Andrzej Glabinski - Academia.edu (original) (raw)
Papers by Andrzej Glabinski
Brain Sciences
Epilepsy is a common brain disorder characterized by a heterogenous etiology. Its main features a... more Epilepsy is a common brain disorder characterized by a heterogenous etiology. Its main features are recurrent seizures. Despite many clinical studies, about 30% of cases are refractory to treatment. Recent studies suggested the important role of immune-system elements in its pathogenesis. It was suggested that a deregulated inflammatory process may lead to aberrant neural connectivity and the hyperexcitability of the neuronal network. The aim of our study was the analysis of the expression of inflammatory mediators in a mouse model of epilepsy and their impact on the neurodegeneration process located in the brain. We used the KA-induced model of epilepsy in SJL/J mice and performed the analysis of gene expression and protein levels. We observed the upregulation of IL1β and CXCL12 in the early phase of KA-induced epilepsy and elevated levels of CCL5 at a later time point, compared with control animals. The most important result obtained in our study is the elevation of CXCL2 expressi...
Neurologia i Neurochirurgia Polska, 2012
FoxP3 (p < 0,001) by³y znamiennie mniejsze u chorych na RRMS. Stwierdzono ujemn¹ korelacjê pomiêd... more FoxP3 (p < 0,001) by³y znamiennie mniejsze u chorych na RRMS. Stwierdzono ujemn¹ korelacjê pomiêdzy stê¿eniem leptyny a MFC dla czynnika transkrypcyjnego FoxP3 w limfocytach nTreg u chorych na RRMS (r =-0,7; p < 0,05). Wnioski: Prozapalny profil adipocytokin i zmniejszenie odsetka limfocytów nTreg sugeruje ich udzia³ w przebiegu reakcji zapalnej u chorych na RRMS niezale¿nie od terapii kortykosteroidami. Korelacja pomiêdzy stê¿eniem leptyny i wskaŸnikiem MFC dla czynnika transkrypcyjnego FoxP3 w limfocytach nTreg u chorych na RRMS wskazuje na ha muj¹cy wp³yw leptyny na jego ekspresjê.
Journal of Immunological Methods, 2010
International Journal of Molecular Sciences, May 8, 2017
The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical fo... more The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). Tumor necrosis factor alpha (TNF-α) or interleukin 17 (IL-17) stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express Vascular cell adhesion molecule 1 (VCAM-1), the receptor responsible for inflammatory cell adhesion, which binds very late antigen 4 (VLA-4) on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-α and IL-17 on the adherence of Th17 cells to bEnd.3. The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.
The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical fo... more The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). TNF-a or IL-17 stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express VCAM-1, the receptor responsible for inflammatory cell adhesion, which binds VLA-4 on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-a and IL-17 on the adherence of Th17 cells to bEnd.3 The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This interaction between Th17 cells and the brain endothelium appears to be mediated by VCAM-1 and some chemotactic cytokines. This observation may suggest potential therapeutic...
Scandinavian Journal of Immunology, 2007
Chemokines and their receptors are important players in organism homeostasis, development and imm... more Chemokines and their receptors are important players in organism homeostasis, development and immune response to inflammatory stimuli. It has been recently confirmed that they are also involved in the development of several autoimmune diseases. In this study, we analysed the expression of two recently identified CC chemokine receptors, CCR7 and CCR8, in the central nervous system (CNS) and in peripheral tissues during chronic relapsing experimental autoimmune encephalomyelitis (ChREAE) -- an animal model of the human demyelinating disease multiple sclerosis (MS). We observed upregulation of both chemokine receptors in the CNS during the first and second attacks of ChREAE, whereas disease remission was characterized by a lower expression of those receptors. An analysis of the kinetics of CCR7 and CCR8 expression in the CNS during the first attack of the disease showed a constant increase in the first few days after the onset of clinical signs. This expression correlated with the clinical severity of ChREAE. CCR7-positive mononuclear cells were detected mostly in perivascular inflammatory cuffs in the CNS. In peripheral tissues (the spleen and kidneys) expression of both receptors was not upregulated during active ChREAE. These findings suggest that CCR7 and CCR8 may play a significant role in the pathogenesis of EAE and probably MS.
Journal of Neuroimmunology, 1994
The blood-brain barrier and immune cell homing to the CNS The blood-brain barrier (BBB) isolates ... more The blood-brain barrier and immune cell homing to the CNS The blood-brain barrier (BBB) isolates the CNS from the rest of the organism. The anatomic foundation of this structure is a syncytium of cerebrovascular endothelial cells sealed together by tight junctions. The endothelial basal lamina, located at the abluminal side of endothelium, borders the perivascular (Virchow-Robin) space. The perivascular space is continuous with the subarachnoid compartment and is itself bordered by the glia limitans, formed by astrocytic and microglial end feet. Within the perivascular space, on either side of the endothelial basal lamina, dwell a unique population of phagocytic cells variously termed perivascular macrophages, perivascular microglia, perivascular cells or pericytes. These cells form a ®rst line of defense once the BBB is breached. Astrocytes are also important for BBB development and function: their processes attach to the basement membrane shared with the endothelial cells and peri...
Aktualności Neurologiczne
Fingolimod jest pierwszym zarejestrowanym doustnym lekiem stosowanym w terapii stwardnienia rozsi... more Fingolimod jest pierwszym zarejestrowanym doustnym lekiem stosowanym w terapii stwardnienia rozsianego. Jego aktywny metabolit-fosforan fingolimodu poprzez działanie na receptory S1PR reguluje uwalnianie limfocytów z tkanek limfoidalnych do krążenia, wykazując efekt immunosupresyjny. Najnowsze badania dowodzą jednak, że na korzystny efekt działania fingolimodu składa się również wielopłaszczyznowe działanie neuroprotekcyjne. Fingolimod przenika przez barierę krew-mózg i wpływa na wykazujące ekspresję receptorów S1PR komórki ośrodkowego układu nerwowego: astrocyty, progenitory oligodendrocytów, mikroglej, a także neurony. Fingolimod pobudza produkcję czynników neurotroficznych oraz hamuje produkcję tlenku azotu przez komórki astrogleju, zmniejszając nasilenie proceu neurodegeneracji. Co więcej, zmniejsza ekspresję prozapalnych cytokin indukowanych przez TNF w astrocytach, zmniejszając ich potencjał prozapalny. Pobudza zarówno migrację, jak i proliferację komórek progenitorowych oligodendrocytów, będących źródłem oligodendrocytów-jedynych komórek ośrodkowego układu nerwowego zdolnych do syntezy mieliny. Leczenie fingolimodem znacząco nasila mechanizmy regeneracyjne w przebiegu autoimmunologicznego zapalenia mózgu i rdzenia kręgowego. Ponadto zmniejsza reaktywność mikrogleju i spowalnia związany z odpowiedzią zapalną proces nuerodegeneracji. Długotrwała aplikacja fingolimodu redukuje wrażliwość komórek nerwowych na czynniki neurotoksyczne, sugeruje bezpośrednie działanie neuroprotekcyjne. Obecnie w różnych fazach badań klinicznych znajdują się selektywne inhibitory poszczególnych podtypów receptorów dla S1P, pozbawione charakterystycznych dla fingolimodu działań niepożądanych oraz posiadające korzystniejsze właściwości farmakokinetyczne. Należą do nich: siponimod, ponesimod oraz ozanimod.
Nutrients
Epidemiological data indicate that a diet rich in plant polyphenols has a positive effect on brai... more Epidemiological data indicate that a diet rich in plant polyphenols has a positive effect on brain functions, improving memory and cognition in humans. Direct activity of ingested phenolics on brain neurons may be one of plausible mechanisms explaining these data. This also suggests that some phenolics can cross the blood-brain barrier and be present in the brain or cerebrospinal fluid. We measured 12 phenolics (a combination of the solid-phase extraction technique with high-performance liquid chromatography) in cerebrospinal fluid and matched plasma samples from 28 patients undergoing diagnostic lumbar puncture due to neurological disorders. Homovanillic acid, 3-hydroxyphenyl acetic acid and caffeic acid were detectable in cerebrospinal fluid reaching concentrations (median; interquartile range) 0.18; 0.14 µmol/L, 4.35; 7.36 µmol/L and 0.02; 0.01 µmol/L, respectively. Plasma concentrations of caffeic acid (0.03; 0.01 µmol/L) did not correlate with those in cerebrospinal fluid (ρ = ...
International Journal of Molecular Sciences
The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical fo... more The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). Tumor necrosis factor alpha (TNF-α) or interleukin 17 (IL-17) stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express Vascular cell adhesion molecule 1 (VCAM-1), the receptor responsible for inflammatory cell adhesion, which binds very late antigen 4 (VLA-4) on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-α and IL-17 on the adherence of Th17 cells to bEnd.3. The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.
The American Journal of Pathology, Feb 1, 1997
Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leu... more Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leukocytes. Two subfamilies, aand 3-cheemokines, have been described, based on structural, genetic, and functional considerations. In acute Supported by grant RO1NS32151 from the National Institutes of Health (R. M. Ransohoff) and grant FG 1079A1/T from the National Multiple Sclerosis Society (M. Tani). V. Tuohy is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society. R. Ransohoff's research is also supported by the Williams Family Fund for Multiple Sclerosis Research.
Methods in Enzymology, 1997
Experimental Models of Multiple Sclerosis, 2005
ABSTRACT
The American journal of pathology, 1997
Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leu... more Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leukocytes. Two subfamilies, alpha- and beta-chemokines, have been described, based on structural, genetic, and functional considerations. In acute experimental autoimmune encephalomyelitis (EAE), chemokines are up-regulated systemically and in central nervous system (CNS) tissues at disease onset. Functional significance of this expression was supported by other studies; intervention with an antichemokine antibody abrogated passive transfer of EAE, and chemokines expressed in brains of transgenic mice recruited appropriate leukocyte populations into the CNS compartment. Chemokine expression in the more relevant circumstance of chronic EAE has not been addressed. We monitored the time course and cellular sources of chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha, interferon-gamma-inducible protein of 10 kd, KC, and regulated on activation, normal T-ce...
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience
In this paper, we discuss the potential involvement of a new family of cytokines, termed chemokin... more In this paper, we discuss the potential involvement of a new family of cytokines, termed chemokines, in CNS inflammatory pathology. Chemokines are a family of proinflammatory cytokines which are able to stimulate target-cell-specific directional migration of leukocytes. Because of this feature, chemokines may be potent mediators of inflammatory processes. We have previously reported observations indicating that chemokines may be involved in the process of lesion formation during autoimmune inflammation within CNS, and, in particular, are likely participants in the process of influx of inflammatory cells into the CNS parenchyma. We observed also that mechanical injury of brain and subsequent post-traumatic inflammation may in part be mediated by chemokines. Chemokines undoubtedly co-operate with cell-associated adhesion molecules during recruitment of leukocytes from blood to CNS. The sequential expression of soluble and membrane-bound signals for leukocyte migration is an intricate ...
Journal of Molecular Neuroscience, 2014
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS... more Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Four distinct disease courses are known, although approximately 90 % of patients are diagnosed with the relapsing-remitting form (RRMS). The name "multiple sclerosis" pertains to the underlying pathology: the presence of demyelinating plaques in the CNS, in particular in the periventricular region, corpus callosum, cervical spine, and the cerebellum. There are ongoing efforts to discover biomarkers that would allow for an unequivocal diagnosis, assess the activity of inflammatory and neurodegenerative processes, or warn of disease progression. At present, small noncoding RNA particles-microRNA (miRNA, miR) seem to be particularly noteworthy, as they take part in posttranscriptional regulation of expression of various genes. Changes in composition as well as function This article was based on author's doctoral thesis entitled "Evaluation of microRNA expression as potential biomarkers of activation of the immune system in the course of multiple sclerosis (MS)" and contains excerpts thereof.
Journal of Stroke and Cerebrovascular Diseases, 2014
The aim of this research was to assess the neurologic status of patients a year after endarterect... more The aim of this research was to assess the neurologic status of patients a year after endarterectomy with the use of National Institutes of Health Stroke Scale (NIHSS) and the degree of disability using the modified Rankin Scale (mRS) and to examine the patients&amp;amp;amp;#39; subjective evaluation of their health. One hundred two patients with symptomatic internal carotid artery stenosis who underwent endarterectomy and attended a 1-year follow-up examination were enrolled in the study. The material comprised 72 (70.6%) men and 30 (29.4%) women. Before the surgery, the patients&amp;amp;amp;#39; neurologic status was assessed according to the NIHSS, and their functional status was rated with the mRS. Additionally, the patients were asked to assess their life quality on a 10-point Likert scale. The mean NIHSS score before the operation was 2.76 points (SD 2.47), whereas a year after it was 2.05 points (SD 1.84) (P &amp;amp;amp;lt; .0001). The NIHSS scores that improved significantly a year after endarterectomy were level of consciousness-questions and commands, motor leg, and sensory (P &amp;amp;amp;lt; .05). The patients&amp;amp;amp;#39; neurologic status assessed with the NIHSS improved significantly 1 year after carotid endarterectomy mostly because of the improvement in their verbal and motor communication ability, physical condition and agility, and reduction in sensory disturbances. The observed changes in the neurologic status were reflected in the functional status and subjective life quality assessment, which appeared to be significantly better a year after the surgical treatment.
Journal of Neurovirology, 1999
Experimental autoimmune encephalomyelitis (EAE) is an in¯ammatory disease of the central nervous ... more Experimental autoimmune encephalomyelitis (EAE) is an in¯ammatory disease of the central nervous system (CNS) considered to be an animal model for multiple sclerosis (MS). The detailed mechanism that speci®es accumulation of in¯ammatory cells within the CNS in these conditions remains a subject of active investigation. Chemokines including IP-10, GRO-a, MCP-1 are produced in EAE tissues selectively by parenchymal astrocytes, but the regulatory stimuli that govern this expression remain undetermined. The unexpected occurrence of increased EAE susceptibility in Balb/c GKO mice (lacking IFN-g) offered an opportunity to examine the spectrum of chemokine expression during immune-mediated in¯ammation in the absence of a single regulatory cytokine. We found that chemokines MCP-1 and GRO-a were upregulated in the CNS of mice with EAE despite the GKO genotype. IP-10, which is highly expressed in the CNS of mice with an intact IFN-g gene and EAE, was strikingly absent. In vitro experiments con®rmed that IFNg selectively stimulates astrocytes for IP-10 expression. These results indicate that IP-10 is dependent upon IFN-g for its upregulation during this model disease, and document directly that astrocyte expression of chemokines during EAE is governed by pro-in¯ammatory cytokines.
Journal of Clinical Immunology, 2008
Chemokines and their receptors are involved in the development of multiple sclerosis (MS). Methyl... more Chemokines and their receptors are involved in the development of multiple sclerosis (MS). Methylprednisolone (MP) and mitoxantrone (MTX) are commonly used in the treatment of MS. In this study, we analyzed the expression of chemokine receptors CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5 in peripheral blood mononuclear cells (PBMC) from MS patients before and after treatment with MP or MTX. We observed a significant upregulation of expression of CXCR1 and CXCR2 in untreated MS patients. Treatment of MS with MP stimulated further increase of expression of both receptors. Therapy for MS with MTX resulted in decrease of CXCR2 expression. There was a negative correlation between the expression of CXCR1 and CXCR2 and the cumulative dose of MTX received by patients. These results suggest that CXCR1 and CXCR2 may be involved in MS pathogenesis and that treatment of this disease with MP and MTX may influence expression of those receptors.
Brain Sciences
Epilepsy is a common brain disorder characterized by a heterogenous etiology. Its main features a... more Epilepsy is a common brain disorder characterized by a heterogenous etiology. Its main features are recurrent seizures. Despite many clinical studies, about 30% of cases are refractory to treatment. Recent studies suggested the important role of immune-system elements in its pathogenesis. It was suggested that a deregulated inflammatory process may lead to aberrant neural connectivity and the hyperexcitability of the neuronal network. The aim of our study was the analysis of the expression of inflammatory mediators in a mouse model of epilepsy and their impact on the neurodegeneration process located in the brain. We used the KA-induced model of epilepsy in SJL/J mice and performed the analysis of gene expression and protein levels. We observed the upregulation of IL1β and CXCL12 in the early phase of KA-induced epilepsy and elevated levels of CCL5 at a later time point, compared with control animals. The most important result obtained in our study is the elevation of CXCL2 expressi...
Neurologia i Neurochirurgia Polska, 2012
FoxP3 (p < 0,001) by³y znamiennie mniejsze u chorych na RRMS. Stwierdzono ujemn¹ korelacjê pomiêd... more FoxP3 (p < 0,001) by³y znamiennie mniejsze u chorych na RRMS. Stwierdzono ujemn¹ korelacjê pomiêdzy stê¿eniem leptyny a MFC dla czynnika transkrypcyjnego FoxP3 w limfocytach nTreg u chorych na RRMS (r =-0,7; p < 0,05). Wnioski: Prozapalny profil adipocytokin i zmniejszenie odsetka limfocytów nTreg sugeruje ich udzia³ w przebiegu reakcji zapalnej u chorych na RRMS niezale¿nie od terapii kortykosteroidami. Korelacja pomiêdzy stê¿eniem leptyny i wskaŸnikiem MFC dla czynnika transkrypcyjnego FoxP3 w limfocytach nTreg u chorych na RRMS wskazuje na ha muj¹cy wp³yw leptyny na jego ekspresjê.
Journal of Immunological Methods, 2010
International Journal of Molecular Sciences, May 8, 2017
The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical fo... more The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). Tumor necrosis factor alpha (TNF-α) or interleukin 17 (IL-17) stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express Vascular cell adhesion molecule 1 (VCAM-1), the receptor responsible for inflammatory cell adhesion, which binds very late antigen 4 (VLA-4) on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-α and IL-17 on the adherence of Th17 cells to bEnd.3. The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.
The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical fo... more The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). TNF-a or IL-17 stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express VCAM-1, the receptor responsible for inflammatory cell adhesion, which binds VLA-4 on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-a and IL-17 on the adherence of Th17 cells to bEnd.3 The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This interaction between Th17 cells and the brain endothelium appears to be mediated by VCAM-1 and some chemotactic cytokines. This observation may suggest potential therapeutic...
Scandinavian Journal of Immunology, 2007
Chemokines and their receptors are important players in organism homeostasis, development and imm... more Chemokines and their receptors are important players in organism homeostasis, development and immune response to inflammatory stimuli. It has been recently confirmed that they are also involved in the development of several autoimmune diseases. In this study, we analysed the expression of two recently identified CC chemokine receptors, CCR7 and CCR8, in the central nervous system (CNS) and in peripheral tissues during chronic relapsing experimental autoimmune encephalomyelitis (ChREAE) -- an animal model of the human demyelinating disease multiple sclerosis (MS). We observed upregulation of both chemokine receptors in the CNS during the first and second attacks of ChREAE, whereas disease remission was characterized by a lower expression of those receptors. An analysis of the kinetics of CCR7 and CCR8 expression in the CNS during the first attack of the disease showed a constant increase in the first few days after the onset of clinical signs. This expression correlated with the clinical severity of ChREAE. CCR7-positive mononuclear cells were detected mostly in perivascular inflammatory cuffs in the CNS. In peripheral tissues (the spleen and kidneys) expression of both receptors was not upregulated during active ChREAE. These findings suggest that CCR7 and CCR8 may play a significant role in the pathogenesis of EAE and probably MS.
Journal of Neuroimmunology, 1994
The blood-brain barrier and immune cell homing to the CNS The blood-brain barrier (BBB) isolates ... more The blood-brain barrier and immune cell homing to the CNS The blood-brain barrier (BBB) isolates the CNS from the rest of the organism. The anatomic foundation of this structure is a syncytium of cerebrovascular endothelial cells sealed together by tight junctions. The endothelial basal lamina, located at the abluminal side of endothelium, borders the perivascular (Virchow-Robin) space. The perivascular space is continuous with the subarachnoid compartment and is itself bordered by the glia limitans, formed by astrocytic and microglial end feet. Within the perivascular space, on either side of the endothelial basal lamina, dwell a unique population of phagocytic cells variously termed perivascular macrophages, perivascular microglia, perivascular cells or pericytes. These cells form a ®rst line of defense once the BBB is breached. Astrocytes are also important for BBB development and function: their processes attach to the basement membrane shared with the endothelial cells and peri...
Aktualności Neurologiczne
Fingolimod jest pierwszym zarejestrowanym doustnym lekiem stosowanym w terapii stwardnienia rozsi... more Fingolimod jest pierwszym zarejestrowanym doustnym lekiem stosowanym w terapii stwardnienia rozsianego. Jego aktywny metabolit-fosforan fingolimodu poprzez działanie na receptory S1PR reguluje uwalnianie limfocytów z tkanek limfoidalnych do krążenia, wykazując efekt immunosupresyjny. Najnowsze badania dowodzą jednak, że na korzystny efekt działania fingolimodu składa się również wielopłaszczyznowe działanie neuroprotekcyjne. Fingolimod przenika przez barierę krew-mózg i wpływa na wykazujące ekspresję receptorów S1PR komórki ośrodkowego układu nerwowego: astrocyty, progenitory oligodendrocytów, mikroglej, a także neurony. Fingolimod pobudza produkcję czynników neurotroficznych oraz hamuje produkcję tlenku azotu przez komórki astrogleju, zmniejszając nasilenie proceu neurodegeneracji. Co więcej, zmniejsza ekspresję prozapalnych cytokin indukowanych przez TNF w astrocytach, zmniejszając ich potencjał prozapalny. Pobudza zarówno migrację, jak i proliferację komórek progenitorowych oligodendrocytów, będących źródłem oligodendrocytów-jedynych komórek ośrodkowego układu nerwowego zdolnych do syntezy mieliny. Leczenie fingolimodem znacząco nasila mechanizmy regeneracyjne w przebiegu autoimmunologicznego zapalenia mózgu i rdzenia kręgowego. Ponadto zmniejsza reaktywność mikrogleju i spowalnia związany z odpowiedzią zapalną proces nuerodegeneracji. Długotrwała aplikacja fingolimodu redukuje wrażliwość komórek nerwowych na czynniki neurotoksyczne, sugeruje bezpośrednie działanie neuroprotekcyjne. Obecnie w różnych fazach badań klinicznych znajdują się selektywne inhibitory poszczególnych podtypów receptorów dla S1P, pozbawione charakterystycznych dla fingolimodu działań niepożądanych oraz posiadające korzystniejsze właściwości farmakokinetyczne. Należą do nich: siponimod, ponesimod oraz ozanimod.
Nutrients
Epidemiological data indicate that a diet rich in plant polyphenols has a positive effect on brai... more Epidemiological data indicate that a diet rich in plant polyphenols has a positive effect on brain functions, improving memory and cognition in humans. Direct activity of ingested phenolics on brain neurons may be one of plausible mechanisms explaining these data. This also suggests that some phenolics can cross the blood-brain barrier and be present in the brain or cerebrospinal fluid. We measured 12 phenolics (a combination of the solid-phase extraction technique with high-performance liquid chromatography) in cerebrospinal fluid and matched plasma samples from 28 patients undergoing diagnostic lumbar puncture due to neurological disorders. Homovanillic acid, 3-hydroxyphenyl acetic acid and caffeic acid were detectable in cerebrospinal fluid reaching concentrations (median; interquartile range) 0.18; 0.14 µmol/L, 4.35; 7.36 µmol/L and 0.02; 0.01 µmol/L, respectively. Plasma concentrations of caffeic acid (0.03; 0.01 µmol/L) did not correlate with those in cerebrospinal fluid (ρ = ...
International Journal of Molecular Sciences
The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical fo... more The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). Tumor necrosis factor alpha (TNF-α) or interleukin 17 (IL-17) stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express Vascular cell adhesion molecule 1 (VCAM-1), the receptor responsible for inflammatory cell adhesion, which binds very late antigen 4 (VLA-4) on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-α and IL-17 on the adherence of Th17 cells to bEnd.3. The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.
The American Journal of Pathology, Feb 1, 1997
Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leu... more Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leukocytes. Two subfamilies, aand 3-cheemokines, have been described, based on structural, genetic, and functional considerations. In acute Supported by grant RO1NS32151 from the National Institutes of Health (R. M. Ransohoff) and grant FG 1079A1/T from the National Multiple Sclerosis Society (M. Tani). V. Tuohy is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society. R. Ransohoff's research is also supported by the Williams Family Fund for Multiple Sclerosis Research.
Methods in Enzymology, 1997
Experimental Models of Multiple Sclerosis, 2005
ABSTRACT
The American journal of pathology, 1997
Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leu... more Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leukocytes. Two subfamilies, alpha- and beta-chemokines, have been described, based on structural, genetic, and functional considerations. In acute experimental autoimmune encephalomyelitis (EAE), chemokines are up-regulated systemically and in central nervous system (CNS) tissues at disease onset. Functional significance of this expression was supported by other studies; intervention with an antichemokine antibody abrogated passive transfer of EAE, and chemokines expressed in brains of transgenic mice recruited appropriate leukocyte populations into the CNS compartment. Chemokine expression in the more relevant circumstance of chronic EAE has not been addressed. We monitored the time course and cellular sources of chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha, interferon-gamma-inducible protein of 10 kd, KC, and regulated on activation, normal T-ce...
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience
In this paper, we discuss the potential involvement of a new family of cytokines, termed chemokin... more In this paper, we discuss the potential involvement of a new family of cytokines, termed chemokines, in CNS inflammatory pathology. Chemokines are a family of proinflammatory cytokines which are able to stimulate target-cell-specific directional migration of leukocytes. Because of this feature, chemokines may be potent mediators of inflammatory processes. We have previously reported observations indicating that chemokines may be involved in the process of lesion formation during autoimmune inflammation within CNS, and, in particular, are likely participants in the process of influx of inflammatory cells into the CNS parenchyma. We observed also that mechanical injury of brain and subsequent post-traumatic inflammation may in part be mediated by chemokines. Chemokines undoubtedly co-operate with cell-associated adhesion molecules during recruitment of leukocytes from blood to CNS. The sequential expression of soluble and membrane-bound signals for leukocyte migration is an intricate ...
Journal of Molecular Neuroscience, 2014
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS... more Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS). Four distinct disease courses are known, although approximately 90 % of patients are diagnosed with the relapsing-remitting form (RRMS). The name "multiple sclerosis" pertains to the underlying pathology: the presence of demyelinating plaques in the CNS, in particular in the periventricular region, corpus callosum, cervical spine, and the cerebellum. There are ongoing efforts to discover biomarkers that would allow for an unequivocal diagnosis, assess the activity of inflammatory and neurodegenerative processes, or warn of disease progression. At present, small noncoding RNA particles-microRNA (miRNA, miR) seem to be particularly noteworthy, as they take part in posttranscriptional regulation of expression of various genes. Changes in composition as well as function This article was based on author's doctoral thesis entitled "Evaluation of microRNA expression as potential biomarkers of activation of the immune system in the course of multiple sclerosis (MS)" and contains excerpts thereof.
Journal of Stroke and Cerebrovascular Diseases, 2014
The aim of this research was to assess the neurologic status of patients a year after endarterect... more The aim of this research was to assess the neurologic status of patients a year after endarterectomy with the use of National Institutes of Health Stroke Scale (NIHSS) and the degree of disability using the modified Rankin Scale (mRS) and to examine the patients&amp;amp;amp;#39; subjective evaluation of their health. One hundred two patients with symptomatic internal carotid artery stenosis who underwent endarterectomy and attended a 1-year follow-up examination were enrolled in the study. The material comprised 72 (70.6%) men and 30 (29.4%) women. Before the surgery, the patients&amp;amp;amp;#39; neurologic status was assessed according to the NIHSS, and their functional status was rated with the mRS. Additionally, the patients were asked to assess their life quality on a 10-point Likert scale. The mean NIHSS score before the operation was 2.76 points (SD 2.47), whereas a year after it was 2.05 points (SD 1.84) (P &amp;amp;amp;lt; .0001). The NIHSS scores that improved significantly a year after endarterectomy were level of consciousness-questions and commands, motor leg, and sensory (P &amp;amp;amp;lt; .05). The patients&amp;amp;amp;#39; neurologic status assessed with the NIHSS improved significantly 1 year after carotid endarterectomy mostly because of the improvement in their verbal and motor communication ability, physical condition and agility, and reduction in sensory disturbances. The observed changes in the neurologic status were reflected in the functional status and subjective life quality assessment, which appeared to be significantly better a year after the surgical treatment.
Journal of Neurovirology, 1999
Experimental autoimmune encephalomyelitis (EAE) is an in¯ammatory disease of the central nervous ... more Experimental autoimmune encephalomyelitis (EAE) is an in¯ammatory disease of the central nervous system (CNS) considered to be an animal model for multiple sclerosis (MS). The detailed mechanism that speci®es accumulation of in¯ammatory cells within the CNS in these conditions remains a subject of active investigation. Chemokines including IP-10, GRO-a, MCP-1 are produced in EAE tissues selectively by parenchymal astrocytes, but the regulatory stimuli that govern this expression remain undetermined. The unexpected occurrence of increased EAE susceptibility in Balb/c GKO mice (lacking IFN-g) offered an opportunity to examine the spectrum of chemokine expression during immune-mediated in¯ammation in the absence of a single regulatory cytokine. We found that chemokines MCP-1 and GRO-a were upregulated in the CNS of mice with EAE despite the GKO genotype. IP-10, which is highly expressed in the CNS of mice with an intact IFN-g gene and EAE, was strikingly absent. In vitro experiments con®rmed that IFNg selectively stimulates astrocytes for IP-10 expression. These results indicate that IP-10 is dependent upon IFN-g for its upregulation during this model disease, and document directly that astrocyte expression of chemokines during EAE is governed by pro-in¯ammatory cytokines.
Journal of Clinical Immunology, 2008
Chemokines and their receptors are involved in the development of multiple sclerosis (MS). Methyl... more Chemokines and their receptors are involved in the development of multiple sclerosis (MS). Methylprednisolone (MP) and mitoxantrone (MTX) are commonly used in the treatment of MS. In this study, we analyzed the expression of chemokine receptors CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5 in peripheral blood mononuclear cells (PBMC) from MS patients before and after treatment with MP or MTX. We observed a significant upregulation of expression of CXCR1 and CXCR2 in untreated MS patients. Treatment of MS with MP stimulated further increase of expression of both receptors. Therapy for MS with MTX resulted in decrease of CXCR2 expression. There was a negative correlation between the expression of CXCR1 and CXCR2 and the cumulative dose of MTX received by patients. These results suggest that CXCR1 and CXCR2 may be involved in MS pathogenesis and that treatment of this disease with MP and MTX may influence expression of those receptors.