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Systemic inflammation can have devastating effects on the central nervous system via its resident immune cells, the microglia. One of the primary mediators of this inflammation is inflammasomes, multiprotein complexes that trigger a release of inflammatory proteins when activated. Melatonin, a hormone with anti-inflammatory effects, is an attractive candidate for suppressing such inflammation. In this study, we have investigated how melatonin alters the microRNA (miRNA) transcriptome of microglial cells. For that purpose, we have performed RNA sequencing on a lipopolysaccharide and adenosine triphosphate (LPS + ATP) induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation model in the N9 mouse microglial cell line, with and without melatonin pre-treatment. We have identified 136 differentially expressed miRNAs in cells exposed to LPS + ATP compared to controls and 10 differentially expressed miRNAs in melatonin pre-treated cells compared to the inflammasome group. We have identified miR-155-3p as a miRNA that is upregulated with inflammasome activation and downregulated with melatonin treatment. We further confirmed this pattern of miR-155-3p expression in the brains of mice injected intraperitoneally with LPS. Moreover, an overexpression study with miRNA-155-3p mimic supported the idea that the protective effects of melatonin in NLRP3 inflammasome activation are partly associated with miRNA-155-3p inhibition.

The development of the CNS is a complex and well-regulated process, where stem cells differentiate into committed cells depending on the stimuli from the microenvironment. Alterations of oxygen levels were stated to be significant in terms of brain development and neurogenesis during embryonic development, as well as the adult neurogenesis. As a product of oxygen processing, hydrogen peroxide (H2O2) has been established as a key regulator, acting as a secondary messenger, of signal transduction and cellular biological functions. H2O2 is involved in survival, proliferation, and differentiation of neural stem cells into committed cells of the CNS. Effects of different concentrations of exogenous H2O2 on neuronal differentiation and the molecular pathways involved are yet to be clearly understood. Here, we investigated the concentration-dependent effects of H2O2 on differentiation of neural stem cells using CGR8 embryonic mouse stem cell line. We have demonstrated that treated doses of H2O2 suppress neural differentiation; additionally, our study suggests that relatively high doses of exogenous H2O2 suppress the differentiation process of neural stem cells through AKT and p38 pathways.

The development of the CNS is a complex and well-regulated process, where stem cells differentiate into committed cells depending on the stimuli from the microenvironment. Alterations of oxygen levels were stated to be significant in terms of brain development and neurogenesis during embryonic development, as well as the adult neurogenesis. As a product of oxygen processing, hydrogen peroxide (H

Resveratrol is a natural polyphenolic compound with a wide range of biological activities such as antioxidant, anti-carcinogenic, anti-obesity, anti-aging, anti-inflammatory, immunomodulatory properties. Accumulating evidence suggests that resveratrol has pharmacological benefits in life-threatening diseases, including cardiovascular disease, cancer, diabetes, and neurodegenerative diseases. Resveratrol is widely known for its anti-inflammatory properties; however, signaling mechanisms of anti-inflammatory action are still elusive. Studies have illustrated that resveratrol can control different regulatory pathways by altering the expression and consequently regulatory effects of microRNAs. Our study aims to clarify the regulatory mechanisms of resveratrol in its anti-inflammatory features in the N9 microglial cell line. Our results demonstrated that resveratrol inhibits LPS- and ATP-activated NLRP3 inflammasome and protects microglial cells upon oxidative stress, proinflammatory cytokine production, and pyroptotic cell death resulting from inflammasome activation. Additionally, resveratrol inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling and activates AMPK/Sirt1 pathways. Furthermore, our results indicated that resveratrol downregulated inflammasome-induced miR-155 expression. Then, inhibition of AMPK and Sirt1 pathways has significantly reversed protective effect of resveratrol on miR-155 expression. To sum up, our results suggest that resveratrol suppresses the NLRP3 inflammasome and miR-155 expression through AMPK and Sirt1 pathways in microglia.

Alzheimer's disease (AD) is one of the most severe neurodegenerative diseases observed in the elderly population. Although the hallmarks of AD have been identified, the methods for its definitive diagnosis and treatment are still lacking. Extracellular vesicles (EVs) have become a promising source for biomarkers since the identification of their content. EVs are released from multiple cell types and, when released from neurons, they pass from the brain to the blood with their cargo molecules. Hence, neuron-specific EV-resident microRNAs (miRNAs) are promising biomarkers for diagnosis of AD. This study aimed to identify altered miRNA content in small neuron-derived extracellular vesicles (sNDEVs) isolated from AD patients and healthy individuals. Furthermore, we examined the role of sNDEV-resident miRNAs in neuron-glia cellular interaction to understand their role in AD propagation. We identified 10 differentially expressed miRNAs in the sNDEVs of patients via next-generation sequencing and validated the most dysregulated miRNA, let-7e, with qRT-PCR. Let-7e was significantly increased in the sNDEVs of AD patients compared with those of healthy controls in a larger cohort. First, we evaluated the diagnostic utility of let-7e via ROC curve analysis, which revealed an AUC value of 0.9214. We found that IL-6 gene expression was increased in human microglia after treatment with sNDEVs of AD patients with a high amount of let-7e. Our study suggests that sNDEV-resident let-7e is a potential biomarker for AD diagnosis, and that AD patient-derived sNDEVs induce a neuroinflammatory response in microglia.

Since their first discovery more than 20 years ago, miRNAs have been subject to deliberate research and analysis for revealing their physiological or pathological involvement. Regulatory roles of miRNAs in signal transduction, gene expression, and cellular processes in development, differentiation, proliferation, apoptosis, and homeostasis also imply their critical role in disease pathogenesis. Their roles in cancer, neurodegenerative diseases, and other systemic diseases have been studied broadly. In these regulatory pathways, their mutations and target sequence variations play critical roles to determine their functional repertoire. In this chapter, we summarize studies that investigated the role of mutations, polymorphisms, and other variations of miRNAs in respect to pathological processes.

Since their first discovery more than 20 years ago, miRNAs have been subject to deliberate research and analysis for revealing their physiological or pathological involvement. Regulatory roles of miRNAs in signal transduction, gene expression, and cellular processes in development, differentiation, proliferation, apoptosis, and homeostasis also imply their critical role in disease pathogenesis. Their roles in cancer, neurodegenerative diseases, and other systemic diseases have been studied broadly. In these regulatory pathways, their mutations and target sequence variations play critical roles to determine their functional repertoire. In this chapter, we summarize studies that investigated the role of mutations, polymorphisms, and other variations of miRNAs in respect to pathological processes.

Neuronal senescence, triggered by telomere shortening, oncogene activation, DNA damage, or oxidative stress, has been associated with neurodegenerative diseases' pathogenesis. Therefore, preventing neuronal senescence could be a novel treatment strategy for neurodegenerative diseases. Lithium (Li), the first-line treatment against bipolar disorder, has been shown to have neuroprotective effects in clinical, pre-clinical, and in vitro studies. Lithium can protect cells from senescence, and its effect on neuronal senescence was investigated in our study. Furthermore, we also investigated the effects of lithium on the senescence-associated miR-34a/Sirt1/p53 pathway. In this study, hydrogen peroxide was used as an inducer for the "stress-induced premature senescence" model. In the senescence model, we have assessed Li's effects on senescence by analyzing ß-galactosidase activity, Sudan Black B, and senescence-associated heterochromatin foci (SAHF) stainings, and on cell cycle arrest by BrdU staining. Furthermore, expression levels of senescence and cell cycle arrest-related proteins (p53, p21, p16INK4a, and SIRT1) by western blotting. Finally, the effects of Li on senescence-associated miR-34a levels were measured by quantitative PCR. We show via Sudan Black B staining, β-Gal activity assay, and by detecting SAHF, Li protects against senescence in neuronal cells. Then, lithium's effect on signaling has also been determined on pathways involved in senescence and cell cycle arrest. Moreover, we have observed that Li has a modulatory effect on miR-34a expression. Therefore, we posit that Li suppresses senescence in neuronal cells and that this effect is mediated through miR-34a/Sirt1/p53 axis.

Objectives: Microglial cells are the central regulators of inflammatory responses in the brain and spinal cord. In addition to surveillance during resting state, they become activated due to microbial molecules and pathological insults. Endogenously expressed Activated protein C (APC) is an anticoagulant molecule with anti-inflammatory and cytoprotective roles, mediated by one of its receptors, Endothelial protein C receptor (EPCR). This study aimed to examine the basal and inducible expression of EPCR and unravel the regulatory mediators of its expression in microglia. Methods: We studied probable effects of Lipopolysaccharide (LPS), Peptidoglycan (PGN), and Polyinosinic–polycytidylic acid [Poly(I:C)] on EPCR mRNA and protein levels in N9 mouse microglial cells by qPCR and flow cytometry. Then, Cyclosporin A (CsA) and Mithramycin A (MMA) were used to inhibit transcription factors in the promoter region of the EPCR gene, which are Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1), and specificity protein 1 (Sp1). Results: As a result, the Sp1 transcription factor’s chemical inhibition impaired the upregulating effects of LPS and PGN on EPCR expression. Conclusion: Thus, our data suggest that LPS and PGN gave rise to increased EPCR levels in microglia, mainly through the Sp1 transcription factor.

The NLRP3 inflammasome is a multiprotein complex that activates caspase-1 and triggers the release of the proinflammatory cytokines IL-1 beta and IL-18 in response to diverse signals. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute CNS injuries and chronic neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In the current study, we demonstrated that Sulforaphane (SFN), a dietary natural product, inhibits NLRP3 inflammasome mediated IL-1 beta and IL-18 secretion and pyroptosis in murine microglial cells. SFN decreased the secretion of IL-1 beta and IL-18, and their mRNA levels in LPS primed microglia triggered by ATP. SFN suppressed the overexpression of cleaved caspase-1 and NLRP3 protein expressions as measured by caspase activity assay and western blot, respectively. SFN also prevented caspase-1 dependent pyroptotic cell death in microglia. Our data indicate that SFN suppresses NLRP3 inflammasome via the inhibition of NF-kappa B nuclear translocation and Nrf2 mediated miRNAs expression modulation in murine microglia.

Alzheimer's disease is a chronic and progressive neurodegenerative disorder, which is the most common cause of dementia worldwide. Although amyloid plaques and neurofibrillary tangles are identified as the hallmarks of the disease, the only valid diagnostic method yet is post-mortem imaging of these molecules in brain sections. Exosome is a type of extracellular vesicles secreted into extracellular space and plays fundamental roles in healthy and pathological conditions, including cell-to-cell communication. In this study, we aimed to investigate the proteomic contents of neuron-derived exosomes (NDEs) from AD patients and healthy controls (HCs) to identify a possible marker for AD diagnosis. We identified alpha-globin, beta-globin, and delta-globin increase in neuron-derived exosomes of AD patients compared to HCs with LC-MS/MS proteomics analysis. Then, we confirmed the high hemoglobin (Hb) level in NDEs of AD patients with ELISA. We found the area under the curve of hemoglobin level as 0.6913 with ROC analysis. Cargo proteins of NDEs may be useful diagnostic biomarker for AD.

Introduction Emerging evidence suggests central roles of miRNAs in the pathogenesis of bipolar disorder (BD). Exosomes are membrane-bound vesicles acting as “biological cargo carriers” of various types of molecules including microRNAs. In this study, we aimed to investigate circulating exosomal microRNAs as potential diagnostic biomarkers for BD. Methods The exosomes were precipitated from plasma samples of patients with BD (n = 69; 15 depressed, 27 manic, 27 euthymic) and healthy controls (n = 41). Total RNA was extracted from the exosomes and the levels of miRNAs were assayed by qPCR. Dysregulated miRNAs were subjected to Kyoto Encyclopedia of Genes and Genomes” (KEGG) pathway analysis by DIANA-miRPath v3.0 to identify the predicted targets and the related pathways. Results Thirteen miRNAs showed significant differences between patients with BD and healthy individuals; among these, MiR-484, -652–3p, -142–3p remained significantly downregulated and miR-185–5p remained significantly upregulated after accounting for multiple comparisons and adjustments for potential confounders. There were no significant alterations among different states of BD. The KEEG analysis of four dysregulated miRNAs highlighted several target pathways including PI3K/Akt signaling, fatty acid biosynthesis/metabolism, extracellular matrix and adhesion pathways. Conclusion Our findings suggest that dysregulation of miRNAs might be involved in the underlying pathophysiology of BD through several biological pathways; and highlight the importance of the exosomal miRNAs for biomarker research in BD. Further longitudinal studies may clarify the roles of exosomal miRNAs and their targets in the neurobiology of BD.

Ethyl pyruvate is a molecule with anti-inflammatory and pro-metabolic effects. Ethyl pyruvate has been shown to ameliorate the clinical and pathological findings of neurodegenerative diseases such as Alzheimer’s and Parkinson’s Diseases in rodents. Its anti-inflammatory and neuroprotective effects are widely investigated in animal and cellular models. Our study aimed to investigate the mechanism of the impact of Ethyl pyruvate on NLRP3 inflammasome activation in the N9 microglial cell line. Our results indicated that ethyl pyruvate significantly suppressed LPS and ATP-induced NLRP3 inflammasome activation, decreased active caspase-1 level, secretion of IL-1β and IL-18 cytokines, and reduced the level of pyroptotic cell death resulting from inflammasome activation. Furthermore, ethyl pyruvate reduced the formation of total and mitochondrial ROS and suppressed inflammasome-induced HMGB1 upregulation and nuclear NF-κB translocation and reversed the inflammasome activation-induced miRNA expression profile for miR-223 in N9 cells. Our study suggests that ethyl pyruvate effectively suppresses the NLRP3 inflammasome activation in microglial cells regulation by miR-223 and NF-κB/HMGB1 axis.

During the past 35 years, recombinant DNA technology has allowed the production of a wide range of hematopoietic and neurotrophic growth factors including erythropoietin (EPO). These have emerged as promising protein drugs in various human diseases. Accumulated evidences have recently demonstrated the neuroprotective effect of EPO in preclinical models of acute and chronic degenerative disorders. Nevertheless, tissue protective effect of EPO could not be translated to the clinical trials because of common lethal thromboembolic events, erythropoiesis and hypertension. Although chemically modified nonerythropoietic analogs of EPO bypass these side effects, high expense, development of antidrug antibodies, and promotion of tumorigenicity are still concern especially in long-term use. As an alternative, nonerythropoietic EPO mimetic peptides can be used as candidate drugs with their high potency and selectivity, easy production, low cost, and immunogenicity properties. Recent experimental studies suggest that these peptides prevent ischemic brain injury and neuroinflammation. The results of clinical trial in patients with neuropathic pain are also promising. Herein, we summarize these studies and review advanced experimental and in silico methods in peptide drug discovery.

During the past 35 years, recombinant DNA technology has allowed the production of a wide range of hematopoietic and neurotrophic growth factors including erythropoietin (EPO). These have emerged as promising protein drugs in various human diseases. Accumulated evidences have recently demonstrated the neuroprotective effect of EPO in preclinical models of acute and chronic degenerative disorders. Nevertheless, tissue protective effect of EPO could not be translated to the clinical trials because of common lethal thromboembolic events, erythropoiesis and hypertension. Although chemically modified nonerythropoietic analogs of EPO bypass these side effects, high expense, development of antidrug antibodies, and promotion of tumorigenicity are still concern especially in long-term use. As an alternative, nonerythropoietic EPO mimetic peptides can be used as candidate drugs with their high potency and selectivity, easy production, low cost, and immunogenicity properties. Recent experimental studies suggest that these peptides prevent ischemic brain injury and neuroinflammation. The results of clinical trial in patients with neuropathic pain are also promising. Herein, we summarize these studies and review advanced experimental and in silico methods in peptide drug discovery.

Erythropoietin (EPO) is an erythropoiesis stimulating growth factor and hormone. EPO has been widely used in the treatment of chronic renal failure, cancer, and chemotherapy-related anemia for three decades. However, many clinical trials showed that EPO treatment may be associated with tumorigenesis and cancer progression. EPO is able to cross blood-brain barriers, and this may lead to an increased possibility of central nervous system tumors such as glioblastoma. Indeed, EPO promotes glioblastoma growth and invasion in animal studies. Additionally, EPO increases glioblastoma cell survival, proliferation, migration, invasion, and chemoresistancy in vitro. However, the exact mechanisms of cancer progression induced by EPO treatment are not fully understood. Posttranscriptional gene regulation through microRNAs may contribute to EPO's cellular and biological effects in tumor progression. Here, we aimed to study whether tumor suppressive microRNA, miR-451, counteracts the positive effects of EPO on U87 human glioblastoma cell line. Migration and invasion were evaluated by scratch assay and transwell invasion assay, respectively. We found that EPO decreased basal miR-451 expression and increased cell proliferation, migration, invasion, and cisplatin chemoresistancy in vitro. miR-451 overexpression by transfection of its mimic significantly reversed these effects. Furthermore, ectopic expression of miR-451 inhibited expression of its own target genes, such as metalloproteinases-2 and -9, which are stimulated by EPO treatment and involved in carcinogenesis processes, especially invasion. These findings suggest that miR-451 mimic delivery may be useful as adjuvant therapy in addition to chemotherapy and anemia treatment by EPO and should be tested in experimental glioblastoma models.

Conversion of astrocytes to neurons, via de-differentiation to neural stem cells (NSC), may be a new approach to treat neurodegenerative diseases and brain injuries. The signaling factors affecting such a cell conversion are poorly understood, and they are hard to identify in complex disease models or conventional cell cultures. To address this question, we developed a serum-free, strictly controlled culture system of pure and homogeneous “astrocytes generated from murine embryonic stem cells (ESC).” These stem cell derived astrocytes (mAGES), as well as standard primary astrocytes resumed proliferation upon addition of FGF. The signaling of FGF receptor tyrosine kinase converted GFAP-positive mAGES to nestin-positive NSC. ERK phosphorylation was necessary, but not sufficient, for cell cycle re-entry, as EGF triggered no de-differentiation. The NSC obtained by de-differentiation of mAGES were similar to those obtained directly by differentiation of ESC, as evidenced by standard phenotyping, and also by transcriptome mapping, metabolic profiling, and by differentiation to neurons or astrocytes. The de-differentiation was negatively affected by inflammatory mediators, and in particular, interferon-γ strongly impaired the formation of NSC from mAGES by a pathway involving phosphorylation of STAT1, but not the generation of nitric oxide. Thus, two antagonistic signaling pathways were identified here that affect fate conversion of astrocytes independent of genetic manipulation. The complex interplay of the respective signaling molecules that promote/inhibit astrocyte de-differentiation may explain why astrocytes do not readily form neural stem cells in most diseases. Increased knowledge of such factors may provide therapeutic opportunities to favor such conversions.

MicroRNAs (miRNAs) have recently emerged as a new class of modulators of gene expression. miRNAs control protein synthesis by targeting mRNAs for translational repression or degradation at the posttranscriptional level. These noncoding RNAs are endogenous, single-stranded molecules approximately 22 nucleotides in length and have roles in multiple facets of immunity, from regulation of development of key cellular players to activation and function in immune responses. Recent studies have shown that dysregulation of miRNAs involved in immune responses leads to autoimmunity. Multiple sclerosis (MS) serves as an example of a chronic and organ-specific autoimmune disease in which miRNAs modulate immune responses in the peripheral immune compartment and the neuroinflammatory process in the brain. For MS, miRNAs have the potential to serve as modifying drugs. In this review, we summarize current knowledge of miRNA biogenesis and mode of action and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We also review the role of miRNAs in autoimmunity, focusing on emerging data regarding miRNA expression patterns in MS. Finally, we discuss the potential of miRNAs as a disease marker and a novel therapeutic target in MS. Better understanding of the role of miRNAs in MS will improve our knowledge of the pathogenesis of this disease. Copyright © 2011 Kemal Ugur Tufekci et al.

MicroRNAs (miRNAs) are tiny regulators of gene expression on the posttranscriptional level. Since the discovery of the first miRNA 20 years ago, thousands of them have been described. The discovered miRNAs have regulatory functions in biological and pathological processes. Biologically, miRNAs have been implicated in development, differentiation, proliferation, apoptosis, and immune responses. In this work, we summarize the role of miRNA in biological processes taking into account the various areas named above.

About 20 years have passed since the discovery of the first microRNA (miRNA) and by now microRNAs are implicated in a variety of physiological and pathological processes. Since the discovery of the powerful effect miRNAs have on biological processes, it has been suggested that mutations affecting miRNA function may play a role in the pathogenesis of human diseases. Over the past several years microRNAs have been found to play a major role in various human diseases. In addition, many studies aim to apply miRNAs for diagnostic and therapeutic applications in human diseases. In this chapter, we summarize the role of miRNAs in pathological processes and discuss how miRNAs could be used as disease biomarkers.

Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Inflammatory responses manifested by glial reactions, T cell infiltration, and increased expression of inflammatory cytokines, as well as other toxic mediators derived from activated glial cells, are currently recognized as prominent features of PD. The consistent findings obtained by various animal models of PD suggest that neuroinflammation is an important contributor to the pathogenesis of the disease and may further propel the progressive loss of nigral dopaminergic neurons. Furthermore, although it may not be the primary cause of PD, additional epidemiological, genetic, pharmacological, and imaging evidence support the proposal that inflammatory processes in this specific brain region are crucial for disease progression. Recent in vitro studies, however, have suggested that activation of microglia and subsequently astrocytes via mediators released by injured dopaminergic neurons is involved. However, additional in vivo experiments are needed for a deeper understanding of the mechanisms involved in PD pathogenesis. Further insight on the mechanisms of inflammation in PD will help to further develop alternative therapeutic strategies that will specifically and temporally target inflammatory processes without abrogating the potential benefits derived by neuroinflammation, such as tissue restoration.

Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Inflammatory responses manifested by glial reactions, T cell infiltration, and increased expression of inflammatory cytokines, as well as other toxic mediators derived from activated glial cells, are currently recognized as prominent features of PD. The consistent findings obtained by various animal models of PD suggest that neuroinflammation is an important contributor to the pathogenesis of the disease and may further propel the progressive loss of nigral dopaminergic neurons. Furthermore, although it may not be the primary cause of PD, additional epidemiological, genetic, pharmacological, and imaging evidence support the proposal that inflammatory processes in this specific brain region are crucial for disease progression. Recent in vitro studies, however, have suggested that activation of microglia and subsequently astrocytes via mediators released by injured dopaminergic neurons is involved. However, additional in vivo experiments are needed for a deeper understanding of the mechanisms involved in PD pathogenesis. Further insight on the mechanisms of inflammation in PD will help to further develop alternative therapeutic strategies that will specifically and temporally target inflammatory processes without abrogating the potential benefits derived by neuroinflammation, such as tissue restoration.

Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases as strict regulation of integrated mitochondrial functions is essential for neuronal signaling, plasticity, and transmitter release. Many lines of evidence suggest that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD). Several PD-associated genes interface with mitochondrial dynamics regulating the structure and function of the mitochondrial network. Mitochondrial dysfunction can induce neuron death through a plethora of mechanisms. Both mitochondrial dysfunction and neuroinflammation, a common denominator of PD, lead to an increased production of reactive oxygen species, which are detrimental to neurons. The transcription factor nuclear factor E2-related factor 2 (Nrf2, NFE2L2) is an emerging target to counteract mitochondrial dysfunction and its consequences in PD. Nrf2 activates the antioxidant response element (ARE) pathway, including a battery of cytoprotective genes such as antioxidants and anti-inflammatory genes and several transcription factors involved in mitochondrial biogenesis. Here, the current knowledge about the role of mitochondrial dysfunction in PD, Nrf2/ARE stress-response mechanisms, and the evidence for specific links between this pathway and PD are summarized. The neuroprotection of nigral dopaminergic neurons by the activation of Nrf2 through several inducers in PD is also emphasized as a promising therapeutic approach.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although the exact cause of the dopaminergic neurodegeneration remains elusive, recent postmortem and experimental studies have revealed an essential role for neuroinflammation that is initiated and driven by activated microglial and infiltrated peripheral immune cells and their neurotoxic products (such as proinflammatory cytokines, reactive oxygen species, and nitric oxide) in the pathogenesis of PD. A bacterial endotoxin-based experimental model of PD has been established, representing a purely inflammation-driven animal model for the induction of nigrostriatal dopaminergic neurodegeneration. This model, by itself or together with genetic and toxin-based animal models, provides an important tool to delineate the precise mechanisms of neuroinflammation-mediated dopaminergic neuron loss. Here, we review the characteristics of this model and the contribution of neuroinflammatory processes, induced by thein vivoadministration of bacterial endotoxin, to neurodegeneration. Furthermore, we summarize the recent experimental therapeutic strategies targeting endotoxin-induced neuroinflammation to elicit neuroprotection in the nigrostriatal dopaminergic system. The potential of the endotoxin-based PD model in the development of an early-stage specific diagnostic biomarker is also emphasized.

To the Editor: We read, with interest, the clinical trial study of erythropoietin (EPO) on patients with stroke by Ehrenreich et al and the comment paper by Dame.1,2 This clinical study has failed to show any effect of EPO on patients with acute ischemic stroke. Furthermore, the combination of EPO with thrombolytic therapy caused serious side effects such as intracerebral hemorrhage. Stroke Therapy Academic Industry Roundtable (STAIR) …