Amelioration of Behavioral Impairments and Neuropathology by Antiepileptic Drug Topiramate in a Transgenic Alzheimer's Disease Model Mice, APP/PS1.

Alzheimer's disease (AD) is a neurodegenerative disease that is the main cause of dementia in the elderly. The aggregation of ß-amyloid peptides is one of the characterizing pathological changes of AD. Topiramate is an antiepileptic drug, which in addition, is used in the treatment of many neuropsychiatric disorders. In this study, the therapeutic effects of topiramate were investigated in a transgenic mouse model of cerebral amyloidosis (APP/PS1 mice). Before, during, and after topiramate treatment, behavioral tests were performed. Following a treatment period of 21 days, topiramate significantly ameliorated deficits in nest-constructing capability as well as in social interaction. Thereafter, brain sections of mice were analyzed, and a significant attenuation of microglial activation as well as ß-amyloid deposition was observed in sections from topiramate-treated APP/PS1 mice. Therefore, topiramate could be considered as a promising drug in the treatment of human AD.

Protective Effects of Forskolin on Behavioral Deficits and Neuropathological Changes in a Mouse Model of Cerebral Amyloidosis.

The production of amyloid-ß peptides in the brains of patients with Alzheimer disease (AD) may contribute to memory loss and impairments in social behavior. Here, an efficient adenylate cyclase activator, forskolin, was orally administered by gavage (100 mg/kg body weight) to 5-month-old transgenic APP/PS1 mice, which serve as an animal model of cerebral amyloidosis. Analyses of nest construction, sociability, and immunohistochemical features were used to determine the effects of forskolin treatment. After a relatively short term of treatment (10 days), forskolin-treated transgenic mice showed restored nest construction ability (p < 0.05) and their sociability (p < 0.01). There was a reduction of Aß plaque deposition in the cortex and in the hippocampus. Furthermore, expression of transforming growth factor ß, glial fibrillary acidic protein, and Iba-1 in the cortex was reduced in the forskolin-treated group, suggesting regulation of the inflammatory response mediated by activated microglia and astrocytes in the brains of the APP/PS1 mice (p < 0.01). Taken together, these findings suggest that forskolin shows neuroprotective effects in APP/PS1 Tg mice and may be a promising drug in the treatment of patients with AD.

Systemic administration of valproic acid stimulates overexpression of microtubule-associated protein 2 in the spinal cord injury model to promote neurite outgrowth.

OBJECTIVES: Growing body of evidence suggests that neurite outgrowth is a key determinant in the re-networking of damaged neuronal circuits as well as synaptogenesis. The essential molecule in this interesting process is microtubule-associated protein 2 (MAP2) studies demonstrated that inhibition of MAP2 by antisense Oligonucleotide hinders neurite outgrowth. METHODS: In the current study, we evaluated the effects of valproic acid (VPA), a histone deacetylase inhibitor on the expression of MAP2 in the rat spinal cord injury model by real time RT-PCR and immunoreactivity assays. RESULTS: We revealed that a significant increase in the MAP2 overexpression occurred in VPA-treated group compared to the sham group by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and immunoreactivity assays for MAP2 gene expression. DISCUSSION: The present findings indicated that systemic administration of VPA stimulated MAP2 gene expression and also supports the involvement of the MAP2-mediated de novo re-arborization and neurite outgrowth of neurons, which might contribute to successful neuronal re-wirings. Thus, VPA has promising applications in the treatment of many neurological problems, such as neurotrauma, Alzheimer and Parkinson's disease, and others.

Icariin ameliorates neuropathological changes, TGF-ß1 accumulation and behavioral deficits in a mouse model of cerebral amyloidosis.

Icariin, a major constituent of flavonoids from the Chinese medicinal herb Epimedium brevicornum, exhibits multiple biological properties, including anti-inflammatory, neuroregulatory and neuroprotective activities. Therefore, Icariin might be applied in treatment of neurodegenerative disorders, including Alzheimer's disease (AD), which is neuropathologically characterized by ß-amyloid aggregation, hyperphosphorylated tau and neuroinflammation. Potential therapeutic effects of Icariin were investigated in an animal model of cerebral amyloidosis for AD, transgenic APP/PS1 mouse. Icariin was suspended in carboxymethylcellulose and given orally to APP/PS1 mice. Therapeutic effects were monitored by behavioral tests, namely nesting assay, before and during the experimental treatment. Following an oral treatment of 10 days, Icariin significantly attenuated Aß deposition, microglial activation and TGF-ß1 immunoreactivity at amyloid plaques in cortex and hippocampus of transgenic mice 5 months of age, and restored impaired nesting ability. Our results suggest that Icariin might be considered a promising therapeutic option for human AD.

Key network approach reveals new insight into Alzheimer's disease.

Alzheimer's disease (AD) is a severe neurodegenerative disorder without curative treatment. Extensive data on pathological molecular processes have been accumulated over the last years. These data combined allows a systems biology approach to identify key regulatory elements of AD and to establish a model descriptive of the disease process which can be used for the development of therapeutic agents. In this study, the authors propose a closed network that uses a set of nodes (amyloid beta, tau, beta-secretase, glutamate, cyclin-dependent kinase 5, phosphoinositide 3-kinase and hypoxia-induced factor 1 alpha) as key elements of importance to the pathogenesis of AD. The proposed network, in total 39 nodes, is able to become a novel tool capable of providing new insights into AD, such as feedback loops. Further, it highlights interconnections between pathways and identifies their combination for therapy of AD.

Accumulation of connective tissue growth factor+ cells during the early phase of rat traumatic brain injury.

BACKGROUND: Glial scar formation is a common histopathological feature of traumatic brain injury (TBI). Astrogliosis and expression of transforming growth factor beta (TGF-ß) are key components of scar formation and blood-brain barrier modulation. Connective tissue growth factor (CTGF) is considered a cytokine mediating the effects of TGF-ß. METHODS: Here, we studied the CTGF expression in an open-skull weight-drop-induced TBI, with a focus on the early phase, most amenable to therapy. RESULTS: In normal rat brains of our study, CTGF+ cells were rarely observed. Significant parenchymal accumulation of CTGF+ non-neuron cells was observed 72 h post-TBI and increased continuously during the investigating time. We also observed that the accumulated CTGF+ non-neuron cells were mainly distributed in the perilesional areas and showed activated astrocyte phenotypes with typical stellate morphologic characteristics. CONCLUSION: Our observations demonstrated the time-dependent and lesion-associated accumulation of cellular CTGF expression in TBI, suggesting a pathological role of CTGF in TBI. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3963462091241165.

Accumulation of fascin+ cells during experimental autoimmune neuritis.

BACKGROUND: 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. Fascin is an evolutionarily highly conserved cytoskeletal protein of 55 kDa containing two actin binding domains that cross-link filamentous actin to hexagonal bundles. METHODS: Here we have studied by immunohistochemistry the spatiotemporal accumulation of Fascin + cells in sciatic nerves of EAN rats. RESULTS: A robust accumulation of Fascin + cell was observed in the peripheral nervous system of EAN which was correlated with the severity of neurological signs in EAN. CONCLUSION: Our results suggest a pathological role of Fascin in EAN. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticphatology.diagnomx.eu/vs/6734593451114811.

Entada africana fraction CH2Cl2/MEOH 5% inhibits inducible nitric oxide synthase and pro-inflammatory cytokines gene expression induced by lipopolysaccharide in microglia.

BACKGROUND: Inflammatory response in the CNS mediated by microglia cells play an important role in host defense and is implicated in the pathology of neurodegenerative diseases. We investigated the capacity of Entada africana to protect microglia from inflammatory insults by exploring the effect of the CH2Cl2/MEOH 5% fraction (Ea5) on pro-inflammatory cytokines mRNA expression. Finally, we studied the effect of Ea5 on the inhibition of p38 MAPK Kinase. The results were compared to those obtained with Baicalin, a well reported anti-inflammatory flavonoid. METHODS: Barks from E. africana were harvested in 2010, in the west region of Cameroon. A crude extract was prepared using CH2Cl2/MEOH 1:1 V/V. The crude extract obtained was further fractionated by flash chromatography. A mouse microglia cell line (N9) was stimulated by LPS with or without different concentrations of Baicalin and Ea5. The release of NO was evaluated using the Griess method. The expression of pro-inflammatory cytokines mRNA (TNFα, IL-1ß, IL-6) and iNOS/NO were measured by RT- PCR. The inhibition of p38 MAPK Kinase was assessed using ELISA. RESULTS: We found that Ea5, as well as Baicalin inhibited LPS-induced NO production in a dose dependent manner. Ea5 was most active in term of NO inhibition (87.07%), in comparison to Baicalin (70.85%). The expression of TNFα, IL-1ß, IL-6 and iNOS was strongly suppressed by Ea5 in microglia. Ea5 also inhibited the activity of p38MAPK Kinase, up to 30% for the concentrations tested, whereas a prominent inhibition was obtained with Baicalin. CONCLUSION: These results suggest that E. africana may contain promising compounds useful for the treatment of diseases cause by over-activation of microglia such as Alzheimer disease and other neurological diseases.

Oridonin ameliorates neuropathological changes and behavioural deficits in a mouse model of cerebral amyloidosis.

Alzheimer's disease (AD) is the most common form of neurodegeneration and the major cause of dementia. This multifactorial disorder is clinically defined by progressive behavioural and cognitive deficits, and neuropathologically characterized by ß-amyloid aggregation, hyperphosphorylated tau and neuroinflammation. Oridonin, a diterpenoid isolated from Chinese herb Rabdosia rubescens, has multiple biological properties, especially anti-inflammatory and neuroregulatory activities. Potential therapeutic effects of Oridonin were investigated in an animal model of cerebral amyloidosis for AD, transgenic APP/PS1 mice. Oridonin was suspended in carboxymethylcellulose or loaded with a nanostructured emulsion, and was orally administrated or injected. Before, during and following the experimental treatments, behavioural tests were performed with these transgenic mice and their naive littermates. Following relatively short-term treatments of 10 days, brain tissue of mice were removed for immunohistochemical assays. The results indicate that both oral treatment and injection of Oridonin significantly attenuated ß-amyloid deposition, plaque-associated APP expression and microglial activation in brain of transgenic mice. Furthermore, injection of Oridonin-nanoemulsion ameliorated deficits in nesting, an important affiliative behaviour, and in social interaction. Additional in vitro studies indicated that Oridonin effectively attenuated inflammatory reaction of macrophage and microglial cell lines. Our results suggest that Oridonin might be considered a promising therapeutic option for human AD or other neurodegenerative diseases.

A fraction of stem bark extract of Entada africana suppresses lipopolysaccharide-induced inflammation in RAW 264.7 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Entada africana is a plant used in African traditional medicine for the treatment of stomachache, fever, liver related diseases, wound healing, cataract and dysentery. AIMS OF THE STUDY: This study aimed at evaluating the anti-inflammatory activity of fractions of the stem bark extract of the plant using lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages model. MATERIALS AND METHODS: The crude extract was prepared using the mixture CH2Cl2/MeOH (1:1, v/v) and fractionated by flash chromatography using solvents of increasing polarity to obtain five different fractions. The effects of the fractions on the cells viability were studied by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and their inhibitory activity against LPS-induced nitric oxide (NO) production screened by Griess test. The most active fraction was further investigated for its effects on reactive oxygen species (ROS) production using flux cytometry, the expression of inducible nitric oxide synthase (iNOS), pro-and anti-inflammatory cytokines (IL1ß, TNFα, IL6, IL10 and IL13) by RT-PCR, and the activity of the enzyme p38 MAPK kinase by enzyme-linked immunosorbent assay (ELISA). RESULTS: The fractions presented no significant effect on the viability of macrophages at 100 µg/ml after 24h incubation. The CH2Cl2/MeOH 5% (Ea5) fraction was found to be the most potent in inhibiting NO production with a half inhibition concentration (IC50)=18.36 µg/ml, and showed the highest inhibition percentage (89.068%) in comparison with Baicalin (63.34%), an external standard at 50 µg/ml. Ea5, as well as Baicalin significantly (P<0.05) inhibited the expression of TNFα, IL6 and IL1ß mRNA, attenuated mRNA expression of inducible NO synthase in a concentration-dependent manner, stimulated the expression of anti-inflammatory cytokines (IL10 and IL13), and showed a 30% inhibition of the activity of p38 MAPK kinase. CONCLUSION: The results of the present study indicate that the fraction Ea5 of Entada africana possesses most potent in vitro anti-inflammatory activity and may contain compounds useful as a therapeutic agent in the treatment of inflammatory related diseases cause by over-activation of macrophages.

Erythropoietin is a hypoxia inducible factor-induced protective molecule in experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN), an autoantigen-specific T-cell-mediated disease model for human demyelinating inflammatory disease of the peripheral nervous system, is characterized by self-limitation. Here we investigated the regulation and contribution of erythropoietin (EPO) in EAN self-limitation. In EAN sciatic nerves, hypoxia, and protein and mRNA levels of hypoxia-inducible factor 1α (HIF-1α), HIF-2α, EPO and EPO receptor (EPOR) were induced in parallel at disease peak phase but reduced at recovery periods. Further, the deactivation of HIF reduced EAN-induced EPO/EPOR upregulation in EAN, suggesting the central contribution of HIF to EPO/EPOR induction. The deactivation of EPOR signalling exacerbated EAN progression, implying that endogenous EPO contributed to EAN recovery. Exogenous EPO treatment greatly improved EAN recovery. In addition, EPO was shown to promote Schwann cell survival and myelin production. In EAN, EPO treatment inhibited lymphocyte proliferation and altered helper T cell differentiation by inducing increase of Foxp3(+)/CD4(+) regulatory T cells and decrease of IFN-γ(+)/CD4(+) Th1 cells. Furthermore, EPO inhibited inflammatory macrophage activation and promoted its phagocytic activity. In summary, our data demonstrated that EPO was induced in EAN by HIF and contributed to EAN recovery, and endogenous and exogenous EPO could effectively suppress EAN by attenuating inflammation and exerting direct cell protection, indicating that EPO contributes to the self-recovery of EAN and could be a potent candidate for treatment of autoimmune neuropathies.

Lesional accumulation of heme oxygenase-1+ microglia/macrophages in rat traumatic brain injury.

Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme for heme degradation. Here, we studied the HO-1 expression in an open-skull weight-drop-induced traumatic brain injury, with a focus on the early phase, most amenable to therapy. In normal rat brains of our study, HO-1 cells were rarely observed. Significant parenchymal accumulation of HO-1 non-neuron cells was observed 18 h post-traumatic brain injury and increased continuously during the investigating time. We also observed that the accumulated HO-1 non-neuron cells were mainly distributed in the perilesional areas and showed activated microglia/macrophage phenotypes with ramified or amoeboid morphologic characteristics. Further double-labeling experiments showed that most HO-1 non-neuron cells coexpressed CD68 and CD163, but not glial fibrillary acid protein. Our data suggest that HO-1 expression defines a subtype of activated microglia/macrophages involved in the early processes following traumatic brain injury.

Oral administration of histone deacetylase inhibitor MS-275 ameliorates neuroinflammation and cerebral amyloidosis and improves behavior in a mouse model.

Alzheimer disease is the most common neurodegenerative disease and the major cause of dementia. In addition to ß-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 ß-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.

Nanosilver: application and novel aspects of toxicology.

Nanomaterials are a challenge to toxicology. The high diversity of novel materials and products will require extensive expertize for evaluation and regulatory efforts. Nanomaterials are of substantial scientific and economic potential. Here, we will focus on nanosilver, a material not only with medical applications, but a rapidly increasing use in surprisingly many products. Consequently, toxicological evaluation has to cover an increasing range of complex topics. The toxicology of nanosilver is advancing rapidly; regulatory efforts by Federal Drug Agency and European Environment Protection Agencies are substantial. Current toxicological data, ranging from in vitro studies with cell lines to rodent experiments and ecological evaluation, are numerous, and many groups are providing continuously new data. However, standard classification based on nanosize only is neglecting nanoshape, which adds another level of complexity to the analysis of biological effects. A surprising neglect in nanosilver toxicology so far is the analysis of effects of nanosilver on amyloidosis. Amyloid diseases are widespread in humans and a severe health hazard. The known potential of silver to stimulate amyloidosis in rodents will require a timely and balanced evaluation of nanosilvers.

Lesional infiltration of receptor activator of nuclear factor-κB ligand⁺ cells in experimental autoimmune neuritis rats.

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.

Effects of valproic acid, a histone deacetylase inhibitor, on improvement of locomotor function in rat spinal cord injury based on epigenetic science.

BACKGROUND: The primary phase of traumatic spinal cord injury (SCI) starts by a complex local inflammatory reaction such as secretion of pro-inflammatory cytokines from microglia and injured cells that substantially contribute to exacerbating pathogenic events in secondary phase. Valproic acid (VPA) is a histone deacetylase inhibitor. Acetylation of histones is critical to cellular inflammatory and repair processes. METHODS: In this study, rats were randomly assigned to five experimental groups (laminectomy, untreated, and three VPA-treated groups). For SCI, severe contusion was used. In treated groups, VPA was administered intraperitoneally at doses of 100, 200 and 400 mg/kg daily three hours after injury for 7 days. To compare locomotor improvement among experimental groups, behavioral assessments were performed by the Basso, Beattie and Bresnahan (BBB) rating scale. The expression of neurotrophins was evaluated by RT-PCR and real-time PCR. RESULTS: VPA administration increased regional brain-derived neurotrophic factor and glial cell-derived neurotrophic factor mRNA levels. Local inflammation and the expression of the lysosomal marker ED1 by activated macrophages/microglial cells were reduced by VPA and immunoreactivity of acetylated histone and microtubule-associated protein were increased. CONCLUSION: The results showed a reduction in the development of secondary damage in rat spinal cord trauma with an improvement in the open field test (BBB scale) with rapid recovery.

Lesional accumulation of CD163+ macrophages/microglia in rat traumatic brain injury.

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.

The profile of ß-amyloid precursor protein expression of rats induced by aluminum.

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.

Immunolocalization of Toll-like receptors 2 and 4 as well as their endogenous ligand, heat shock protein 70, in rat traumatic brain injury.

OBJECTIVE: 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. METHODS: Rat TBI was induced using an open-skull weight-drop model. TLR2, TLR4, MyD88 and HSP70 expression was studied by immunohistochemistry. RESULTS: 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. DISCUSSION: 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.

HDAC inhibitor MS-275 attenuates the inflammatory reaction in rat experimental autoimmune prostatitis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.