Publications by authors named "Erdem Tüzün"

206 Publications

Central Role of T Follicular Helper Cells in Myasthenia Gravis.

Noro Psikiyatr Ars 2021 Mar 16;58(1):68-72. Epub 2021 Jan 16.

Department of Ophthalmology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China.

Myasthenia gravis (gMG) is a critical autoimmune disease, which has a serious impact on the life and survival of patients. Ocular Myasthenia Gravis (oMG) is often the initial manifestation of MG and has the potential to progress to gMG. However, to date no distinct mechanism has been found to clarify the pathogenesis of conversion from oMG to gMG. Recent studies have shown that the development and clinical progression of MG is closely associated with the abnormal function of follicular helper T (Tfh) cells. Thus, this article reviews the recently achieved research progress on the involvement of Tfh cells in MG immunopathogenesis and focuses on the role of Tfh cells and related-factors (IL-21, CXCL13, CXCR5, bcl-6 etc.) in germinal center formation and antibody production in MG immune response.
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http://dx.doi.org/10.29399/npa.27193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980705PMC
March 2021

Association of the kynurenine pathway metabolites with clinical, cognitive features and IL-1β levels in patients with schizophrenia spectrum disorder and their siblings.

Schizophr Res 2021 Feb 17;229:27-37. Epub 2021 Feb 17.

Department of Psychiatry, Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address:

Objective: There is evidence suggesting that tryptophan (TRP)-kynurenine (KYN) pathway dysregulation is involved in the pathophysiology of schizophrenia and is regulated by inflammatory cytokines. The study investigate for the first time whether this dysregulation occurs in advanced stages of the disease as a byproduct or emerges as one of the early and inherited manifestations of schizophrenia.

Method: Sera of 148 patients with schizophrenia spectrum disorders (SCZ), 139 unaffected siblings (SIB) and 210 controls were investigated. Serum interleukin (IL)-1β levels were measured by ELISA, and TRP, KYN and kynurenic acid (KYNA) levels were measured by a high-performance liquid chromatography system. Also, we collected clinical data by applying Comprehensive Assessment of Symptoms and History in SCZ, and SIS-R in SIB and control groups.

Results: Compared to controls, SCZ and SIB groups had lower TRP and higher KYNA levels. TRP levels showed significant differences only between SCZ and controls (p < 0.01). KYNA levels of both SCZ (p ≤ 0.001) and SIB (p < 0.05) were higher than controls. No statistical significance was found for KYN levels across groups. SCZ and SIB groups had higher serum IL-1β levels than controls (p ≤ 0.001).

Conclusions: Patients with SCZ and their siblings exhibited similar clinical features and TRP metabolite levels suggesting that TRP-KYN dysregulation may be an inherited component of the disease putatively conferring increased risk to schizophrenia. Elevation of IL-1β is one of the factors promoting overconsumption of the TRP-KYN pathway leading to increased production of neuroregulatory KYNA and presumably to neurodegeneration.
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http://dx.doi.org/10.1016/j.schres.2021.01.014DOI Listing
February 2021

Common Denominators in the Immunobiology of IgG4 Autoimmune Diseases: What Do Glomerulonephritis, Pemphigus Vulgaris, Myasthenia Gravis, Thrombotic Thrombocytopenic Purpura and Autoimmune Encephalitis Have in Common?

Front Immunol 2020 29;11:605214. Epub 2021 Jan 29.

Neuroimmunology, Institute of Clinical Chemistry and Department of Neurology, Medical Faculty, Christian-Albrechts-University Kiel, Kiel, Germany.

IgG4 autoimmune diseases (IgG4-AID) are an emerging group of autoimmune diseases that are caused by pathogenic autoantibodies of the IgG4 subclass. It has only recently been appreciated, that members of this group share relevant immunobiological and therapeutic aspects even though different antigens, tissues and organs are affected: glomerulonephritis (kidney), pemphigus vulgaris (skin), thrombotic thrombocytopenic purpura (hematologic system) muscle-specific kinase (MuSK) in myasthenia gravis (peripheral nervous system) and autoimmune encephalitis (central nervous system) to give some examples. In all these diseases, patients' IgG4 subclass autoantibodies block protein-protein interactions instead of causing complement mediated tissue injury, patients respond favorably to rituximab and share a genetic predisposition: at least five HLA class II genes have been reported in individual studies to be associated with several different IgG4-AID. This suggests a role for the HLA class II region and specifically the DRβ1 chain for aberrant priming of autoreactive T-cells toward a chronic immune response skewed toward the production of IgG4 subclass autoantibodies. The aim of this review is to provide an update on findings arguing for a common pathogenic mechanism in IgG4-AID in general and to provide hypotheses about the role of distinct HLA haplotypes, T-cells and cytokines in IgG4-AID.
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http://dx.doi.org/10.3389/fimmu.2020.605214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878376PMC
January 2021

The search for an autoimmune origin of psychotic disorders: Prevalence of autoantibodies against hippocampus antigens, glutamic acid decarboxylase and nuclear antigens.

Schizophr Res 2021 Feb 11;228:462-471. Epub 2021 Feb 11.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address:

The etiology of psychotic disorders is still unknown, but in a subgroup of patients symptoms might be caused by an autoimmune reaction. In this study, we tested patterns of autoimmune reactivity against potentially novel hippocampal antigens. Serum of a cohort of 621 individuals with psychotic disorders and 257 controls were first tested for reactivity on neuropil of rat brain sections. Brain reactive sera (67 diseased, 27 healthy) were further tested for antibody binding to glutamic acid decarboxylase (GAD) isotype 65 and 67 by cell-based assay (CBA). A sub-cohort of 199 individuals with psychotic disorders and 152 controls was tested for the prevalence of anti-nuclear antibodies (ANA) on HEp2-substrate as well as for reactivity to double-stranded DNA, ribosomal P (RPP), and cardiolipin (CL). Incubation of rat brain with serum resulted in unidentified hippocampal binding patterns in both diseased and control groups. Upon screening with GAD CBA, one of these patterns was identified as GAD65 in one individual with schizophrenia and also in one healthy individual. Two diseased and two healthy individuals had low antibody levels targeting GAD67 by CBA. Antibody reactivity on HEp-2-substrate was increased in patients with schizoaffective disorder, but only in 3 patients did antibody testing hint at a possible diagnosis of systemic lupus erythematosus. Although reactivity of serum to intracellular antigens might be increased in patients with psychotic disorder, no specific targets could be identified. GAD antibodies are very rare and do not seem increased in serum of patients with psychotic disorders.
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http://dx.doi.org/10.1016/j.schres.2020.12.038DOI Listing
February 2021

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson's disease patients.

Sci Rep 2021 Jan 27;11(1):2316. Epub 2021 Jan 27.

Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

Our aim was to identify the differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMC) of Parkinson's disease (PD) patients and healthy controls by microarray technology and analysis of related molecular pathways by functional annotation. Thirty PD patients and 30 controls were enrolled. Agilent Human 8X60 K Oligo Microarray was used for gene level expression identification. Gene ontology and pathway enrichment analyses were used for functional annotation of DEGs. Protein-protein interaction analyses were performed with STRING. Expression levels of randomly selected DEGs were quantified by real time quantitative polymerase chain reaction (RT-PCR) for validation. Flow cytometry was done to determine frequency of regulatory T cells (Tregs) in PBMC. A total of 361 DEGs (143 upregulated and 218 downregulated) were identified after GeneSpring analysis. DEGs were involved in 28 biological processes, 12 cellular components and 26 molecular functions. Pathway analyses demonstrated that upregulated genes mainly enriched in p53 (CASP3, TSC2, ATR, MDM4, CCNG1) and PI3K/Akt (IL2RA, IL4R, TSC2, VEGFA, PKN2, PIK3CA, ITGA4, BCL2L11) signaling pathways. TP53 and PIK3CA were identified as most significant hub proteins. Expression profiles obtained by RT-PCR were consistent with microarray findings. PD patients showed increased proportions of CD49d Tregs, which correlated with disability scores. Survival pathway genes were upregulated putatively to compensate neuronal degeneration. Bioinformatics analysis showed an association between survival and inflammation genes. Increased CD49d Treg ratios might signify the effort of the immune system to suppress ongoing neuroinflammation.
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http://dx.doi.org/10.1038/s41598-021-81961-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841172PMC
January 2021

Serum levels of inflammasome pathway factors in clinically isolated syndrome and multiple sclerosis patients: a pilot study.

Cent Eur J Immunol 2020 27;45(2):237-240. Epub 2020 Jul 27.

Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

Pathogenic roles of nuclear factor κB (NF-κB) pathway and NLRP3 inflammasome complex factors are involved in multiple sclerosis (MS) development. Activation of the NF-κB, NLRP3, and caspase-1 cascade results in production of proinflammatory cytokines that lead to stimulation of macrophages, lymphocytes, and glial cells. Although increased levels of inflammasome complex factors are observed in MS, contribution of inflammasome pathway to conversion from clinically isolated syndrome (CIS) to relapsing remitting MS (RRMS) has been scarcely investigated. To examine predictive value of inflammasome factors in CIS-MS conversion, levels of NLRP3, caspase-1, and NFκB are measured by ELISA in sera of age-gender matched CIS (n = 18; 8 converting, 10 non-converting) and RRMS (n = 23) patients. CIS and RRMS patients have comparable serum levels of NLRP3, caspase-1, and NFκB. Similarly, no statistically significant difference can be found among converting and non-converting CIS patients by means of inflammasome complex factor levels. Inflammasome factors are presumably overexpressed at early stages of MS. Therefore, they are unlikely to be used as biomarkers to predict CIS-MS conversion.
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http://dx.doi.org/10.5114/ceji.2020.96877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792443PMC
July 2020

Adaptive immunity cells are differentially distributed in the peripheral blood of glycine receptor antibody-positive patients with focal epilepsy of unknown cause.

Epilepsy Res 2021 Feb 25;170:106542. Epub 2020 Dec 25.

Neuroscience Department, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

Aim: Glycine receptor (GlyR) autoantibodies (Ab) have been recently detected in epilepsy patients. Our study aimed to investigate the peripheral blood distribution of B and T cell subgroups responsible for antibody production to find clues supporting the distinct organization of adaptive immunity in focal epilepsy of unknown cause (FEUC).

Method: Seven GlyR-Ab positive and 15 GlyR-Ab negative FEUC patients and 25 age-sex matched healthy individuals were included. Peripheral blood mononuclear cells were isolated and immunophenotyped by flow cytometry.

Results: There were no significant differences between CD19 B, CD3 T, CD4 helper T, CD8 cytotoxic T, and CD19CD24CD38 regulatory B cell ratios among the groups. GlyR-Ab negative epilepsy patients had significantly higher CD19IgDCD27 naive B cells and GlyR-Ab positive patients showed reduced percentages of CD19CD38CD138 plasma cells than healthy controls. By contrast, GlyR-Ab positive patients exhibited significantly increased CD3CD4CD25regulatory T (Treg) cells and CD3CD4CD25CD127 Treg cells and relatively increased CD19IgD-CD27 memory B cells without attaining statistical significance.

Conclusion: The increase of Tregs, which are capable of suppressing B cells, maybe a compensating countermeasure to prevent the conversion of effector B cell subgroups. Thus, our findings lend support to the involvement of adaptive immunity in focal epilepsy of unknown cause.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106542DOI Listing
February 2021

CSF levels of HoxB3 and YKL-40 may predict conversion from clinically isolated syndrome to relapsing remitting multiple sclerosis.

Mult Scler Relat Disord 2021 Feb 17;48:102697. Epub 2020 Dec 17.

Department of Neurology, Istanbul Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey.

Introduction: Multiple sclerosis (MS) often initiates with an acute episode of neurological disturbance, known as clinically isolated syndrome (CIS). There is an unmet need for biomarkers that differentiate patients who will convert to MS and who will remain as CIS after the first attack.

Methods: First attack serum and cerebrospinal fluid (CSF) samples of 33 CIS patients were collected and these patients were divided as those who converted to MS (CIS-MS, n=17) and those who continued as CIS (CIS-CIS, n=16) in a 3-year follow-up period. Levels of homeobox protein Hox-B3 (HoxB3) and YKL-40 were measured by ELISA in samples of CIS-CIS, CIS-MS, relapsing remitting MS (RRMS) patients (n=15) and healthy controls (n=20).

Results: CIS-CIS patients showed significantly reduced CSF levels of YKL-40 and increased serum/CSF levels of HoxB3 compared with CIS-MS and RRMS patients. CIS-MS and RRMS patients had comparable YKL-40 and HoxB3 level profiles. Receiver operating characteristic (ROC) curve analysis showed the highest sensitivity for CSF HoxB3 measurements in prediction of CIS-MS conversion. Kaplan-Meier analysis demonstrated that CIS patients with lower CSF HoxB3 (<3.678 ng/ml) and higher CSF YKL-40 (>654.9 ng/ml) displayed a significantly shorter time to clinically definite MS.

Conclusion: CSF levels of HoxB3 and YKL-40 appear to predict CIS to MS conversion, especially when applied in combination. HoxB3, which is a transcription factor involved in immune cell activity, stands out as a potential candidate molecule with biomarker capacity for MS.
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http://dx.doi.org/10.1016/j.msard.2020.102697DOI Listing
February 2021

A Case of HaNDL with Low Cerebrospinal Fluid Level of Neurofilament Light Chain.

Case Rep Neurol 2020 Sep-Dec;12(3):334-338. Epub 2020 Oct 2.

Department of Neurology, Haseki Research and Training Hospital, Health Sciences University, Istanbul, Turkey.

Diagnosis of the syndrome of headache and neurological deficits with cerebrospinal fluid (CSF) lymphocytosis (HaNDL) is based on clinical features, and no diagnostic biomarkers are available. We present a case presenting with characteristic features of HaNDL and an MRI lesion in the splenium of corpus callosum. CSF neurofilament light chain (NFL) levels were assessed in this patient together with 7 additional HaNDL patients, 18 multiple sclerosis (MS) patients, and 15 primary headache patients. Both HaNDL and primary headache patients showed significantly lower NFL levels than MS patients. Our results suggest that increased CSF levels of NFL and neuroaxonal loss are not characteristic features of HaNDL. Neurological disorders mimicking HaNDL often present with increased levels of NFL, and thus CSF measurement of NFL might be useful in differential diagnosis of HaNDL.
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http://dx.doi.org/10.1159/000508944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588683PMC
October 2020

Expression of Akt1 and p-Akt1 in peripheral T cell subsets of multiple sclerosis patients.

Acta Neurol Belg 2020 Oct 9. Epub 2020 Oct 9.

Department of Immunology, Istanbul University, Aziz Sancar Institute of Experimental Medicine, Vakif Gureba C. Fatih, Istanbul, Turkey.

Multiple sclerosis is an autoimmune disorder induced by the infiltration of autoreactive immune cells into the central nervous system. Akt/PKB signaling pathway is crucially involved in T cell development and survival. We aimed to determine whether Akt1 expression levels of regulatory T (Treg) cells are altered in MS and are associated with disease activity. Relapsing-remitting multiple sclerosis (RR-MS, n = 17) patients and healthy individuals (n = 20) were enrolled. Peripheral blood mononuclear cells were isolated and anti-CD3, -CD4, -CD8, -CD25, -CD127 monoclonal antibodies were used to identify the T cell subsets. After stimulation with phorbol myristate acetate/ionomycin, the Akt1 and phosphorylated-Akt1 (p-Akt1) levels of T cell subsets were detected with intracellular staining using flow cytometry. Total Akt1 and p-Akt1 expression levels were found to be suppressed in CD4T cell and Treg populations of RR-MS patients. Progression indices were positively correlated with Akt1 expression levels of Tregs indicating that the Akt pathway might partake in the progression of multiple sclerosis. Flow cytometry may effectively be used for the evaluation of the Akt pathway activity. Our findings suggest that the magnitude of suppression of the Akt pathway might serve as a biomarker for the prognosis of multiple sclerosis.
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http://dx.doi.org/10.1007/s13760-020-01518-9DOI Listing
October 2020

Determination of Paraneoplastic neuropathy in newly diagnosed breast tumor patients.

eNeurologicalSci 2020 Dec 19;21:100265. Epub 2020 Aug 19.

Department of Pathology, Health Sciences University Haydarpasa Numune Education and Research Hospital, Turkey.

Objective: The presence of paraneoplastic neuropathy in newly diagnosed breast tumor patients will be investigated. Aim of study is conduce of early diagnosis of the disease and new biomarkers responsible for the pathogenesis to be identify.

Materials And Methods: Thirty-two patients admitted to the Oncology outpatient clinic with newly diagnosed breast cancer were included in the study. After the neurological examination of the patients, Lanss neuropathic pain scale and blood tests were performed. Before chemotherapy all patients underwent electromyography (EMG). Two tubes of 5 cc of venous blood were obtained by screening onconeuronal antibodies.

Results: Patients included in the study; 1 (3.1%) grade 1, 14 (43.8%) grade 2, 17 (53.1%) grade 3 invasive breast cancer was diagnosed. Perineural invasion was detected in 5 (15.6%) patients. Progesterone receptor positivity was found in 26 (81.2%) patients and estrogen receptor positivity was found in 27 (84.4%) patients. In 7 (21.9%) patients, CERBB2 was positive for Ki 67 in 25 (78.1%) patients. Neuropathic findings were present in 6 (18.8%) patients. Sensory neuropathy was detected by electrophsiologic tests in only 2 (6.2%) patients. A total of 12 (37.5%) patients had onconeuroneal antibody positivity. Antibody positivity was significantly higher in patients with high grade tumor ( = 0.008).

Conclusion: Paraneoplastic neuropathies can be confused with neuropathies due to non-cancerous causes both clinically and electrophysiologically. When approaching paraneoplastic neuropathies, pathological findings should be carefully reviewed and evaluated with other findigs.It should be remembered that an underlying breast tumor may be present in women with cancer-related neuropathic complaints.
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http://dx.doi.org/10.1016/j.ensci.2020.100265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494455PMC
December 2020

Peripheral blood expression levels of inflammasome complex components in two different focal epilepsy syndromes.

J Neuroimmunol 2020 10 22;347:577343. Epub 2020 Jul 22.

Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

Background: Although the role of inflammation in epilepsy pathogenesis has been extensively investigated, the inflammasome complex, a key component of neuroinflammation, has been understudied in epilepsy patients.

Methods: To better understand the involvement of this system in epilepsy, levels of inflammasome complex components (NLRP1, NLRP3, CASP1, ASC), end-products of inflammasome complex activity [IL-1β, IL-18, nitric oxide synthase (NOS) isoforms] and other inflammatory factors (NFκB, IL-6, TNF-α) were measured in peripheral blood of patients with focal epilepsy of unknown cause (FEoUC) (n = 47), mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (n = 35) and healthy controls using real time qPCR and/or ELISA.

Results: Inflammasome complex associated factors were either downregulated or unchanged in epilepsy patients. Likewise, flow cytometry studies failed to show an increase in ratios of NLRP3-expressing CD3+ and CD14+ peripheral blood mononuclear cells (PBMC) in epileptic patients. Anti-neuronal antibody positive epilepsy patients showed increased NLRP1 and neuronal NOS mRNA expression levels, whereas patients under poly-therapy showed reduced serum inflammasome levels. FEoUC patients demonstrated increased PBMC NFκB mRNA expression levels and serum IL-1β and IL-6 levels. Both MTLE-HS and FEoUC patients displayed higher ratios of NFκB-expressing CD14+ PBMC than healthy controls.

Conclusions: Although previous clinical studies have implicated increased inflammasome complex expression levels in epilepsy, our results indicate suppressed inflammasome complex activity in the peripheral blood of focal epilepsy patients. Alternatively, the IL-6-NFκB signaling pathway, appears to be activated in focal epilepsy, suggesting that factors of this pathway might be targeted for future theranostic applications.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577343DOI Listing
October 2020

The cerebral blood flow deficits in Parkinson's disease with mild cognitive impairment using arterial spin labeling MRI.

J Neural Transm (Vienna) 2020 09 6;127(9):1285-1294. Epub 2020 Jul 6.

Institute of Biomedical Engineering, Bogazici University, Istanbul, Turkey.

Parkinson's disease (PD) with mild cognitive impairment (PD-MCI) is currently diagnosed based on an arbitrarily predefined standard deviation of neuropsychological test scores, and more objective biomarkers for PD-MCI diagnosis are needed. The purpose of this study was to define possible brain perfusion-based biomarkers of not only mild cognitive impairment, but also risky gene carriers in PD using arterial spin labeling magnetic resonance imaging (ASL-MRI). Fifteen healthy controls (HC), 26 cognitively normal PD (PD-CN), and 27 PD-MCI subjects participated in this study. ASL-MRI data were acquired by signal targeting with alternating radio-frequency labeling with Look-Locker sequence at 3 T. Single nucleotide polymorphism genotyping for rs9468 [microtubule-associated protein tau (MAPT) H1/H1 versus H1/H2 haplotype] was performed using a Stratagene Mx3005p real-time polymerase chain-reaction system (Agilent Technologies, USA). There were 15 subjects with MAPT H1/H1 and 11 subjects with MAPT H1/H2 within PD-MCI, and 33 subjects with MAPT H1/H1 and 19 subjects with MAPT H1/H2 within all PD. Voxel-wise differences of cerebral blood flow (CBF) values between HC, PD-CN and PD-MCI were assessed by one-way analysis of variance followed by pairwise post hoc comparisons. Further, the subgroup of PD patients carrying the risky MAPT H1/H1 haplotype was compared with noncarriers (MAPT H1/H2 haplotype) in terms of CBF by a two-sample t test. A pattern that could be summarized as "posterior hypoperfusion" (PH) differentiated the PD-MCI group from the HC group with an accuracy of 92.6% (sensitivity = 93%, specificity = 93%). Additionally, the PD patients with MAPT H1/H1 haplotype had decreased perfusion than the ones with H1/H2 haplotype at the posterior areas of the visual network (VN), default mode network (DMN), and dorsal attention network (DAN). The PH-type pattern in ASL-MRI could be employed as a biomarker of both current cognitive impairment and future cognitive decline in PD.
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http://dx.doi.org/10.1007/s00702-020-02227-6DOI Listing
September 2020

Effects of Teriflunomide on B Cell Subsets in MuSK-Induced Experimental Autoimmune Myasthenia Gravis and Multiple Sclerosis.

Immunol Invest 2020 Jun 29:1-14. Epub 2020 Jun 29.

Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University , Istanbul, Turkey.

Antigen-specific immune responses are crucially involved in both multiple sclerosis (MS) and myasthenia gravis (MG). Teriflunomide is an immunomodulatory agent approved for treatment of MS through inhibition of lymphocyte proliferation. MG associated with muscle-specific tyrosine kinase (MuSK) antibodies often manifests with a severe disease course, prompting development of effective treatment methods. To evaluate whether teriflunomide treatment may ameliorate MuSK-autoimmunity, experimental autoimmune MG (EAMG) was induced by immunizing C57BL/6 (B6) mice three times with MuSK in complete Freund's adjuvant (CFA) (n = 17). MuSK-immunized mice were treated daily with teriflunomide (n = 8) or PBS (n = 9) starting from the third immunization (week 8) to termination (week 14). Clinical severity of EAMG was monitored. Immunological alterations were evaluated by measurement of anti-MuSK IgG, neuromuscular junction deposits, and flow cytometric analysis of lymph node cells. In MS patients under teriflunomide treatment, the peripheral blood B cell subset profile was analyzed. B6 mice treated with teriflunomide displayed relatively preserved body weight, lower EAMG prevalence, reduced average clinical grades, higher inverted screen scores, diminished anti-MuSK antibody and NMJ deposit levels. Amelioration of EAMG findings was associated with reduced memory B cell ratios in the lymph nodes. Similarly, MS patients under teriflunomide treatment showed reduced memory B cell, plasma cell, and plasmablast ratios. Teriflunomide treatment has effectively ameliorated MuSK-autoimmunity and thus may putatively be used in long-term management of MuSK-MG as an auxiliary treatment method. Teriflunomide appears to exert beneficial effects through inhibition of effector B cells.
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http://dx.doi.org/10.1080/08820139.2020.1785491DOI Listing
June 2020

Co-existence of multiple sclerosis and anti-NMDA receptor encephalitis: A case report and review of literature.

Mult Scler Relat Disord 2020 Jul 30;42:102075. Epub 2020 Apr 30.

Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a serious autoimmune disorder characterized by psychiatric symptoms, seizures and movement disorder. Predisposing factors have been reported since the time it was described, and its pathophysiology has been tried to be clarified over the years. Although overlap with other demyelinating diseases had been reported, such an association between Multiple Sclerosis (MS) anti ANTİ-NMDAR encephalitis is limited to only a few case reports. In this article, a patient diagnosed with relapsing remitting multiple sclerosis (RRMS) for ten years who then developed NMDA-R encephalitis while on disease modifying treatment will be presented and possible common pathophysiology with previously reported literature will be discussed.
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http://dx.doi.org/10.1016/j.msard.2020.102075DOI Listing
July 2020

Laboratory and clinical correlates of brain atrophy in Neuro-Behçet's disease.

J Neurol Sci 2020 Jul 19;414:116831. Epub 2020 Apr 19.

Department of Neurology, İstanbul Faculty of Medicine, İstanbul University, İstanbul, Turkey.

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http://dx.doi.org/10.1016/j.jns.2020.116831DOI Listing
July 2020

Glial fibrillary acidic protein (GFAP)-antibody in children with focal seizures of undetermined cause.

Acta Neurol Belg 2020 Apr 24. Epub 2020 Apr 24.

Department of Neuroscience, Aziz Sancar Institute for Experimental Medical Research, Istanbul University, Istanbul, Turkey.

Anti-neuronal antibodies that are related with autoimmune encephalitis syndromes may also be found in children with new onset seizures or chronic epilepsy. To unravel the significance of autoimmune astrocytopathy in epilepsy, we investigated serum antibody to glial fibrillary acidic protein (GFAP), another autoantigen described in autoimmune encephalitis with seizures, in 38 children with focal seizures of undetermined cause. GFAP antibody was screened with cell based assay and indirect immunohistochemistry and was found in two boys with normal brain MRI and unrevealing medical history prior to seizures. The 2-year-old boy had chronic treatment-resistant frontal lobe epilepsy. The 2.5-year-old boy had a single episode of focal seizures and remained seizure free thereafter in a follow-up period of 4 years. Nevertheless, he showed severe cognitive and language impairment. These results suggest that autoimmune astrocytopathy may be present in some epilepsy patients. Whether this immune response is a bystander effect generated by seizure-induced astrocytosis or directly involved in epileptogenesis needs to be further studied.
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http://dx.doi.org/10.1007/s13760-020-01361-yDOI Listing
April 2020

Serum glial fibrillary acidic protein (GFAP)-antibody in idiopathic intracranial hypertension.

Int J Neurosci 2020 Apr 28:1-5. Epub 2020 Apr 28.

Department of Neuroscience, Aziz Sancar Institute for Experimental Medical Research, Istanbul University, Istanbul, Turkey.

Idiopathic intracranial hypertension (IIH), a disease of obscure origin, is characterized by headache and visual disturbances due to increased intracranial pressure. Recent line of evidence has suggested involvement of inflammation in IIH pathogenesis thus bringing forward anti-glial autoimmunity as a potential contributor of IIH. Glial fibrillary acidic protein (GFAP) is a major astrocytic autoantigen associated with a specific form of meningoencephalitis. In this study, we investigated the presence of GFAP-antibody in 65 sera (49 obtained during active disease and 16 during remission) and in 15 cerebrospinal fluid (CSF) samples of 58 consecutively recruited IIH patients using cell based assay and indirect immunohistochemistry. GFAP-antibody was found in active period sera of 2 IIH patients with classical symptoms and good treatment response. Two remission period sera obtained at different time points from one of these cases showed lower titers of GFAP-antibody positivity. IgG from positive samples yielded an astrocytic immunoreactivity pattern. None of the CSF samples showed GFAP-antibodies. These results suggest that anti-astrocyte autoimmunity might be present in a fraction of IIH patients. Exact pathogenic significance of this association needs to be further studied.
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http://dx.doi.org/10.1080/00207454.2020.1758084DOI Listing
April 2020

[Episodes with goose bumps caused by anti-LGI-1 encephalitis].

Lakartidningen 2020 04 8;117. Epub 2020 Apr 8.

forskare, överläkare i neurologi,, Hässleholms sjukhus; institutionen för kliniska vetenskaper, Lunds universitet.

Anti-LGI-1 encephalitis is a type of autoimmune encephalopathy, where antibodies react against the cell surface protein leucine-rich glioma inactivated protein 1 (LGI-1). It presents with a subacute confusion, changes in behaviour, short-term memory deficits and seizures. A piloerectile semiology is common, which has been described as reflecting insular ictal activity. Patients may have temporal lobe abnormalities on brain MRI and EEG. More than half of the patients with limbic encephalitis associated with anti-LGI1 antibodies have hyponatremia. The diagnosis of anti-LGI-1 encephalitis can be made by the detection of antibodies against LGI-1 in serum and/or cerebrospinal fluid. Prompt diagnosis and treatment are important to avoid long-term disability. This case report describes a man with episodes of goose bumps and mild confusion caused by anti-LGI-1 encephalitis.
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April 2020

Small ubiquitin-related modifier (SUMO) 3 and SUMO4 gene polymorphisms in Parkinson's disease.

Neurol Res 2020 Jun 2;42(6):451-457. Epub 2020 Apr 2.

Istanbul Faculty of Medicine, Department of Neurology, Istanbul University, Istanbul, Turkey.

: The ubiquitin/proteasome system is one of the main axes of the pathogenesis of Parkinson's disease (PD). Small ubiquitin-related modifier (SUMO) proteins are involved in many biochemical events including regulation of transcriptional activity, modulation of signal transduction pathways, and response to cellular stress indicating a role for SUMO in the ubiquitin/proteasome system.: In this study, our aim was to examine the prevalence of SUMO gene variants and their clinical associations in PD. Fifty-four consecutively recruited PD patients (34 male, 20 female) and 74 age-gender matched healthy controls (37 male, 37 female) were included. SUMO1, 2, 3 and 4 genes were screened by a next generation sequencing method using blood samples of participants. Single nucleotide polymorphisms (SNPs) with a significantly altered prevalence were determined by Bonferroni correction.: Two SNPs in the SUMO4 gene ( and ) and two SNPs in the SUMO3 gene ( and ) were found to have altered prevalence in PD. Although there was no association among these SNPs and clinical features of the patients, an increased family history of cancer was found in patients with SUMO3 gene variants.: Several SUMO SNPs were identified for the first time in PD patients suggesting that SUMO is involved in the pathophysiology of the disease. rs237025 has also been associated with diabetes mellitus indicating a pathogenic mechanism for SUMO that is shared with other degenerative disorders.
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http://dx.doi.org/10.1080/01616412.2020.1724464DOI Listing
June 2020

NLRP1-Mediated Antidepressant Effect of Ketamine in Chronic Unpredictable Mild Stress Model in Rats.

Psychiatry Investig 2020 Apr 24;17(4):283-291. Epub 2020 Mar 24.

Department of Pharmacology, Kocaeli University School of Medicine, Kocaeli, Turkey.

Objective: NOD-like receptor protein 1 (NLRP1) inflammasome complex has been recently associated with chronic unpredictable mild stress (CUMS) model of depression. Our aim was to investigate whether ketamine-induced antidepressant effect is associated with suppression of NLRP1.

Methods: Wistar albino rats were divided into control, CUMS, CUMS+acute ketamine (a single 10 mg/kg dose) and CUMS+chronic ketamine (daily 10 mg/kg injections for 3 weeks) groups (n=10 for each group). Sucrose preference test and forced swimming test were performed to assess anhedonia and immobility time respectively for the severety of depression symptoms. Brain tissues were dissected and prefrontal cortex and hippocampus regions were used for real-time polymerase chain reaction (PCR) and immunohistochemical analysis.

Results: CUMS procedure significantly induced depressive-like symptoms whereas both acute and chronic ketamine treatment ameliorated them. mRNA expression levels of NLRP1, caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), NF-κB, endothelial nitric oxide synthase, IL-1β, IL-6, toll-like receptor 4 (TLR-4) and purinergic 2×7 receptor (P2X7R) and numbers of Iba- 1+and GFAP+glial cells were reduced by acute and/or chronic ketamine treatment.

Conclusion: In the present study for the first time upstream and downstream elements of the NLRP1 inflammasome complex are shown to be suppressed by ketamine thus reinforcing the involvement of NLRP1 in the physiopathology of depression.
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http://dx.doi.org/10.30773/pi.2019.0189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176563PMC
April 2020

Neuroinflammation Mediators are Reduced in Sera of Parkinson's Disease Patients with Mild Cognitive Impairment.

Noro Psikiyatr Ars 2020 Mar 11;57(1):15-17. Epub 2019 Jul 11.

Department of Neurology, Istanbul Faculty of Medicine, İstanbul University, İstanbul, Turkey.

Introduction: Cognitive impairment is common in Parkinson's disease (PD) and PD patients with mild cognitive impairment (PD-MCI) are at increased risk of developing Parkinson's disease dementia (PDD). Reliable biomarkers are required for objective identification of cognitive decline in PD. In this pilot study, serum levels of well-known mediators of neuroinflammation were measured in PD patients with or without MCI to find out the involvement of neuroinflammation and microglial activation in PD-MCI.

Methods: 36 PD-MCI, 25 PD patients with normal cognition (PD-NC) and 19 healthy controls were recruited. Serum levels of NLR family pyrin domain containing 1 (NLRP1), NLRP3, caspase-1, NF-kB, IL-1b and IL-18 were measured by ELISA and a panel of neuropsychological tests was administered.

Results: PD-MCI patients showed significantly reduced levels of NF-kB, IL-1b and IL-18, whereas NLRP1, NLRP3 and caspase-1 levels were comparable among PD-NC and PD-MCI patients. IL-18 levels were positively correlated with Addenbrooke's Cognitive Examination-Revised and Symbol Digit Modalities Test scores.

Conclusion: Levels of several microglial activation mediators are reduced in PD-MCI patients inferring a protective role to certain inflammation factors against cognitive decline in PD.
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http://dx.doi.org/10.29399/npa.23624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024832PMC
March 2020

Nivolumab-induced autoantibody negative limbic encephalitis in a patient with Hodgkin lymphoma.

Leuk Lymphoma 2020 06 12;61(6):1519-1521. Epub 2020 Feb 12.

Department of Neurology, Haydarpasa Numune Training and Research Hospital, Saglik Bilimleri University, Istanbul, Turkey.

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http://dx.doi.org/10.1080/10428194.2020.1725508DOI Listing
June 2020

Impact of epilepsy on language and discourse: Two self-limited focal epileptic syndromes of childhood.

Epilepsy Behav 2020 01 2;102:106671. Epub 2019 Dec 2.

Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, İstanbul Universty, Istanbul, Turkey.

Self-limited focal epilepsy with centro-temporal spikes, also known as Rolandic epilepsy (RE), is a well-established focal epilepsy of childhood, characterized with language impairment. To investigate the relationship between language deficits and clinical parameters of self-limited focal epilepsies of childhood (SFEC), 21 patients with RE, 10 patients with childhood occipital epilepsy of Gastaut type (COE-G) (another SFEC that is not typically associated with language impairment), and 31 healthy controls were recruited. A broad panel of language tests also including narration sample was administered, and clinical features were documented. The language was significantly impaired in both RE and COE-G. Patients with COE-G showed worse scores than patients with RE in subtests measuring semantic functions. Clinical parameters were not associated with impaired language domains. Language impairment is experienced in different types of SFEC, emphasizing the broad representation of the language network. In SFEC, recent activity of epilepsy does not affect the severity of language dysfunction.
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http://dx.doi.org/10.1016/j.yebeh.2019.106671DOI Listing
January 2020

Plasma levels of inflammatory mediators in vestibular migraine.

Int J Neurosci 2020 Apr 24;130(4):330-335. Epub 2019 Oct 24.

Faculty of Medicine, Department of Neurology, Dokuz Eylül University, Izmir, Turkey.

Vestibular migraine (VM) is an under-recognized entity with substantial burden for the individual and society. The underlying mechanism of VM and its distinction from other migraine mechanisms still remain unclear. Inflammatory pathways have been suggested to contribute to vestibular migraine. Our aim was to further investigate the possible role of inflammation in the pathophysiology of VM. We recruited 30 patients with VM diagnosed according to ICHD-3 criteria and 50 gender- and age-matched controls. Blood samples were obtained from 11 VM patients during an attack and from 13 VM patients under prophylactic treatment. Plasma levels of calcitonin gene related peptide (CGRP), neurokinin A (NKA), substance P (SP), NLRP1, NLRP3, caspase-1, IL-1β, IL-6, TNF-α and NFκB were measured by ELISA. IL-6 levels were significantly reduced in VM patients, whereas levels of other inflammation parameters were comparable to those of healthy controls. Levels of inflammatory mediators were not correlated with clinical parameters. Likewise, there were no significant differences among VM patients with and without headache attack and prophylactic treatment. Our results argue against involvement of systemic inflammation in the pathophysiology of VM.
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http://dx.doi.org/10.1080/00207454.2019.1681994DOI Listing
April 2020

Cytokine-chemokine and cognitive profile of multiple sclerosis patients with predominant optic nerve and spinal cord involvement.

J Spinal Cord Med 2019 Sep 26:1-7. Epub 2019 Sep 26.

Department of Neurology, Haydarpasa Numune Education and Research Hospital , Istanbul , Turkey.

: Clinical disease activity in multiple sclerosis (MS) may manifest as predominant involvement of optic nerves and spinal cord, as exemplified by opticospinal multiple sclerosis (OSMS) often encountered in Asian countries. Our aim was to compare the clinical features, neuropsychological profile and cytokine/chemokine levels of patients with conventional MS (CMS) and MS presenting predominantly with spinal cord and optic nerve attacks (MS-SCON). Cross-sectional study. MS Outpatient Clinic. Fourteen MS-SCON patients, 20 CMS patients without myelitis and optic neuritis attacks and 21 healthy individuals. IL-8, IL-10, IFN-γ, IL-17 and TNF-α levels were measured by multiplex assay and CXCL2 and CXCL5 levels were measured by ELISA. A panel of neuropsychological tests, Beck depression inventory, 9-hole peg and timed 25-foot walk tests were employed. CMS and MS-SCON patients showed similar clinical features. Both CMS and MS-SCON patients displayed reduced IL-8 and CXCL2 and increased TNF-α levels, while IL-10 and CXCL5 levels were identical among all groups. Neuropsychological and motor function test performances of CMS and MS-SCON patients were highly comparable. CMS and MS-SCON present with similar clinical, neuropsychological and immunological features. Therefore, optic nerve and spinal cord-dominant form of MS does not necessarily establish a distinct entity in our region. Cognitive networks of the central nervous system may be damaged during the disease course of MS, despite the absence of cerebral or cerebellar clinical attacks.
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http://dx.doi.org/10.1080/10790268.2019.1666238DOI Listing
September 2019

Insomnia and Dysautonomia with Contactin-Associated Protein 2 and Leucine-Rich Glioma Inactivated Protein 1 Antibodies: A "Forme Fruste" of Morvan Syndrome?

Case Rep Neurol 2019 Jan-Apr;11(1):80-86. Epub 2019 Feb 28.

Department of Neuroscience, Aziz Sancar Institute of Experimental Medical Research, Istanbul University, Istanbul, Turkey.

Morvan syndrome (MoS) is typically characterized by neuromyotonia, sleep dysfunction, dysautonomia, and cognitive dysfunction. However, MoS patients with mild peripheral nerve hyperexcitability (PNH) or encephalopathy features have been described. A 46-year-old woman presented with a 2-month history of constipation, hyperhidrosis, and insomnia. Neurologic examination revealed muscle twitching and needle electromyography showed myokymic discharges in all limbs. No clinical or electrophysiological features of neuromyotonia were present. Although the patient denied any cognitive symptoms, neuropsychological assessment revealed executive dysfunction, while other cognitive domains were preserved. Cranial and spinal MRIs were unrevealing and tumor investigation proved negative. Polysomnography examination revealed total insomnia, which was partially reversed upon immune-modulatory therapy. Investigation of a broad panel of antibodies revealed serum leucine-rich glioma inactivated protein 1 and contactin-associated protein 2 antibodies. The features of this case indicate that the presentation of PNH syndromes may show significant variability and that MoS patients may not necessarily exhibit full-scale PNH and encephalopathy symptoms.
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http://dx.doi.org/10.1159/000497817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739709PMC
February 2019

Impact of fingolimod on CD4+ T cell subset and cytokine profile of relapsing remitting multiple sclerosis patients.

J Neuroimmunol 2019 12 11;337:577065. Epub 2019 Sep 11.

Department of Neuroscience, Aziz Sancar Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey.

Fingolimod inhibits the egress of lymphocytes from lymphatic tissues and also directly affects their functions by modulation of the sphingosine-1-phosphate receptor 1 (S1P1). Our aim was to evaluate the impact of fingolimod on diverse CD4+ T cell subsets, and cytokines. Sixty-six relapsing remitting multiple sclerosis (RRMS) patients were treated with oral fingolimod (0.5 mg) for 6 months, and blood samples were collected at baseline, 3 months, and 6 months. Serum levels of seven cytokines and five chemokines were measured by multiplex immunoassay, and frequencies of peripheral blood mononuclear cell subsets were assessed by flow cytometry, and compared with those of 60 healthy controls. CCL2 (p = 0.039), and CCL5 (p = 0.001) levels were significantly higher in fingolimod-treated patients than healthy controls, whereas end-of-study serum levels of IL-6, IL-8, IL-17A, IL-22, IL-23, TNF-α, CXCL10, and CXCL13 were comparable to the baseline levels. Six months of fingolimod treatment reduced CD3+ T cell (mean ± standard deviation, 72.9% ± 5.5 vs. 60.1% ± 11.1, p < 0.001), CD4+ T cell (62.2% ± 8.5 vs. 24.6% ± 12.9, p < 0.001), CD4+CD25hi regulatory T cell (Treg) (3.4% ± 1.3 vs. 2.0% ± 1.4, p < 0.01), and CD19+ B cell (13.2% ± 5.8 vs. 5.3% ± 2.7, p < 0.001) frequencies, while CD8+ T cells (31.8% ± 7.8 vs. 57.8% ± 13.2, p < 0.001) were increased, and NK and NKT cells remained unchanged. The proportions of intracytoplasmic IL-4, IL-10, IFN-γ, and TNF-α-producing T cells were increased, whereas IL-17-producing cells remained relatively constant as measured by flow cytometry. Fingolimod appears to primarily diminish lymphocyte subsets involved in antigen presentation (CD19+ B and CD4+ T cells) rather than immune cells (CD8+ T, NK, and NKT cells) in charge of host defense against pathogens. In contrast, a relative increase is observed in pro- and anti-inflammatory cytokine-producing T helper subsets (IFN-γ, TNF-α, IL-4, and IL-10-producing CD4+ T cells), suggesting that effector T cells are suppressed to a lesser degree by S1P1 modulation.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577065DOI Listing
December 2019

Diagnosing acute brain dysfunction due to sepsis.

Neurol Sci 2020 Jan 14;41(1):25-33. Epub 2019 Sep 14.

Department of Neuroscience, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.

Developments in the management of critically ill patients suffering organ dysfunctions have demonstrated that brain is the prominent organ to be effected during critical illness. Acute brain dysfunction due to pathologic neuroinflammatory processes associated with sepsis is commonly seen and related to morbidity and mortality in the ICU treatment. Studies reported that survivors of sepsis may suffer long-term cognitive dysfunction that affects quality of life. However, there are no specific approaches to diagnose acute brain dysfunction in the early phase to target protective measures. In recent years, imaging methods and biomarkers are the most important issues of studies. This review will address the current diagnostic approaches to acute brain dysfunction related to sepsis.
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http://dx.doi.org/10.1007/s10072-019-04069-xDOI Listing
January 2020

Antidepressant-like effects of agmatine and NOS inhibitors in chronic unpredictable mild stress model of depression in rats: The involvement of NLRP inflammasomes.

Brain Res 2019 12 10;1725:146438. Epub 2019 Sep 10.

Marmara University School of Pharmacy, Department of Pharmacology and Psychopharmacology Research Unit, Istanbul, Turkey. Electronic address:

Innate immunity activation in the central nervous system (CNS) is known to contribute to the development of depression through NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome assembly. Furthermore, administration of agmatine (AGM), a nitric oxide synthase (NOS) inhibitor, reverses stress-induced NLRP3 inflammasome activation in rats. We examined the effects of chronically-administered nitric oxide (NO) pathway modulating drugs on NLRP1/3-mediated neuroinflammatory responses and depressive-like behaviors in chronic unpredictable mild stress (CUMS) depression model of rats. CUMS model was applied to the adult male Sprague-Dawley rats for 6 weeks and the treatments were daily administered via intraperitoneal route in the last 3 weeks of CUMS procedure. Depressive-like behaviors were assessed by sucrose preference and forced swimming tests. The levels of NLRP inflammasome components (NLRP1, NLRP3, ASC, caspase-1 and IL-1β) were investigated in the prefrontal cortex by real time PCR and western blot methods. CUMS-induced depressive-like behaviors were coupled with the overactivation of NLRP1 and NLRP3 inflammasome sensors and increased levels of IL-1β. Depressive-like behaviors were ameliorated by chronic AGM and NOS inhibitor treatments. AGM and other NOS inhibitor treatments were found to be more effective in suppressing NLRP3 and NLRP1, respectively. All inhibitor reagents downregulated inflammasome components and IL-1β. These results suggest that both neuronal NLRP1 and microglial NLRP3 inflammasomes are involved in chronic stress-induced depressive-like behaviors. The antidepressant effects of AGM, iNOS and nNOS inhibitors are associated with the downregulation of CNS inflammasome expression levels. NO-pathway modulating drugs might provide novel therapeutic strategies for depression.
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http://dx.doi.org/10.1016/j.brainres.2019.146438DOI Listing
December 2019