Wyniki wyszukiwania - Biblioteka Nauki

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The role of astroglia and purinergic signaling in the early stages of EAE

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Koza K. , Sulkowski G. , Lenkiewicz A. , Struzynska L.

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nr 1

EN

In the CNS an intensive communication between neurons and glial cells occurs. Activation of astrocytes is observed under different pathological conditions, including multiple sclerosis, which results in overexpression of number of proteins, like GFAP and S-100β, which is involved in development of infl ammatory reaction. There is a growing number of evidence that different brain pathologies are characterized by very early active contribution of astrocytes to neurodegenerative axonal damage. Our study presents time-dependent analysis of astroglia-specifi c protein expression in different phases of EAE (from 4 to 25 days after immunization). The biphasic response of astroglia was observed ñ upregulation of both proteins, GFAP and S-100β, in the early stages of the disease and in the peak of the neurological defi cits in animals (10 dpi). Astrocytes build a network within the CNS and are connected by gap junctions, formed by connexins, mostly Cx43 which was shown to induce ATP release via hemichannels. In the cross-talk between astrocytes and neurons may be involved purinergic receptor P2X7, ATP-gated ion channel activated in pathological conditions and participating in regulation of infl ammatory response. In the EAE rats, in the early stages of the disease, we observed the enhanced level of Cx43 protein and P2X7R protein which was accompanied by changes in mRNA profi le. We conclude that early activation of astroglia in the inductive phase of EAE occurs which is connected with the overexpression of purinergic receptor P2X7. The results suggest that in MS/EAE pathology activation of astroglia in the preclinical stage, may contribute to the axonal damage and subsequent infl ammation, and that the purinergic signaling may play a role in both these phenomena.

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Alterations of dopamine transport and dopamine D2 receptor binding in rat brain as a consequences of total cerebral ischemia caused by cardiac arrest

88%

Waskiewicz J. , Sulkowski G. , Januszewski S. , Kapuscinski A. , Rafalowska U.

Acta Neurobiologiae Experimentalis

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1999

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tom 59

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nr 3

3

Astroglial reaction in the early asymptomatic phase of experimental autoimmune encephalomyelitis

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Grygorowicz T. , Sulkowski G. , Sulejczak D. , Lenkiewicz A. , Struzynska L.

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tom 69

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nr 3

EN

Under different pathological conditions activation of astrocytes of neuroprotective or neurotoxic nature is observed. There is a growing number of evidence that many pathological states of brain are characterized by very early active contribution of astrocytes to neurodegenerative axonal damage. Astroglia posses defense mechanisms against glutamate excitotoxicity (transporter systems) but may also contribute to the enhanced release of this potentially toxic amino acid trough exocytosis, P2X7 purinergic receptors, hemichannels or reversing of glutamate transporters. These cells are also a main source of ATP, active signaling molecule, which activates many purinergic receptors in brain, including P2X7R, which participates in development of infl ammation and neurodegeneration phenomena. The aim of this study was to investigate the expression of astroglia-specifi c proteins during the course of EAE using immunochemical and immunohistochemical analysis. We observed early activation of astroglia in the inductive phase of EAE (4 day p.i.) which was connected with overexpression of GFAP and S-100β. Expression of Cx43, protein that forms hemichannels was also enhanced so as the expression of P2X7R. Additionally, the level of GLT-1 glutamate transporter’s protein increase signifi cantly. The results suggest that in EAE pathology very early activation of astroglia takes place in the preclinical stage of the disease. The exact nature of this activation will be investigated.

4

Glutamate receptors antagonists attenuate neurological deficits and modulate neuroinflammation in Lewis rat subjected to experimental autoimmune encephalomyelitis

88%

Sulkowski G. , Dabrowska-Bouta B. , Chalimoniuk M. , Lenkiewicz A. , Struzynska L.

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tom 73

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nr 1

EN

Experimental autoimmune encephalomyelitis (EAE) is an animal model that mimics many aspects of multiple sclerosis (MS). Chronic or relapsing inflammation of the central nervous system results in the destruction of myelin sheath and cytokines play an important role in the pathogenesis of both MS and EAE. Myelin, oligodendrocytes and neurons are lost due to an inflammatory attack by leukocytes infiltrating the central nervous system (CNS) and releasing cytotoxic cytokines, anti CNS antibodies and large amounts of the excitatory neurotransmitter glutamate. Pharmacological studies have suggested that glutamate receptors mediate white matter injury in a variety of CNS diseases, including multiple sclerosis (MS). Memantine and amantadine are ionotropic glutamate receptors (iGluRs) antagonists. Memantine, a clinically applied drug with N-methyl-D-aspartate (NMDA) receptor antagonistic effects, dose-dependently ameliorates neurological deficits in Lewis rats subjected to experimental autoimmune encephalomyelitis (EAE). The aim of the present study was to investigate the effects of memantine and amantadine on the expression of proinflammatory cytokines such interleukin 1beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and various chemokines in the brain of EAE rats. Real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western Blot were used to analyze the cytokine profile. We noticed increased expression of array of cytokines in experimental group when compared to the control. Dramatic increase of IL-1β, IL-6, TNF-α, and chemokines concentration corresponding to the intensity of neurological symptoms and loss of weight was observed in EAE rats. Administration of iGluR antagonists at an advanced stage of unremitting EAE resulted in amelioration of the disease. Cytokine analysis revealed that memantine significantly decreased the expression of interleukins: IL-6 (65%), IL-1β (60%) and TNF-α (45%) whereas treatment with amantadine reduced only the expression of IL-6 (60%) and TNF-α (15%) when compared to EAE animals. These results show that antagonists of iGlu receptors modulate the course of the disease by reducing the expression of proinflammatory cytokines thereby confirming the involvement of glutamate receptors into pathological mechanisms operating during EAE. This study was supported by grant nr NN401620038 from Polish Ministry of Science and Higher Education

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The effect of a sphingosine-1-phosphate receptors modulator on the transcriptional profile of genes linked to glutamate homeostasis in the sporadic and genetic animal models of Alzheimer’s disease

88%

Wencel P. , Sulkowski G. , Dabrowska-Bouta B. , Strosznajder R. P. , Struzynska L.

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nr Suppl.1

EN

INTRODUCTION: Alzheimer’s disease (AD) is neurodegenerative disorder characterized by progressive memory impairment and cognitive failure which leads to dementia in aged population. Lots of data indicate glutamate-mediated neurotoxicity as a one of the pathomechanisms responsible for neuronal cell death during the course of AD. AIM(S): In this study, we examined the effect of fingolimod (FTY720‑modulator of sphingosine‑1‑phosphate receptors) on the transcription of genes involved in the homeostasis of glutamatergic system in animal models of AD. METHOD(S): 3‑ and 12‑month‑old (3M, 12M) FVB/ APP+ transgenic mice with the London (V717I) APP mutation were used in this study. Mice without the mutation (APP- ) were used as a control. The sporadic AD model was induced by injection of streptozotocin (STZ, icv. 2,5 mg/kg b.w.) in ACSF (vehicle) to 3M C57BL/6 mice. Animals received FTY720 (1mg/kg b.w.) or NaCl (vehicle) for 2 weeks. Brain cortex was isolated and qPCR methods were applied. RESULTS: Our results indicate a different model‑dependent profile of changes in gene expression. We observed significant upregulation of Slc17a7(VGluT1), Grin1(- GluN1), and Grm3 (mGluR3) gene expression in APP+ 12M mice. A significant elevation of Gria1(GluR‑1) and Grin1 (GluN1) mRNA levels with an accompanying decrease of Slc17a8 (VGluT3) and Grm5 (mGluR5) was observed in STZ mice. The administration of FTY720 led to a decrease in Gria2 (GluR-2) and Grm3 mRNA levels, as well as, an elevation of Slc1a3 (GluT‑1), Slc17a7, and Slc17a8 mRNA in STZ mice compared to appropriate controls. Transcriptional changes in vesicular glutamate transporters (Slc17a7 and Slc17a8) as well as glutamate receptors genes (Grin1, Gria1, Grm3,5) suggest that they may be involved in the mechanisms leading to AD. CONCLUSIONS: FTY720 may potentially modulate the expression of genes involved in homeostasis of the glutamatergic system in the model of sporadic AD. FINANCIAL SUPPORT: Supported by the National Science Centre grant no. NCN2014/15/B/NZ3/01049

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Glutamate excitotoxicity in pathogenesis of multiple sclerosis

88%

Sulkowski G. , Struzynska L. , Dabrowska-Bouta B. , Kwiatkowska-Pozer B. , Rafalowska U.

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tom 65

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nr 3

7

Effects of IFN-beta1a and IFN-beta1b treatment on the expression of cytokines, inducible NOS (NOS type II), and myelin proteins in animal model of multiple sclerosis

75%

Lubina-Dabrowska N. , Stepien A. , Sulkowski G. , Dabrowska-Bouta B. , Langfort J. , Chalimoniuk M.