Cytokines role in neurodegenerative events.
ABSTRACT During the past decade, the concepts about the development and progression of neurodegenerative diseases, as well as of neurotoxic insults, have been completely revised mainly because of the recognition that most neurological disorders are the consequence of a complex relationship between glia and neurons. Following an insult to the CNS, glia becomes activated and releases new molecules not normally detectable in quiescent cells. Cytokines are among these molecules and have been implicated in the modulation of neurodegeneration. Here, tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) contribute to neurodegeneration and the molecular mechanisms involved will be shortly reviewed.
Article: Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor.[show abstract] [hide abstract]
ABSTRACT: Alterations in the inflammatory system have been associated with schizophrenia and major depression, while bipolar disorder has been less studied. Most previous studies examined small samples, and the literature is inconsistent with regard to specific underlying immune mechanisms. In the present study, we examined markers representing different inflammatory pathways, and the aim was to investigate whether the levels of inflammatory parameters in a representative sample of bipolar disorder and schizophrenia are elevated compared to healthy controls, and to investigate whether the inflammatory profile is different between the groups. Plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), high-sensitivity CRP (hs-CRP), soluble CD40L ligand (sCD40L), and von Willebrand factor (vWf) were measured with ELISA techniques in a catchment area based sample of consecutively referred patients with severe mental disorders [N = 311, comprising bipolar disorder (n = 125) and schizophrenia (n = 186)] and in healthy volunteers (n = 244). Plasma levels of sTNF-R1 and vWf were statistically significantly increased in both bipolar disorder and schizophrenia compared to controls (p < 0.00001), and were also increased in unmedicated patients, but there were no major differences between the two diagnostic groups. Controlling for age, gender, ethnicity, cardiovascular disorders, kidney and liver function, and other confounders did not affect the results. There were no differences in other inflammation factors between the groups. The present results indicate specific alterations of endothelium-related inflammation processes in both bipolar disorder and schizophrenia.Bipolar Disorders 11/2009; 11(7):726-34. · 5.29 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: There is increasing evidence that soluble factors in inflammatory central nervous system diseases not only regulate the inflammatory process but also directly influence electrophysiological membrane properties of neurons and astrocytes. In this context, the cytokine TNF-α (tumor necrosis factor-α) has complex injury promoting, as well as protective, effects on neuronal viability. Up-regulated TNF-α expression has also been found in various neurodegenerative diseases such as cerebral malaria, AIDS dementia, Alzheimer's disease, multiple sclerosis, and stroke, suggesting a potential pathogenic role of TNF-α in these diseases as well. We used the neuroblastoma cells SK-N-MC. Transcriptional activity was measured using luciferase reporter gene assays by using lipofectin. We performed cotransfection experiments of NFAT (nuclear factor of activated T cells) promoter constructed with a dominant negative version of NFAT (dn-NFAT). Cell death was performed by MTT (3-(4,5-dimethylthiazol-2-yl)5,5-diphenyltetrazolium bromide) and TUNEL assays. NFAT translocation was confirmed by Western blot. Involvement of NFAT in cell death was assessed by using VIVIT. P53, Fas-L, caspase-3, and caspase-9 expressions were carried out by Western blot. The mechanisms involved in TNF-α-induced cell death were assessed by using microarray analysis. TNF-α causes neuronal cell death in the absence of glia. TNF-α treatment results in nuclear translocation of NFAT through activation of calcineurin in a Ca(2+) independent manner. We demonstrated the involvement of FasL/Fas, cytochrome c, and caspase-9 but the lack of caspase-3 activation. NB cell death was absolutely reverted in the presence of VIVIT, and partially diminished by anti-Fas treatment. These data demonstrate that TNF-α promotes FasL expression through NFAT activation in neuroblastoma cells and this event leads to increased apoptosis through independent caspase-3 activation.PLoS ONE 01/2011; 6(1):e16100. · 4.09 Impact Factor
Article: Transcriptional responses of the nerve agent-sensitive brain regions amygdala, hippocampus, piriform cortex, septum, and thalamus following exposure to the organophosphonate anticholinesterase sarin.[show abstract] [hide abstract]
ABSTRACT: Although the acute toxicity of organophosphorus nerve agents is known to result from acetylcholinesterase inhibition, the molecular mechanisms involved in the development of neuropathology following nerve agent-induced seizure are not well understood. To help determine these pathways, we previously used microarray analysis to identify gene expression changes in the rat piriform cortex, a region of the rat brain sensitive to nerve agent exposure, over a 24-h time period following sarin-induced seizure. We found significant differences in gene expression profiles and identified secondary responses that potentially lead to brain injury and cell death. To advance our understanding of the molecular mechanisms involved in sarin-induced toxicity, we analyzed gene expression changes in four other areas of the rat brain known to be affected by nerve agent-induced seizure (amygdala, hippocampus, septum, and thalamus). We compared the transcriptional response of these four brain regions to sarin-induced seizure with the response previously characterized in the piriform cortex. In this study, rats were challenged with 1.0 × LD₅₀ sarin and subsequently treated with atropine sulfate, 2-pyridine aldoxime methylchloride, and diazepam. The four brain regions were collected at 0.25, 1, 3, 6, and 24 h after seizure onset, and total RNA was processed for microarray analysis. Principal component analysis identified brain region and time following seizure onset as major sources of variability within the dataset. Analysis of variance identified genes significantly changed following sarin-induced seizure, and gene ontology analysis identified biological pathways, functions, and networks of genes significantly affected by sarin-induced seizure over the 24-h time course. Many of the molecular functions and pathways identified as being most significant across all of the brain regions were indicative of an inflammatory response. There were also a number of molecular responses that were unique for each brain region, with the thalamus having the most distinct response to nerve agent-induced seizure. Identifying the molecular mechanisms involved in sarin-induced neurotoxicity in these sensitive brain regions will facilitate the development of novel therapeutics that can potentially provide broad-spectrum protection in five areas of the central nervous system known to be damaged by nerve agent-induced seizure.Journal of Neuroinflammation 07/2011; 8:84. · 3.83 Impact Factor