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ABSTRACT: Alzheimer disease is the most common neurodegenerative disease and the major cause of dementia. In addition to β-amyloid aggregation and hyperphosphorylated tau, neuroinflammation also plays important roles in the pathophysiology of this multifactorial disorder. Histone deacetylase catalyzes deacetylation of histones and has important roles in the regulation of gene expression. Histone deacetylase inhibitors have been reported to exhibit neuroprotective and anti-neuroinflammatory activities and have therapeutic effects in several animal models of neurodegenerative diseases. Here, an efficient benzamide histone deacetylase inhibitor, MS-275, was orally administered by gavage to transgenic APP/PS1 mice, an animal model of cerebral amyloidosis for Alzheimer disease. After 10 days of treatment, MS-275 significantly ameliorated microglial activation and β-amyloid deposition in cerebral cortex and/or hippocampus. This was associated with improved nesting behavior, an important affiliative/social behavior. MS-275 also attenuated inflammatory activation of a mouse macrophage cell line in vitro. These results suggest that MS-275 may be a therapeutic option for Alzheimer disease and other neuroinflammatory diseases.
Journal of neuropathology and experimental neurology. 03/2013; 72(3):178-85.
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ABSTRACT: Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system. Receptor activator of NF-κB ligand (RANKL), a member of the tumor necrosis factor family, regulates proliferation of mature T cells. Here, we have studied the expression of RANKL in sciatic nerves of EAN rats. EAN was induced in male Lewis rats. The spatiotemporal expression of RANKL in sciatic nerves of EAN rats was investigated using immunohistochemistry. In sciatic nerves of normal rats RANKL(+) cells were rarely seen. EAN induced a significant accumulation of RANKL(+) cells in sciatic nerves and there was a significant positive correlation of the time course of RANKL(+) cell accumulations with neurological scores of EAN rats. The major cellular resources of RANKL in sciatic nerves were T cells and macrophages. The positive association of RANKL(+) cell accumulations with neurological scores of EAN rats together with the known functions of RANKL indicated that RANKL might play a role in pathologic development of EAN and need further investigation.
Neurological Sciences 07/2012; · 1.32 Impact Factor
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ABSTRACT: A robust neuroinflammation, contributing to the development of secondary injury, is a common histopathological feature of traumatic brain injury (TBI). Characterization of leukocytic subpopulations contributing to the early infiltration of the damaged tissue might aid in further understanding of lesion development. Reactive macrophages/microglia can exert protective or damaging effects in TBI. CD163 is considered a marker of M2 (alternatively activated) macrophages. Therefore we investigated the accumulation of CD163(+) macrophages/microglia in the brain of TBI rats. TBI was induced in rats using an open skull weight-drop contusion model and the accumulation of CD163(+) cells was analyzed by immunohistochemistry. In normal rat brains, CD163 was expressed by meningeal, choroid plexus and perivascular macrophages. Significant parenchymal CD163(+) cell accumulation was observed two days post TBI and continuously increased in the investigated survival time. The accumulated CD163(+) cells were mainly distributed to the lesional areas and exhibited macrophage phenotypes with amoeboid morphologic characteristics but not activated microglial phenotypes with hypertrophic morphology and thick processes. Double-labeling experiments showed that most CD163(+) cells co-expressed heme oxygenase-1 (HO-1). In addition, in vitro incubating of macrophage RAW264.7 cells or primary peritoneal macrophages with hemoglobin- haptoglobin (Hb-Hp) complex suppressed LPS-induced inflammatory macrophages phenotype and induced CD163 and HO-1 upregulation, indicating that CD163(+) macrophages/microglia in TBI might have anti-inflammatory effects. And further study is necessary to identify functions of these cells in TBI.
Brain research 04/2012; 1461:102-10. · 2.46 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) are essential to the innate immune system for recognizing not only microbial pathogens but also endogenous ligands from injured cells, suggesting that TLRs are a sensitive detection system to tissue injury and play roles in initiating tissue degeneration/regeneration. In this study, the effects of traumatic brain injury (TBI) on lesional expression of TLR2, TLR4, their most common adaptor molecule myeloid differentiation factor 88 (MyD88) and their endogenous ligand, heat shock protein 70 (HSP70), were investigated.
Rat TBI was induced using an open-skull weight-drop model. TLR2, TLR4, MyD88 and HSP70 expression was studied by immunohistochemistry.
TLR2, TLR4, HSP70 and MyD88 were mainly found in lesioned regions and subcortical white matter. While infiltration of TLR2+ cells became significant on day 2, significant accumulation of TLR4+, MyD88+ and HSP70+ cells was already seen on day 1, and the numbers of immunopositive cells increased continuously until day 4. Furthermore, double staining together with morphological classification showed that major cellular sources for TLR2, TLR4 and MyD88 were macrophages/microglia in lesioned areas and astrocytes in subcortical white matter. But for HSP70, the major cellular sources were neurons in perilesion and macrophages/microglia in lesion areas and astrocytes in subcortical white matter.
In summary, our data reveal distinct patterns of localization of TLR+ resident and infiltrating cells in TBI rat brain. Infiltrating activated monocytic cells are the major source of TLR+ cells. These findings warrant further investigation of the roles of TLRs in controlling immune and degenerative/regenerative processes after TBI.
NeuroImmunoModulation 01/2012; 19(1):10-9. · 2.38 Impact Factor
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ABSTRACT: The environmental agent aluminum has been extensively investigated for a potential relationship with amyloid precursor protein (APP) expression. Despite many investigations, there is at present no definite proof from which to draw a conclusion. Since APP is an integral membrane protein expressed in different tissues and capable of fluxes across the blood-brain barrier (BBB), which may ultimately affect APP level in brain, it is necessary to assess the expression profile among vital body organs. The present study compared aluminum oxide and aluminum chloride injected rats with control rats (saline treated) to observe if aluminum affected APP expression patterns in different organs by immunohistochemistry (IHC). The expression of APP was observed in the brain of aluminum chloride treated rats and in the liver of aluminum oxide injected group. Results of double IHC staining showed that it is Kupffer cells, which are located in liver sinus and expressed APP after aluminum oxide treatment. Oxidative stress is suggested as the potential pathway that aluminum chloride exert effects in brain. These results suggest that different aluminum compounds may impact the expression of APP in brain and liver tissues. The mechanism that aluminum induced liver APP expression still needs further investigation.
Environmental toxicology and pharmacology. 12/2011; 33(2):135-40.
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ABSTRACT: Reactive macrophages/microglia exert both protective or damaging effects in multiple sclerosis (MS), which contribute to the relapsing-remitting nature of MS. CD163 is considered a marker of M2 (alternatively activated) macrophages. In the MS brain, CD163(+) perivascular macrophages express molecules for antigen recognition and presentation. Here we further investigated the accumulation of CD163(+) macrophages/microglia in the parenchyma of MS brains. CD163 expression pattern was investigated in different lesions of brain tissue specimens from five MS brains and five neuropathologically unaffected controls by immunohistochemistry. In the parenchyma of normal brain samples, immunoreactivity (IR) of CD163 was absent. In acute active lesions and at the rim of chronic active lesions of MS, strong accumulation of CD163(+) macrophages/microglia was seen. In chronic inactive lesions and in the center of chronic active lesion, CD163(+) macrophages/microglia were rare. Further, double-labeling showed that parenchymal and perivascular CD163(+) macrophages/microglia were myelin basic protein positive and HLA-DR(+), suggesting that CD163(+) macrophages/microglia could ingest and present antigen. In addition, in vitro incubating macrophage RAW264.7 cells with myelin turned LPS-induced inflammatory macrophages into an anti-inflammatory phenotype, indicating that myelin basic protein positive, CD163(+) macrophages/microglia in MS might have anti-inflammatory effects. The parenchymal CD163(+) macrophages/microglia, which had the capacity for antigen ingestion and presentation, might contribute to the resolution of inflammation in MS.
Journal of neuroimmunology 08/2011; 237(1-2):73-9. · 2.84 Impact Factor
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ABSTRACT: Experimental autoimmune neuritis (EAN) is a well-known animal model of human demyelinating polyneuropathies and is characterized by inflammation and demyelination in the peripheral nervous system. Tim-3 had been identified as a Th1-specific marker negatively regulating autoimmunity or inflammatory diseases. Here we have studied by immunohistochemistry the spatiotemporal accumulation of Tim-3(+) cells in sciatic nerves of EAN rats, particularly focusing on its association with alternatively activated macrophages. Our results showed that time course of Tim-3(+) cell accumulation correlated positively with disease progression of EAN; but distinct major cellular resources of Tim-3 were observed at different disease stages of EAN: during the early phase of EAN, the main cellular resource were T cells, but at the peak and during recovery phase of EAN, Tim-3 was mostly expressed on CD68(+) macrophages or CD163(+) cells. Further investigation suggested that accumulation of CD163(+) cells, particularly their relative abundances to activated macrophages at different time points, were in accordance with the recovery from EAN. Therefore, Tim3(+) cells might include a distinct macrophage population, which may be involved in anti-inflammatory effect and recovery from EAN.
Brain research bulletin 07/2011; 86(3-4):229-34. · 2.18 Impact Factor
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ABSTRACT: Experimental autoimmune prostatitis (EAP) is an autoimmune inflammatory disease of male sex accessory glands and is characterized by a cellular and humoral prostate-specific autoimmune response. EAP shares important clinical and immunological features with human chronic prostatitis and chronic pelvic pain syndrome. MS-275, a potent histone deacetylase inhibitor, has promising anti-inflammatory activities and might be a new agent in the therapy of prostate inflammation.
EAP rats were treated with MS-275 (5 mg/kg, i.p.) once daily. Using immunohistochemistry and PCR assay, we determined immune cellular responses and infiltration into the prostate glands, and changes of mRNA levels of representative inflammatory molecules in prostate tissue. Changes in Foxp3(+) CD4(+) cell populations of lymph nodes and peripheral blood were analyzed by flow cytometry. Additionally, direct anti-inflammatory effects of MS-275 were investigated in vitro with a macrophage cell line.
MS-275 treatment significantly reduced the local accumulation of immune cells and mRNA levels of representative pro-inflammatory molecules in prostate tissue. Furthermore, MS-275 treatment increased percentage of Foxp3(+) CD4(+) Treg cells in lymph nodes and their proportion to CD4(+) cells in peripheral blood, and induced a relative increase of ED2(+) macrophage numbers in EAP prostate. Additional in vitro study showed that MS-275 induced a switch of macrophages from classic M1 to anti-inflammatory M2 phenotype.
In summary, our data demonstrated that MS-275 could effectively suppress inflammatory reaction in EAP, through suppressing immune cells and pro-inflammatory molecules, and inducing anti-inflammatory immune cells and molecules, which may suggest MS-275 as a potential candidate for treatment of inflammatory prostatitis.
The Prostate 05/2011; 72(1):90-9. · 3.48 Impact Factor
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ABSTRACT: Experimental autoimmune prostatitis (EAP) is an autoimmune inflammatory disease of male sex accessory glands and is characterized by a cellular and humoral prostate-specific autoimmune response associated with inflammatory mononuclear cell (MNC) infiltration. EAP shares important clinical and immunological features with human chronic prostatitis and chronic pelvic pain syndrome. Using immunohistochemistry, we determined the pattern of pathological changes during rat EAP development, regarding the cellular responses and infiltration into the prostate gland, and therapeutic effect of FTY720, a modulator of sphingosine-1-phosphate receptors which has shown promising protective effects in animal models and clinical trials of several autoimmune diseases. Significant accumulations of total MNCs, pan-T cells and CD8(+) cells were observed in prostatic stroma as early as 11 days after autoimmune induction. However, accumulation of reactive macrophages became significant 4 days later. After reaching the maximal level at Day 16, the accumulations of all the different cell populations fell back rapidly and returned to normal level by Day 35. Suppressive FTY720 significantly reduced inflammatory infiltration of different immune cell populations and tissue disruption in prostate of EAP rats. Our results therefore suggest that FTY720 might be a potential candidate for treatment of inflammatory prostatitis.
Scandinavian Journal of Immunology 02/2011; 73(6):546-53. · 2.23 Impact Factor
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ABSTRACT: Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system and an animal model of human inflammatory demyelinating polyradiculoneuropathy. AUY954, which targets selectively the sphingosine-1-phosphate receptor 1 (S1P(1)), is known to sequester lymphocytes into secondary lymphoid tissues. In EAN rats, AUY954 greatly prevented paraparesis if administrated from the day of immunization. T cell, B cell, and macrophage infiltration, inflammatory demyelination, and local expression of interleukine-17 and matrix metalloproteinase-9 in sciatic nerves of EAN rats were significantly decreased by AUY954 treatment. Therefore, S1P(1) modulation might be a potential treatment option for inflammatory neuropathies.
Journal of neuroimmunology 10/2009; 216(1-2):59-65. · 2.84 Impact Factor
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ABSTRACT: Experimental autoimmune neuritis (EAN) is a helper T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system and serves as the animal model for human inflammatory demyelinating polyneuropathies. Compound A, a plant-derived phenyl aziridine precursor, was reported to activate glucocorticoid receptors to exert transrepression but not transactivation properties. In this study, we investigated the effects of Compound A in EAN rats. Compound A greatly suppressed paraparesis in EAN, even when administrated after the appearance of the first neurological signs. Accumulation of macrophages and lymphocytes, demyelination, and mRNA levels of inflammatory molecules in sciatic nerves of EAN were greatly attenuated by Compound A. In addition, Compound A inhibited progression of neuropathic pain and repressed microglia but not astrocyte activation and IL-1beta and TNF-alpha up-regulation in EAN spinal cords. In EAN sciatic nerves, Compound A treatment increased numbers of anti-inflammatory M2 macrophages. Furthermore, Compound A induced the switch of macrophages from inflammatory M1 type to anti-inflammatory M2 type in vitro. In lymph nodes of EAN rats, Compound A depressed Th1 and Th17 cytokines, but increased Th2 cytokine and Foxp3 expression. An increase of Foxp3(+)/CD4(+) regulatory T cells was seen in peripheral blood of EAN rats following Compound A treatment. In addition, Compound A did not cause a hyperglycemia effect in EAN rats as compared with the immunosuppressive steroid prednisolone. Therefore, our data demonstrated that Compound A could effectively suppress EAN with reduced side effects by attenuating inflammation, suggesting that Compound A could be a potent candidate for treatment of autoimmune neuropathies.
The Journal of Immunology 09/2009; 183(5):3081-91. · 5.79 Impact Factor
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ABSTRACT: Experimental autoimmune neuritis (EAN) is a well-known animal model of human demyelinating polyneuropathies. Here we have studied the spatiotemporal accumulation of interleukin (IL)-17(+) cells in sciatic nerves of EAN rats and effects of FTY720, an agonist of sphingosine-1-phosphate (S1P) receptors.
In this study, we examined the spatiotemporal expression of IL-17 using immunohistochemistry and RT-PCR, and analysed the IL-17(+) cell proportion in blood and lymph nodes using flow cytometry.
In sciatic nerves of EAN rats, IL-17(+) cells were mainly found to concentrate around blood vessels and IL-17(+) cell accumulation was temporally correlated with severity of neurological signs. FTY720, which has been shown to reduce severity of EAN, attenuated accumulation of IL-17(+) cells in sciatic nerves, decreased IL-17(+) cell proportion in peripheral blood, but increased IL-17(+) cell proportion in lymph nodes, suggesting the involvement of S1P signal pathway in regulating IL-17(+) cell trafficking.
our data are consistent with the possibility that IL-17(+) cells might contribute to the pathogenesis of EAN and the S1P signal pathway may be involved in the in vivo trafficking of IL-17(+) cells.
Neuropathology and Applied Neurobiology 03/2009; 35(5):487-95. · 3.80 Impact Factor
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ABSTRACT: T-regulatory cells expressing the forkhead box transcription factor 3 (Foxp3) play essential roles in immune homeostasis. Experimental autoimmune neuritis (EAN) is an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system. We investigated the distribution of Foxp3(+) cells in sciatic nerves, spleen and lymph nodes of EAN rats, and the influence of FTY720 on the localization of Foxp3(+) cells in EAN rats. In sciatic nerves of EAN rats, accumulation of Foxp3(+) cells was not seen during the pre-symptomatic phase (until Day 9) or during early or peak disease activity. In contrast, Foxp3(+) cell accumulation was regularly seen in the recovery from neurologic disease, suggesting a contribution of Foxp3(+) cells to the resolution of EAN. FTY720 was given at onset of EAN (Day 10) until Day 18. Following FTY720 administration, percentages of Foxp3(+) cells in EAN rats were increased in circulating blood, but reduced in lymph nodes compared to the PBS control. FTY720 treatment suppressed total numbers but increased percentages of Foxp3(+) cells in sciatic nerves of EAN rats. These data not only suggests a protective role of Foxp3(+) cells in EAN but also provides a potential way to alter localization of Foxp3(+) cells in vivo.
Experimental Neurology 01/2009; 216(1):75-82. · 4.70 Impact Factor
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ABSTRACT: Experimental autoimmune neuritis (EAN) is a well-known animal model of Guillain-Barré Syndrome. In this study, we studied the spatiotemporal expression of interleukin-16 (IL-16) in the nervous system of EAN rats and pharmacological effects of minocycline on IL-16 expressions in EAN rats. In sciatic nerves and dorsal/ventral roots of EAN rats, IL-16+ cells, identified as macrophages and T cells, were mainly found to concentrate around blood vessels. However, in spinal cords, IL-16+ microglial cells were mainly found in lumbar dorsal horns. Massive IL-16+ cell accumulation in sciatic nerves and spinal roots was temporally correlated with severity of neurological signs of EAN. Furthermore, a strong correlation of IL-16+ cell accumulation with local demyelination in perivascular areas of sciatic nerves, and significant reduction of IL-16+ cell numbers in sciatic nerves and spinal cords by minocycline suggested a pathological contribution of IL-16+ cells in EAN. Taken together, robust IL-16+ cell accumulation in the nervous system and its temporal correlation with severity of neurological signs in EAN might suggest a pathological role of IL-16 in EAN, which makes IL-16 a potential pharmacological target.
Brain Pathology 06/2008; 19(2):205-13. · 3.99 Impact Factor
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ABSTRACT: Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system (PNS). T cells and macrophages are essential for the initiation and development of EAN. FTY720 acts as an agonist of sphingosine-1-phosphate receptors, resulting in inhibition of lymphocyte egress from secondary lymphoid tissues and thymocytes from thymus. This investigation describes the immunosuppressive effects of FTY720 in EAN, the animal model of autoimmune neuropathies. FTY720 (1 mg/kg body weight) completely suppressed paraparesis if administrated from the day of immunization. Furthermore, FTY720 greatly reduced the severity and duration of EAN even when administrated after the appearance of the first neurological sign. T cell, B cell, and macrophage infiltration and demyelination of sciatic nerves were significantly decreased in FTY720-treated EAN. Therefore, FTY720 might be a potential candidate for treatment of inflammatory neuropathies.
Experimental Neurology 05/2008; 210(2):681-90. · 4.70 Impact Factor
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ABSTRACT: Experimental autoimmune neuritis (EAN) is a widely used animal model of the human acute inflammatory demyelinating polyradiculoneuropathy, which is the most common subtype of Guillain-Barré Syndrome. EAN is pathologically characterized by breakdown of the blood-nerve barrier, infiltration of reactive immune cells, local inflammation, demyelination in the peripheral nervous system and mechanical allodynia. Minocycline is known to have neuroprotective and anti-inflammatory effects. Furthermore, relieve of neuropathic pain following minocycline administration was observed in a variety of animal models. Here, we investigated the effects of minocycline on rat EAN. Suppressive treatment with minocycline (50 mg/kg body weight daily immediately after immunization) significantly attenuated the severity and duration of EAN. Macrophage and T-cell infiltration and demyelination in sciatic nerves of EAN rats treated with minocycline were significantly reduced compared to phosphate-buffered saline (PBS)-treated EAN rats. mRNA expressions of matrix metallopeptidase-9, inducible nitric oxide synthase and pro-inflammatory cytokines interleukin-1 beta and tumour necrosis factor-alpha in EAN sciatic nerves were greatly decreased by administration of minocycline as well. Furthermore, minocycline attenuated mechanical allodynia in EAN rats and greatly suppressed spinal microglial activation. All together, our data showed that minocycline could effectively suppress the peripheral and spinal inflammation (immune activation) to improve outcome in EAN rats, which suggests that minocycline may be considered as a potential candidate of pharmacological treatment for autoimmune-mediated neuropathies.
Journal of Cellular and Molecular Medicine 05/2008; 13(2):341-51. · 4.13 Impact Factor
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ABSTRACT: Global alterations in gene expression have been observed in different traumatic brain injury (TBI) models and are considered of crucial importance to the development of subsequent tissue injury and repair. Cytosine methylation is a well-known process of endogenous DNA modification in mammals and the primary mechanism responsible for changes in epigenetic gene expression. Here we have investigated the early global spatio-temporal changes of the status of cellular DNA methylation in a rat TBI model by immunohistochemistry and analyzed the effects of dexamethasone on these changes. Global cellular hypomethylation was seen as early as day 1 in pannecrosis and day 2 in peripannecrosis following TBI. A sub-population of reactive microglia/macrophages was identified as the major source of hypomethylated cells by double-staining experiments. Further, peripheral administration of dexamethasone suppressed this lesional hypomethylation at day 2 post-injury. In sum, our data suggest that lesional hypomethylation defines a sub-population of activated microglia/macrophages involved in the early processes following traumatic brain injury.
Neuroscience Letters 01/2008; 429(1):1-6. · 2.11 Impact Factor
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Acta Neuropathologica 01/2007; 114(4):437-438. · 9.32 Impact Factor
