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.

Natural Diterpenoid Oridonin Ameliorates Experimental Autoimmune Neuritis by Promoting Anti-inflammatory Macrophages Through Blocking Notch Pathway.

The diterpenoid compound, Oridonin, extracted from the Chinese herb, Rabdosia rubescens, possesses multiple biological activities and properties. Oridonin exhibited efficient anti-inflammatory activity by inducing a switch in macrophage polarization to the anti-inflammatory phenotype through inhibition of the Notch pathway in our in vitro study; therefore, its potential therapeutic effects were further investigated in the animal model of human Guillain-Barré syndrome (GBS) and other polyneuropathies - experimental autoimmune neuritis (EAN). Either preventive or therapeutic treatments with Oridonin greatly attenuated disease peak severity, suppressed paraparesis, shortened disease duration, and even delayed EAN onset. Progression of neuropathic pain, demyelination, inflammatory cellular accumulations, and inflammatory cytokines in peripheral nerves were significantly attenuated. Meanwhile, accumulation of immune cells in the spinal roots and microglial activation in the lumbar spinal cord were also reduced. Interestingly, Oridonin treatment significantly increased the proportion of anti-inflammatory macrophages and made them locally dominant among all infiltrated macrophages in the peripheral nerves. The down-regulation of local Notch pathway proteins, together with our in vitro results indicated their possible involvement. Taken together, our results demonstrated that Oridonin effectively suppressed EAN by attenuating local inflammatory reaction and increasing the proportion of immune regulating macrophages in the peripheral nerves, possibly through blockage of the Notch pathway, which suggests Oridonin as a potential therapeutic candidate for human GBS and neuropathies.

Computer-aided identification of protein targets of four polyphenols in Alzheimer's disease (AD) and validation in a mouse AD model.

Natural polyphenols are a large class of phytochemicals with neuroprotective effects. Four polyphenolic compounds: hesperidin, icariin, dihydromyricetin and baicalin were selected to evaluate their effects on Alzheimer's disease (AD). We analyzed by an inverse docking procedure (INVDOCK) the potential protein targets of these polyphenols within the KEGG AD pathway. Consequently, their therapeutic effects were evaluated and compared in a transgenic APP/PS1 mouse model of AD. These polyphenols were docked to several targets, including APP, BACE, PSEN, IDE, CASP, calpain and TNF-α, suggesting potential in vivo activities. Five month old transgenic mice were treated with these polyphenols. Icariin and hesperidin restored behavioral deficits and ameliorated Aß deposits in both the cortex and hippocampus while baicalin and dihydromyricetin showed no substantial effects. Our findings suggest that hesperidin and icariin could be considered potential therapeutic candidates of human AD.

Health-promoting effects of the citrus flavanone hesperidin.

Hesperidin, a member of the flavanone group of flavonoids, can be isolated in large amounts from the rinds of some citrus species. Considering the wide range of pharmacological activities and widespread application of hesperidin, this paper reviews preclinical and clinical trials of hesperidin and its related compounds, including their occurrence, pharmacokinetics, and some marketed products available. Preclinical studies and clinical trials demonstrated therapeutical effects of hesperidin and its aglycone hesperetin in various diseases, such as neurological disorders, psychiatric disorders, and cardiovascular diseases and others, due to its anti-inflammatory, antioxidant, lipid-lowering, and insulin-sensitizing properties.

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.

Natural polyphenols binding to amyloid: a broad class of compounds to treat different human amyloid diseases.

Polyphenols are a large group of phytonutrients found in herbal beverages and foods. They have manifold biological activities, including antioxidative, antimicrobial, and anti-inflammatory properties. Interestingly, some polyphenols bind to amyloid and substantially ameliorate amyloid diseases. Misfolding, aggregation, and accumulation of amyloid fibrils in tissues or organs leads to a group of disorders, called amyloidoses. Prominent diseases are Alzheimer's, Parkinson's, and Huntington's disease, but there are other, less well-known diseases wherein accumulation of misfolded protein is a prominent feature. Amyloidoses are a major burden to public health. In particular, Alzheimer's disease shows a strong increase in patient numbers. Accelerated development of effective therapies for amyloidoses is a necessity. A viable strategy can be the prevention or reduction of protein misfolding, thus reducing amyloid build-up by restoring the cellular aggretome. Amyloid-binding polyphenols affect amyloid formation on various levels, e.g. by inhibiting fibril formation or steering oligomer formation into unstructured, nontoxic pathways. Consequently, preclinical studies demonstrate reduction of amyloid-formation by polyphenols. Amyloid-binding polyphenols might be suitable lead structures for development of imaging agents for early detection of disease and monitoring amyloid deposition. Intake of dietary polyphenols might be relevant to the prevention of amyloidoses. Nutraceutical strategies might be a way to reduce amyloid diseases.

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.

Hesperidin ameliorates behavioral impairments and neuropathology of transgenic APP/PS1 mice.

In addition to cognitive impairments, deficits in non-cognitive behaviors are also common neurological sequelae in Alzheimer's disease and its animal models. Hesperidin, a flavanone glycoside found abundantly in citrus fruits, was orally given (100 mg/kg body weight) to 5-month-old transgenic APP/PS1 mice, a mouse model of cerebral amyloidosis for Alzheimer's disease. After a relatively short-term treatment of 10 days, hesperidin significantly restored deficits in non-cognitive nesting ability and social interaction. Further immunohistochemical analysis showed significantly attenuated ß-amyloid deposition, plaque associated APP expression, microglial activation and TGF-ß immunoreactivity in brains of APP/PS1 mice, which suggests that ameliorated behavioral impairments might be attributable to reduced Aß deposition and attenuated neuro-inflammatory reaction. Additionally, efficient anti-inflammatory effects of hesperidin were confirmed in vitro. Our findings suggest that hesperidin might be a potential candidate for the treatment of AD or even other neurodegenerative diseases.

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.

Plant polyphenols in the treatment of age-associated diseases: revealing the pleiotropic effects of icariin by network analysis.

Polyphenols are a broad class of compounds. Some are ingested in substantial quantities from nutritional sources, more are produced by medicinal plants, and some of them are taken as drugs. It is becoming clear, that a single polyphenol is impacting several cellular pathways. Thus, a network approach is becoming feasible, describing the interaction of a single polyphenol with cellular networks. Here we have selected icariin to draw a prototypic network of icariin activities. Icariin appears to be a promising drug to treat major age-related diseases, like neurodegeneration, memory and depressive disorders, chronic inflammation, diabetes, and osteoporosis. It interacts with several relevant pathways, like PDE, TGF-ß, MAPK, PPAR, NOS, IGF, Sirtuin, and others. Such networks will be useful to future comparative studies of complex effects of polyphenols.

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.

Impact of minocycline on neurodegenerative diseases in rodents: a meta-analysis.

Minocycline is a semisynthetic second-generation tetracycline derivative, and many publications provide evidence of its successful neuroprotection in a variety of animal models. We searched PubMed and Chinese CNKI databases from January 1992 to May 2012 for studies on minocycline in neurodegenerative diseases in rodents. A meta-analysis that adopted weighted Cohen's d effect sizes, percent overlap, Fail-Safe N statistics, and confidence intervals was conducted. In total, 16 English and 3 Chinese articles with high or medium quality were included in this meta-analysis. The treatment benefits for rodents from low-dose (5 mg/kg/day), moderate-dose (45, 50, or 55 mg/kg/day), and high-dose (90 mg/kg/day) minocycline were larger in Huntington's disease, Alzheimer's disease, and stroke mouse models, respectively. In rats, a moderate dose (45 mg/kg/day) of minocycline was most effective. In conclusion, minocycline exerts neuroprotective effects in rodent models of neurodegenerative diseases. Anti-inflammatory, antiapoptotic, and antioxidant activities are discussed as the basis of this effect. However, there is insufficient information from these animal models on side effects of minocycline therapy.

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.

Prognostic relevance of global histone 3 lysine 9 acetylation in ependymal tumors.

OBJECT: Ependymal tumors are highly variable in clinical and molecular behavior and affect both children and adults. Regarding the paucity of appropriate experimental models, the underlying molecular mechanisms of their behavioral variability are poorly understood. Considering the increasing evidence of epigenetic changes in various tumors, in addition to the preclinical success of epigenetic-based therapeutics in tumors of the CNS, epigenetic study of ependymal tumors is warranted. METHODS: Using immunohistochemistry, the authors investigated the patterns of global acetylation of lysine position 9 of histone 3 (H3K9Ac), an epigenetic marker of active gene transcription, in 85 ependymal tumors with various WHO grades and clinicopathological characteristics. RESULTS: Most of the nuclei in all ependymal tumors were H3K9Ac negative (mean ± SD 65.9% ± 26.5 vs 34.1% ± 26.5% positive, p < 0.0001). Subependymomas had more H3K9Ac-positive nuclei (67.2% ± 10.2%) than myxopapillary ependymomas, ependymomas, and anaplastic ependymomas (p < 0.05). Additionally, intracranial parenchymal tumors had significantly fewer H3K9Ac-positive nuclei (13.1% ± 21.9%) than tumors of other CNS localizations (p < 0.001), and supratentorial ventricular tumors had the highest number of H3K9Ac-positive nuclei (66.4% ± 11.8%) among CNS ependymal tumors (p < 0.0001). The H3K9Ac pattern in ependymal tumors also revealed prognostic significance such that tumors with less than 20% acetylated nuclei had a higher probability of recurrence than tumors with 20% or more acetylated nuclei (p = 0.0327), and recurrent tumors had significantly fewer H3K9Ac-positive nuclei than primary ones (16% ± 22.5% vs. 38% ± 25.8%; p < 0.0001). However, the effect of tumor location on survival of patients was nonsignificant in a multivariate survival analysis, and H3K9 acetylation levels of tumors contributed independently to the survival of patients. In addition, ependymal tumors with more than or equal to 20% H3K9 acetylated cells had lower MIB-1 expression than those with less than 20% H3K9 acetylated cells (p < 0.01). CONCLUSIONS: Global H3K9Ac contributes independently to the prognosis of patients with ependymal tumors such that tumors with lower H3K9Ac values have a higher probability of recurrence and are more proliferative. Additionally, subependymomas have a higher H3K9Ac profile than other ependymal tumor subclasses, underlining their benign clinical behavior.

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.

Osteonectin expression in surrounding stroma of craniopharyngiomas: association with recurrence rate and brain infiltration.

Craniopharyngioma is an epithelial tumor of the sellar region with a high survival rate but a high rate of recurrence, especially in children. Hypothalamic involvement, tumor recurrence, and multiple treatments result in clinical deterioration and impaired quality of life. Using immunohistochemistry, we investigated the expression pattern of osteonectin, a marker of tumor invasion and aggressive behavior, in 43 cases of craniopharyngioma. We observed a positive correlation of osteonectin expression in connective-type stromal tissue surrounding the epithelial tumor cells of craniopharyngioma with the extent of central nervous system infiltration and recurrence rate (P < .001). Given the previous success of chemotherapeutic agents that target the tumor microenvironment, our findings on osteonectin expression in stroma of craniopharyngiomas might, hopefully, be a guide to find newer prognostic markers capable of estimating the risk of progression or recurrence. They may also aid in the development of therapeutics that target tumor microenvironment to improve patient outcome.

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.