006) were elevated in bipolar patients. In the bipolar disorder group, p-Gsk3b Ser9/Gsk3b was positively correlated with serum lithium levels (r = 0.478, p = 0.039). Conclusions: Gsk3b inactivation is higher in this group of elderly adults undergoing treatment for bipolar disorder. However, whether the treatment or the disease causes Gsk3b inactivation was confounded by the lack of an unmedicated, bipolar control group and the non-uniform treatment regimens of the bipolar disorder group. Thus, further studies should help distinguish whether Gsk3b inactivation is an effect of drug treatment or an intrinsic characteristic of bipolar disorder.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2012
Phospholipases A 2 (PLA 2 ) are key enzymes in membrane metabolism. The release of fatty acids an... more Phospholipases A 2 (PLA 2 ) are key enzymes in membrane metabolism. The release of fatty acids and lysophospholipids by PLA 2 activates several intra-cellular second messenger cascades that regulate a wide variety of physiological responses. The aim of the present study is to describe a radioenzymatic assay to determine the activity of three main PLA 2 subtypes in platelets, namely extracellular calciumdependent PLA 2 (sPLA 2 ) and intracellular calcium-dependent (cPLA 2 ) and calcium-independent PLA 2 (iPLA 2 ). The differentiation of these distinct PLA 2 subtypes was based on the enzyme substrate preference (arachdonic acid or palmitoyl acid) and calcium concentration. Our results indicate that this new assay is feasible, precise and specific to measure the activity of the aforementioned subtypes of PLA 2 . Therefore, this protocol can be used to investigate modifications of PLA 2 homeostasis in distinct biological models addressing the pathophysiology of many medical and neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2010
Background: Arachidonic acid is released from cellular membranes by the action of phospholipase A... more Background: Arachidonic acid is released from cellular membranes by the action of phospholipase A 2 (PLA 2 ) and is implicated in microtubule-associated protein Tau phosphorylation. Tau hyperphosphorylation affects its ability to stabilize microtubules. Objective: To determine the effect of PLA 2 inhibition on the phosphorylation state of Tau phosphoepitopes in primary cultures of hippocampal neurons. Methods: 4 DIC neurons were incubated at different concentrations of methyl-arachidonylfluorophosphonate (MAFP), an irreversible inhibitor of cPLA 2 and iPLA 2 . Changes on Tau phosphorylation were determined by Western blotting with a panel of anti-Tau antibodies Ser199/202, Ser202/ 205, Ser396 and Ser214). Results: The Ser214 site was hyperphosphorylated upon MAFP treatment. Significant differences were observed with 10 mM (p ¼ 0.01), 50 mM (p ¼ 0.01) and 100 mM (p ¼ 0.05) of MAFP. Less-intense changes were found in other phosphoepitopes. Conclusion: The present findings indicate that the phosphorylation of Ser214 is regulated by c-and/or iPLA 2 , whereas other phosphoepitopes primarily regulated by GKS3b were not affected.
Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA), 2013
The phospholipase A2 (PLA2) enzymes have been implicated in several neuropsychiatry disorders and... more The phospholipase A2 (PLA2) enzymes have been implicated in several neuropsychiatry disorders and activity alterations have been described in brain and platelet. Since brain tissue is not readily available for the measurement of PLA2 activity, it would be of interest to test directly whether PLA2 activities in both tissues are correlated. We performed this task assessing PLA2 activity in platelets and hippocampus collected simultaneously from 19 patients undergoing temporal lobectomy for treatment of refractory epilepsy. Our findings suggest that total PLA2 activity in platelets may reflect the total activity of the enzyme in the brain (rs=0.59, p=0.008). However in our sample no correlations were found between the subgroups of the enzyme in brain and in platelets. This lack of correlations may be due to different effects of drug treatment on the PLA2 subtypes. In face of the difficulty to obtain brain tissues from living patients, further studies with larger drug-free samples are warranted to clarify whether the use of platelets is a reliable strategy to reflect the subtypes of PLA2 activity in the brain.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2012
Preclinical studies indicate that brain-derived neurotrophic factor (BDNF) is involved in neuropl... more Preclinical studies indicate that brain-derived neurotrophic factor (BDNF) is involved in neuroplastic changes underlying enduring cocaine-seeking following withdrawal. However, little is known about temporal changes in serum BDNF levels or the involvement of BDNF in craving and abstinence in early-abstinent cocaine-dependent patients. Twenty-three cocaine-dependent individuals (aged 33.6576.85 years) completed a two-week detoxification program at an inpatient facility. Two serum samples were collected for each patient at baseline and at the end of the protocol. Serum samples were also collected for 46 healthy controls (aged 35.5279.37 years). Demographic, consumption and clinical data were recorded for all patients. Significantly lower serum BDNF levels (po.0001) were observed for cocaine-dependent patients at baseline compared to healthy controls. Serum BDNF levels increased significantly across 12 days of early abstinence (p=.030). Baseline BDNF levels correlated with craving (p=.034). Post-detoxification BDNF levels correlated with craving (p=.018), loss of control (po.000), abstinence measures (p=0.031), depression (p=0.036), and anxiety (p=0.036). Post-detoxification BDNF levels also had predictive value for the loss of control measure of craving. Chronic cocaine use is associated with decreased serum BDNF. A progressive increase in serum BDNF levels during early abstinence Please cite this article as: Corominas-Roso, M., et al., Brain-derived neurotrophic factor serum levels in cocaine-dependent patients during early abstinence. European Neuropsychopharmacology (2012), http://dx.
Background: There is evidence of decreased neurotrophic support in Alzheimer's disease (AD), ... more Background: There is evidence of decreased neurotrophic support in Alzheimer's disease (AD), including its prodromal stages, but it is not clear whether this abnormality represents a marker of this process. Objective: To determine serum concentrations of a panel of neurotrophic factors (BDNF, NGF, and GDNF) in a cross-section of elderly patients with mild cognitive impairment (MCI) and AD compared to cognitively healthy controls, and to evaluate whether abnormal levels of these factors at baseline predict the transition from MCI to dementia. Methods: A total of 134 older adults were enrolled in this study. Twenty-six patients with mild to moderate AD, 62 with MCI, and 46 cognitively healthy older adults (controls) were subjected to a clinical evaluation including several cognitive tests. Peripheral blood was drawn and serum levels of BDNF, NGF, and GDNF were measured by enzyme-linked immunosorbent assay. APOE genotyping was performed by PCR assays. Results: Serum concentrations ...
Prostaglandins, leukotrienes, and essential fatty acids
Phospholipases A(2) (PLA(2)) are ubiquitous enzymes involved in membrane fatty acid metabolism an... more Phospholipases A(2) (PLA(2)) are ubiquitous enzymes involved in membrane fatty acid metabolism and intracellular signalling. Recent studies have shown that PLA(2) subtypes are implicated in the modulation of pathways related to memory acquisition and retrieval. We investigated the effects of cognitive training on platelet PLA(2) activity in healthy elderly individuals. Twenty-three cognitively unimpaired older adults were randomly assigned to receive memory training or standard outpatient care only. Both groups were cognitively assessed by the same protocol, and the experimental group (EG) underwent a four-session memory training intervention. Pre- and post-test measures included prose and list recall, WAIS-III digit symbol, strategy use measures and platelet PLA(2) group activity. After cognitive training, patients in the EG group had significant increase in cytosolic, calcium-dependent PLA(2) (cPLA(2)), extracellular (or secreted), calcium-dependent PLA(2) (sPLA(2)), total platele...
both size and color represented percent differences in metabolite levels were easily distinguishe... more both size and color represented percent differences in metabolite levels were easily distinguished across study groups. Edges were directional and displayed as arrows where size represented percent difference in flux and color the difference in expression level across study groups. Colors ranged from green for decreases to brown for zero and orange to red for increases. Pathways had to be mapped separately and some split in order to allow visual analyses. shows the cholesterol pathway comparing the aged with youngest group; note how easily one can assess the extent of decrease in all metabolites and fluxes. Also note how even in cases of increased gene expression (red arrows) flux was low because the substrates were low. Export of maps into image files allowed assembly of Powerpoint slides for film-strip inspections of pathway changes. Conclusions: These results demonstrate the value of flux and metabolite pathway mapping, especially with integrating gene expression changes. Such complete pathway mapping is only.
The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) lev... more The benefits of physical exercise on improvements in brain-derived neurotrophic factor (BDNF) levels and cognitive functioning have been reported in the literature. However, the variability of individual responses may be linked to genetic differences. BDNF is considered one of the most plausible factors involved in the cognitive benefits associated with physical activity practice. A single nucleotide polymorphism localized in the gene that codes BDNF results in a missense mutation that promotes an amino acid substitution (Val66Met) in the protein. This process has been associated with decreased levels of BDNF secretion, with corresponding impairments in specific cognitive functions. Therefore, the objective of this study was to analyze the effects of a multimodal physical exercise program on peripheral BDNF levels and cognitive functions in elderly individuals with mild cognitive impairment (MCI). The participants were genotyped for the BDNF Val66Met polymorphism. Cognitive function...
Objective: Previous studies suggest that concentration of serotonin ) plays a pathogenic role in ... more Objective: Previous studies suggest that concentration of serotonin ) plays a pathogenic role in various types of epilepsy inhibiting seizures. However, most have not considered the clinical variables of epilepsy, and all of these studies included small and heterogeneous samples with refractory epilepsy, regardless of etiology. In this work, we measured [5-HT]s in hippocampal tissues from a large series of patients with refractory temporal lobe epilepsy caused by hippocampal sclerosis who underwent epilepsy surgery and evaluated the relationship between [5HT] and epilepsy-related clinical variables and psychiatric disorders. Methods: We included 44 patients with refractory unilateral TLE-HS who underwent surgical treatment for epilepsy. Hippocampal samples were collected, and serotonin concentrations were measured with high-pressure liquid chromatography (HPLC). Results: Lower [5-HT]s were correlated with a history of GTC seizures (Student's t-test: p 0.041). There were no differences in [5-HT]s according to the other clinical variables and the presence of psychiatric disorders. Hippocampal serotonin depletion is related to the presence of generalized tonic-clonic seizures 19
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 2010
To assess the serum levels of interleukin 1beta (IL-1beta) in elderly depressed patients in compa... more To assess the serum levels of interleukin 1beta (IL-1beta) in elderly depressed patients in comparison with nondepressed healthy elderly subjects. Cross-sectional study. Tertiary memory clinic. Twenty-three antidepressant-free elderly depressed patients and 44 nondepressed healthy elderly comparison group were enrolled to this study. Serum IL-1beta levels were determined with highly sensitive colorimetric sandwich enzyme-linked immunosorbent assay. Severity of the depressive episode was determined by scores on the Hamilton Depression Scale-21 item and cognitive performance by the scores on the Cambridge Cognition Examination, Mini Mental State Examination clock drawing test, and verbal fluency. IL-1beta serum levels were increased in elderly patients versus nondepressed elderly (t = 2.21, df = 65, p = 0.04). After categorizing elderly depressed subjects into late onset (LOD) versus early onset (EOD), patients with EOD had the highest IL-1beta levels, when compared with nondepressed ...
The journals of gerontology. Series B, Psychological sciences and social sciences, 2014
Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in n... more Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in neurodegenerative cascades. The aim of the present study is to determine the concentrations of brain-derived neurotrophic factor (BDNF), amyloid-β42, total Tau, and phosphorylated Tau in the cerebrospinal fluid (CSF) of patients with LLD and cognitive impairment compared to healthy older adults. We included 25 antidepressant-free patients with LLD (10 with mild cognitive impairment [LLD + MCI] and 15 with no cognitive decline [LLD + NCD]) and 25 healthy older adults as a comparison group. Depressive symptoms were assessed by the 21-item Hamilton Depression Rating Scale (HDRS-21) and cognitive performance by a comprehensive cognitive battery. Patients with LLD + MCI showed significantly lower CSF BDNF levels compared to LLD + NCD and healthy controls (p = .003). There were no significant differences in Alzheimer's disease-related CSF biomarkers between groups. CSF BDNF concentrations w...
association by genotyping an additional 38 SNPs including all coding and tagging SNPs in VDR usin... more association by genotyping an additional 38 SNPs including all coding and tagging SNPs in VDR using 492 cases and 496 controls. Results: We found a novel SNP with nominally significant association (Pϭ0.04) in intron 2. Furthermore, we found multiple significant associations with LOAD with SNPs in intron1, intron 2, and promoter region in VDR (PϽ0.001). Conclusions: These results suggest that VDR is a strong candidate for a genetic risk factor for LOAD.
Background: Glycogen synthase kinase-3 b (GSK3b) is an intracellular enzyme directly implicated i... more Background: Glycogen synthase kinase-3 b (GSK3b) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3b is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3b becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3b (phospho-GSK3b) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3b has never been studied in humans. Methods: In 27 patients with bipolar depression, total GSK3b and phospho-GSK3b were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n ¼ 22) were used as a control group. Results: No differences in phospho-GSK3b or total GSK3b were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho-GSK3b and total GSK3b levels. From baseline to endpoint, lithium treatment inactivated GSK3b by significantly increasing phospho-GSK3b levels (p ¼ 0.010). Clinical improvement (baseline HAM-D d endpoint HAM-D) negatively correlated with the increase in phospho-GSK3b (p ¼ 0.03). Conclusion: The present results show that lithium inactivates platelet GSK3b in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3b as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3b in other neuropsychiatric disorders and as a new therapeutic target per se.
Background: Recent studies evaluated the disease-modifying properties of lithium in mild cognitiv... more Background: Recent studies evaluated the disease-modifying properties of lithium in mild cognitive impairment and dementia. Although potentially effective for these purposes, chronic lithium use in regard to safety in the elderly needs to be better explored.
The search for diagnostic and prognostic markers in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp... more The search for diagnostic and prognostic markers in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) has been an area of active research in the last decades. Biochemical markers are correlates of intracerebral changes that can be identified in biological fluids, namely: peripheral blood (total blood, red and white blood cells, platelets, plasma and serum), saliva, urine and cerebrospinal fluid. An important feature of a biomarker is that it can be measured objectively and evaluated as (1) an indicator of disease mechanisms (markers of core pathogenic processes or the expression of downstream effects of these processes), or (2) biochemical responses to pharmacological or therapeutic intervention, which can be indicative of disease modification. Platelets have been used in neuropharmacological models since the mid-fifties, as they share several homeostatic functions with neurons, such as accumulation and release of neurotransmitters, responsiveness to variations in calcium concentration, and expression of membrane-bound compounds. Recent studies have shown that platelets also express several components related to the pathogenesis of AD, in particular to the amyloid cascade and the regulation of oxidative stress: thus they can be used in the search for biomarkers of the disease process. For instance, platelets are the most important source of circulating forms of the amyloid precursor protein and other important proteins such as Tau and glycogen synthase kinase-3B. Moreover, platelets express enzymes involved in membrane homeostasis (e.g., phospholipase A2), and markers of the inflammatory process and oxidative stress. In this review we summarize the available literature and discuss evidence concerning the potential use of platelet markers in AD.
levels and the allelic-dose of ApoE4 gene in the brains of subjects with Alzheimer's disease (AD)... more levels and the allelic-dose of ApoE4 gene in the brains of subjects with Alzheimer's disease (AD). Methods: We examined the post-mortem brain tissue of AD subjects with different ApoE genotypes (n ¼ 12 ApoE 3/3, 13 ApoE 3/4, and 11 ApoE 4/4; average death age 82 6 11 years) by using a newly developed BACE1 ELISA and by Western blotting. Measurements were performed in the mid-temporal gyrus (MTG) and mid-frontal gyrus (MFG), two cortical areas displaying amyloid beta pathology in AD subjects. Results: BACE1 ELISA and Western blot revealed that BACE1 levels were decreased by 60% in ApoE 4/4 subjects when compared to ApoE 3/3 subjects in both the MTG (p ¼ 0.007) and MFG (p ¼ 0.008) areas. Moreover a 50% decrease in BACE1 levels was observed in ApoE 3/4 subjects when compared to ApoE3/3 (MTG p ¼ 0.017; MFG p ¼ 0.025). Conclusions: These data point in the direction of differential levels of BACE1 expression in the brain of AD subjects with different ApoE genotypes, potentially explaining the large inter-individual variations noted in earlier studies measuring BACE1 levels in AD and control subjects. This suggests that the reported increase in amyloid plaque load in ApoE4 allele carriers may result from clearance defects rather than increased Aß production, and that the molecular mechanisms of AD pathogenesis may be different between ApoE3 and ApoE4 carriers.
Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer's disease (AD),... more Objectives. Abnormalities in neurotrophic systems have been reported in Alzheimer's disease (AD), as shown by decreased serum brain-derived neurotrophic factor (BDNF) levels and association with BDNF genetic polymorphisms. In this study, we investigate whether these findings can be detected in patients with mild cognitive impairment (MCI), which is recognized as a high risk condition for AD. We also address the impact of these variables on the progression of cognitive deficits within the MCI-AD continuum. Methods. One hundred and sixty older adults with varying degrees of cognitive impairment (30 patients with AD, 71 with MCI, and 59 healthy controls) were longitudinally assessed for up to 60 months. Baseline serum BDNF levels were determined by sandwich ELISA, and the presence of polymorphisms of BDNF and apolipoprotein E (Val66Met and APOE * E4, respectively) was determined by allelic discrimination analysis on real time PCR. Modifications of cognitive state were ascertained for non-demented subjects. Results. Mean serum BDNF levels were reduced in patients with MCI and AD, as compared to controls (509.2210.5; 581.9379.4; and 777.5467.8 pg/l respectively; P0.001). Baseline serum BDNF levels were not associated with the progression of cognitive impairment upon follow-up in patients with MCI (progressive MCI, 750.8463.0; stable MCI, 724.0343.4; P0.8), nor with the conversion to AD. Although Val66Met polymorphisms were not associated with the cross-sectional diagnoses of MCI or AD, the presence of Met-BDNF allele was associated with a higher risk of disease-progression in patients with MCI (OR3.0 CI 95% [1.2-7.8], P0.02). We also found a significant interaction between the APOE * E4 and Met-BDNF allele increasing the risk of progression of cognitive impairment in MCI patients (OR4.4 CI 95% [1.6-12.1], P0.004). Conclusion. Decreased neurotrophic support, as indicated by a reduced systemic availability of BDNF, may play role in the neurodegenerative processes that underlie the continuum from MCI to AD. The presence of Met-BDNF allele, particularly in association with APOE * E4, may predict a worse cognitive outcome in patients with MCI.
A¤r›l› Sendromlarda serum beyin-türevli nörotrofik faktör düzeyleri: Major depresyon ile kontroll... more A¤r›l› Sendromlarda serum beyin-türevli nörotrofik faktör düzeyleri: Major depresyon ile kontrollü bir çal›flma Amaç: Bu çal›flmada, a¤r›l› semdromlar›n ortaya ç›kmas›nda stresin rolünün araflt›r›lmas› amac›yla migren ve fibromiyalji tan›l› hastalar›n serum Beyin-türevli Nörotrofik Faktör (BDNF) düzeyleri depresif hastalar›n ve sa¤l›kl› kontrollerin düzeyleri ile karfl›laflt›r›lm›flt›r. Yöntem: Önceden herhangi bir psikiyatrik tan›s› olmayan ve antidepresan tedavi kullanmam›fl olan 27 migren tan›l› hasta ve 19 fibromiyalji tan›l› hasta çal›flmaya al›nm›flt›r. Depresyon grubuna ise en az sekiz haftad›r antidepresan tedavi kullanmayan major depresif bozukluk tan›l› 24 hasta dahil edilmifltir. Bu grupta da depresyona efllik eden baflka bir birinci eksen tan›s› olan hasta yoktur. Herhangi bir psikiyatrik tan›s› bulunmayan ve psikiyatrik tedavi kullanmam›fl olan 26 sa¤l›kl› denek kontrol grubunu oluflturmufltur. Tüm gruplardaki deneklerin depresyon ve di¤er eksen I tan›lar›n›n de¤erlendirlmesi için DSM-IV için Yap›land›-r›lm›fl Klinik Görüflme K›lavuzu (SCID-I) kullan›larak tan›sal görüflme yap›lm›flt›r. Deneklerin depresyon fliddetinin belirlenmesi için Hamilton Depresyon Derecelendirme Ölçe¤i (HAM-D) kullan›lm›flt›r. Migren tan›s› için Uluslararas› Bafla¤r›s› Birli¤i'nin belirledi¤i ölçütlere göre konmufltur. Fibromiyalj› tan›s› için ise American College of Rheumatology ölçütleri kullan›lm›flt›r. Fibromiyalji ve migren has-talar›nda a¤r› fliddeti visual analogue scale (VAS) ile de¤erlendirilmifltir. BDNF ölçümü için serum örne¤i -70°C derecede saklanm›fl ve kit ile beraber verilen Block ve Sample solüsyon ile dilüe edildikten sonra ELISA Kit (Promega; Madison, WI, ABD) ile çal›fl›lm›flt›r. Verilerin de¤erlendirilmesinde, serum BDNF de¤erlerinin ortalamalar›n›n k›yaslanmas› için Kruskal Wallis testi uygulanm›flt›r. Serum BDNF düzeylerinin yaflla iliflkisinin de¤erlendirilmesinde Spearman s›ral› korelasyon testi, cinsiyetle iliflkisinin de¤erlendirilmesinde Bonferroni düzeltmeli Mann Whitney U testi kullan›lm›flt›r. Serum BDNF düzeylerinin HAM-D ve VAS puanlar› ara-s›ndaki iliflkinin test edilmesi için Spearman s›ral› korelasyon testi uygulanm›flt›r. Bulgular: Depresyon grubunun serum BDNF düzeyleri (21.2±11.3 ng/ml), migren grubunun (32.2±10.1 ng/ml), fibromiyalji grubunun (30.7±8.9 ng/ml) ve kontrol grubunun (31.4±8.8 ng/ml) düzeylerinden istatistiksel olarak anlaml› düzeyde düflük bulunmufltur (p<0.0001). Migren, fibromiyalji ve kontrol gruplar› aras›nda serum BDNF düzeyleri aç›s›ndan istatistiksel olarak anlaml› bir farkl›l›k bulunma-m›flt›r. Serum BDNF düzeyleri ile, yafl ve cinsiyet aras›nda istatistiksel olarak an-laml› bir iliflki yoktur. A¤r›l› sendromlarda HAM-D ve VAS puanlar› ile serum BDNF düzeyleri aras›nda istatistiksel olarak anlaml› bir korelasyon olmad›¤› görülmüfltür (s›ras› ile r= 0.085; p= 0.579 ve r= 0.191; p= 0.204). benzer flekilde depresyon grubunda da serum BDNF düzeyleri ile HAM-D puanlar› aras›nda anlaml› bir iliflki yoktur (r= 0.122; p= 0.579). Sonuçlar: A¤r›l› sendromlar stres ile iliflkilendirilse bile, bu çal›flmada, stresin bir belirteci olan serum BDNF düzeyi bu görüflü desteklememifltir. Bu durumun nedeni fibromiyalji veya migren gibi a¤r›l› sendromlarda serum BDNF düzeylerinin periferik trombosit ifllevlerindeki de¤iflimlerden etkilenmesi olabilir. Öte yandan belli bir düzeyde kalan kronik stres durumlar›ndan serum BDNF düzeylerinin etkilenmiyor olmas› da bu durumda rol oynam›fl olabilir. Anahtar sözcükler: BDNF, depresyon, fibromyalji, migren Klinik Psikofarmakoloji Bülteni 2008;18:259-265 ABSTRACT:
An absent response to the niacin skin test has been reported to occur in about 80% of schizophren... more An absent response to the niacin skin test has been reported to occur in about 80% of schizophrenic patients, as compared to 20% of healthy individuals. Niacin provokes redness in skin caused by a capillary vasodilatation mediated by prostaglandins. The metabolism of prostaglandins is regulated by the enzyme phospholipase A2 (PLA2). Several studies have reported increased PLA2 activity in schizophrenia. In this study we investigated the relationship between niacin response and PLA2 activity in 38 drug-free schizophrenic patients and in 28 healthy controls. Twenty-two of these patients were reevaluated after 8 weeks under treatment with new generation antipsychotic drugs. Niacin response was absent in 23% of the schizophrenic patients and in 14% in controls (n.s.). PLA2 activity was higher in schizophrenics than in controls (344+/-115 vs. 290+/-71 pmol/ml/min; p=0.03). Patients with absent response to niacin had the highest PLA2 activity as compared to those with positive response (426+/-155 vs. 319+/-111; p=0.02). After 8 weeks on antipsychotic treatment, PLA2 activity was reduced (355+/-115 before, 267+/-39 after, p=0.001) and 4 out of 13 patients with absent response to niacin converted to positive. The reduction of PLA2 activity in these patients was higher than in patients who remained with absent response (36% vs. 23%). Our data support the findings that absent response to niacin is more frequent in schizophrenic than in healthy individuals although the magnitude of the difference was smaller than that reported in the literature. The relationship between absent response to niacin in schizophrenia and increased PLA2 activity suggests further that the skin test may be useful to easily identify a subgroup of patients with a disordered phospholipid metabolism.
Objective: It has been postulated that mood stabilizers inhibit glycogen synthase kinase 3-beta (... more Objective: It has been postulated that mood stabilizers inhibit glycogen synthase kinase 3-beta (Gsk3b) activity, mainly through its phosphorylation on serine-9 (Ser9). However, in vivo studies addressing Gsk3b activity in patients with bipolar disorder are scarce. Here, we compare Gsk3b inactivation (as indicated by Ser9-phosphorylation) in platelets of elderly patients with bipolar disorder undergoing clinical treatment and healthy elderly adults not taking medication. Methods: Platelet samples were obtained from 37 elderly adults (bipolar disorder = 19, controls = 18). Relative changes in Gsk3b inactivation was estimated by comparing the ratios of phosphorylated Gsk3b to total Gsk3b (p-Gsk3b Ser9/Gsk3b) between the disease and control groups. Results: Phosphorylated-Gsk3b (p , 0.001) and the p-Gsk3b Ser9/Gsk3b ratio (p = 0.006) were elevated in bipolar patients. In the bipolar disorder group, p-Gsk3b Ser9/Gsk3b was positively correlated with serum lithium levels (r = 0.478, p = 0.039). Conclusions: Gsk3b inactivation is higher in this group of elderly adults undergoing treatment for bipolar disorder. However, whether the treatment or the disease causes Gsk3b inactivation was confounded by the lack of an unmedicated, bipolar control group and the non-uniform treatment regimens of the bipolar disorder group. Thus, further studies should help distinguish whether Gsk3b inactivation is an effect of drug treatment or an intrinsic characteristic of bipolar disorder.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2012
Phospholipases A 2 (PLA 2 ) are key enzymes in membrane metabolism. The release of fatty acids an... more Phospholipases A 2 (PLA 2 ) are key enzymes in membrane metabolism. The release of fatty acids and lysophospholipids by PLA 2 activates several intra-cellular second messenger cascades that regulate a wide variety of physiological responses. The aim of the present study is to describe a radioenzymatic assay to determine the activity of three main PLA 2 subtypes in platelets, namely extracellular calciumdependent PLA 2 (sPLA 2 ) and intracellular calcium-dependent (cPLA 2 ) and calcium-independent PLA 2 (iPLA 2 ). The differentiation of these distinct PLA 2 subtypes was based on the enzyme substrate preference (arachdonic acid or palmitoyl acid) and calcium concentration. Our results indicate that this new assay is feasible, precise and specific to measure the activity of the aforementioned subtypes of PLA 2 . Therefore, this protocol can be used to investigate modifications of PLA 2 homeostasis in distinct biological models addressing the pathophysiology of many medical and neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2010
Background: Arachidonic acid is released from cellular membranes by the action of phospholipase A... more Background: Arachidonic acid is released from cellular membranes by the action of phospholipase A 2 (PLA 2 ) and is implicated in microtubule-associated protein Tau phosphorylation. Tau hyperphosphorylation affects its ability to stabilize microtubules. Objective: To determine the effect of PLA 2 inhibition on the phosphorylation state of Tau phosphoepitopes in primary cultures of hippocampal neurons. Methods: 4 DIC neurons were incubated at different concentrations of methyl-arachidonylfluorophosphonate (MAFP), an irreversible inhibitor of cPLA 2 and iPLA 2 . Changes on Tau phosphorylation were determined by Western blotting with a panel of anti-Tau antibodies Ser199/202, Ser202/ 205, Ser396 and Ser214). Results: The Ser214 site was hyperphosphorylated upon MAFP treatment. Significant differences were observed with 10 mM (p ¼ 0.01), 50 mM (p ¼ 0.01) and 100 mM (p ¼ 0.05) of MAFP. Less-intense changes were found in other phosphoepitopes. Conclusion: The present findings indicate that the phosphorylation of Ser214 is regulated by c-and/or iPLA 2 , whereas other phosphoepitopes primarily regulated by GKS3b were not affected.
Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA), 2013
The phospholipase A2 (PLA2) enzymes have been implicated in several neuropsychiatry disorders and... more The phospholipase A2 (PLA2) enzymes have been implicated in several neuropsychiatry disorders and activity alterations have been described in brain and platelet. Since brain tissue is not readily available for the measurement of PLA2 activity, it would be of interest to test directly whether PLA2 activities in both tissues are correlated. We performed this task assessing PLA2 activity in platelets and hippocampus collected simultaneously from 19 patients undergoing temporal lobectomy for treatment of refractory epilepsy. Our findings suggest that total PLA2 activity in platelets may reflect the total activity of the enzyme in the brain (rs=0.59, p=0.008). However in our sample no correlations were found between the subgroups of the enzyme in brain and in platelets. This lack of correlations may be due to different effects of drug treatment on the PLA2 subtypes. In face of the difficulty to obtain brain tissues from living patients, further studies with larger drug-free samples are warranted to clarify whether the use of platelets is a reliable strategy to reflect the subtypes of PLA2 activity in the brain.
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Papers by Leda Talib