The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells

Endocannabinoids are released after brain injury and believed to attenuate neuronal damage by binding to CB(1) receptors and protecting against excitotoxicity. Such excitotoxic brain lesions initially result in primary destruction of brain parenchyma, which attracts macrophages and microglia. These inflammatory cells release toxic cytokines and free radicals, resulting in secondary neuronal damage. In this study, we show that the endocannabinoid system is highly activated during CNS inflammation and that the endocannabinoid anandamide (AEA) protects neurons from inflammatory damage by CB(1/2) receptor-mediated rapid induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) in microglial cells associated with histone H3 phoshorylation of the mkp-1 gene sequence. As a result, AEA-induced rapid MKP-1 expression switches off MAPK signal transduction in microglial cells activated by stimulation of pattern recognition receptors. The release of AEA in injured CNS tissue might therefore represent a new mechanism of neuro-immune communication during CNS injury, which controls and limits immune response after primary CNS damage.     

Inhibition of leukotriene receptors boosts neural progenitor proliferation

Neural stem and progenitor cells serve as a reservoir for new neurons in the adult brain throughout lifetime. One of the critical steps determining the net production of new neurons is neural progenitor proliferation, which needs to be tightly controlled. Since inflammation has detrimental effects on neurogenesis and the 5-lipoxygenase/leukotriene pathway is involved in inflammatory processes, we investigated the effects of leukotrienes and montelukast, a small molecule inhibitor of the leukotriene receptors CysLT(1)R and GPR17, on neural stem and progenitor cell proliferation. We demonstrate expression of the leukotriene receptor GPR17 by neural progenitors and by neural stem cells. Stimulation with excess amounts of leukotrienes did not affect progenitor proliferation, whereas blockade of GPR17 with montelukast strongly elevated neural stem and progenitor proliferation, while maintaining their differentiation fate and potential. This effect was associated with increased ERK1/2 phosphorylation suggesting an involvement of the EGF signaling cascade. Based on our results, montelukast and the inhibition of the 5-LOX pathway might be potent candidates for future therapies employing neurogenesis to promote structural and functional improvement in neurodegeneration, neuropsychiatric disease and ageing.     

Alternatively Activated Macrophages in Spinal Cord Injury and Remission: Another Mechanism for Repair?

Tissues within the central nervous system (CNS) have generally been regarded as immunologically privileged. However, in recent decades, it has been shown that immune reactions in the CNS continuously occur via various types of inflammation following autoimmune diseases and mechanical insults such as spinal cord injury (SCI). Among the various inflammatory cells associated with CNS disease, activated macrophages are classically known to induce detrimental consequences that are mediated by the secretion of pro-inflammatory molecules. Alternatively activated macrophages have recently been shown to modulate various types of CNS inflammation, including SCI. This review summarizes the potential roles of alternatively activated macrophages in the course of CNS inflammation in rodent SCI models.     

An overview of inflammation: mechanism and consequences

Inflammation is an essential response provided by the immune systems that ensures the survival during infection and tissue injury. Inflammatory responses are essential for the maintenance of normal tissue homeostasis. The molecular mechanism of inflammation is quite a complicated process which is initiated by the recognition of specific molecular patterns associated with either infection or tissue injury. The entire process of the inflammatory response is mediated by several key regulators involved in the selective expression of proinflammatory molecules. Prolonged inflammations are often associated with severe detrimental side effects on health. Alterations in inflammatory responses due to persistent inducers or genetic variations are on the rise over the last couple of decades, causing a variety of inflammatory diseases and pathophysiological conditions.     

Inflammation in central nervous system injury

Inflammation is a key component of host defence responses to peripheral inflammation and injury, but it is now also recognized as a major contributor to diverse, acute and chronic central nervous system (CNS) disorders. Expression of inflammatory mediators including complement, adhesion molecules, cyclooxygenase enzymes and their products and cytokines is increased in experimental and clinical neurodegenerative disease, and intervention studies in experimental animals suggest that several of these factors contribute directly to neuronal injury. Most notably, specific cytokines, such as interleukin-1 (IL-1), have been implicated heavily in acute neurodegeneration, such as stroke and head injury. In spite of their diverse presentation, common inflammatory mechanisms may contribute to many neurodegenerative disorders and in some (e.g. multiple sclerosis) inflammatory modulators are in clinical use. Inflammation may have beneficial as well as detrimental actions in the CNS, particularly in repair and recovery. Nevertheless, several anti-inflammatory targets have been identified as putative treatments for CNS disorders, initially in acute conditions, but which may also be appropriate to chronic neurodegenerative conditions.     

An overview of inflammation: mechanism and consequences

Inflammation is an essential response provided by the immune systems that ensures the survival during infection and tissue injury.Inflammatory responses are essential for the maintenance of normal tissue homeostasis.The molecular mechanism of inflammation is quite a complicated process which is initiated by the recognition of specific molecular patterns associated with either infection or tissue injury.The entire process of the inflammatory response is mediated by several key regulators involved in the selective expression of proinflammatory molecules.Prolonged inflammations are often associated with severe detrimental side effects on health.Alterations in inflammatory responses due to persistent inducers or genetic variations are on the rise over the last couple of decades,causing a variety of inflammatory diseases and pathophysiological conditions.     

Induction of differentiation of rat retinal, germinal, neuroepithelial cells by dbcAMP

Little is known about the factors that regulate the production of neurons during the development of the vertebrate central nervous system (CNS); however, evidence from several neuronal cell lines suggests that an increase in intracellular cAMP might trigger the process of differentiation. To determine if a similar process is involved in differentiation during normal CNS neurogenesis, we raised the intracellular level of cAMP in primary cultures of mitotically active, germinal neuroepithelial cells from fetal and postnatal rat retina. This treatment induced differentiation of the CNS precursors, causing the cells to cease DNA synthesis and increase their expression of proteins normally found in differentiated retinal cells. These results indicate that germinal neuroepithelial cell differentiation can be controlled through the cAMP second messenger system, and that the regulation of this system may in part determine the numbers and ratios of the various classes of neurons during the normal development of the CNS.     

Neurogenesis and Neuroprotection in the CNS — Fundamental Elements in the Effect of Glatiramer Acetate on Treatment of Autoimmune Neurological Disorders

Multiple sclerosis (MS) is no longer considered to be simply an autoimmune disease. In addition to inflammation and demyelination, axonal injury and neuronal loss underlie the accumulation of disability and the disease progression. Specific treatment strategies should thus aim to act within the central nervous system (CNS) by interfering with both neuroinflammation and neurodegeneration. Specific treatment strategies to autoimmune neurological disorders should aim to act within the CNS by interfering with both neuroinflammation and neurodegeneration. The cumulative effect of Glatiramer acetate (GA; Copaxone(R), Copolymer 1), an approved drug for the treatment of MS, reviewed herewith, draws a direct linkage between anti-inflammatory immunomodulation, neuroprotection, neurogenesis, and therapeutic activity in the CNS. GA treatment augmented the three processes characteristic of neurogenesis, namely, neuronal progenitor cell proliferation, migration, and differentiation. The newborn neurons manifested massive migration through exciting and dormant migratory pathways, into injury sites in brain regions, which do not normally undergo neurogenesis, and differentiated to mature neuronal phenotype, thus, counteracting the neurodegenerative course of disease. The plausible mechanism underlying this multifactorial effect is the induction of GA-reactive T cells in the periphery and their infiltration into the CNS, where they release immunomodulatory cytokines and neurotrophic factors in the injury site.     

Central modulation of croton oil induced subacute inflammation in rats

Earlier studies from this laboratory have indicated that CNS exerts a modulatory influence over acute inflammation in rats. The present study examines the existence of a similar modulatory effect of CNS on a subacute inflammatory paradigm, the croton oil-induced granuloma pouch in rats. The inflammatory exudate, collected on 6th day after croton oil administration, was found to be substantially less in intracerebroventricular (icv) cannulated and artificial cerebrospinal fluid administered rats as compared to their uncannulated saline (ip) administered counterparts. This effect may be due to stress induced by cannulation. Centrally administered pharmacological agents which attenuate central monoaminergic, cholinergic or prostaglandin systems had insignificant effects on the inflammatory exudate. However, induced increase in central noradrenergic activity was found to attenuate the inflammation when the treatment was done before, but not 48 hr after, the induction of the inflammation. In contrast, induced increase in central serotonergic activity had no effect on the volume of the inflammatory exudate at either time period. Steady state levels of rat brain noradrenaline and serotonin, but not dopamine, were enhanced by the inflammatory procedure. However, these effects may be attributed to the stress induced by croton oil inflammation. The investigation indicates that the modulatory influence of CNS remains limited to the acute phase of inflammation, being exerted mainly by the central noradrenergic system. Once the inflammation has progressed, this modulatory influence of CNS is no longer apparent.     

Control of Cell Survival in Adult Mammalian Neurogenesis

The fact that continuous proliferation of stem cells and progenitors, as well as the production of new neurons, occurs in the adult mammalian central nervous system (CNS) raises several basic questions concerning the number of neurons required in a particular system. Can we observe continued growth of brain regions that sustain neurogenesis? Or does an elimination mechanism exist to maintain a constant number of cells? If so, are old neurons replaced, or are the new neurons competing for limited network access among each other? What signals support their survival and integration and what factors are responsible for their elimination? This review will address these and other questions regarding regulatory mechanisms that control cell-death and cell-survival mechanisms during neurogenesis in the intact adult mammalian brain.     

糖尿病肾病致凝血异常的研究

糖尿病(DM)已成为世界性的常见病,其发病率高,并且随着生活水平的改善,其发病率必然还会进一步加剧。血管病变是DM的重要并发症之一,糖尿病肾病(DN)是糖尿病常见且严重的微血管并发症,与血栓形成密切相关。糖尿病肾病的进展伴随着体内凝血活性和抗凝活性的失调,同时激活自身免疫系统,发生炎症反应。炎症应答过程中释放的炎症因子损伤肾小球内皮细胞,导致抗凝活性减弱。DN患者体内血细胞激活,微粒形成增多会加强凝血活性。此外,纤溶酶抑制剂(PAI-1)与纤溶酶激活剂(t PA)的失衡会引起纤溶系统紊乱。这三个方面引起DN患者体内的高凝状态加重,并因此加速肾功能恶化,导致肾小球率过滤降低,系膜基质增多,最终引起肾小球硬化及终末期肾脏疾病。本文就糖尿病肾病致凝血异常的发生机制做一综述。     

The role of antigen presenting cells in multiple sclerosis

Multiple sclerosis (MS) is a debilitating T cell mediated autoimmune disease of the central nervous system (CNS). Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) have given light to cellular mechanisms involved in the initiation and progression of this organ-specific autoimmune disease. Within the CNS, antigen presenting cells (APC) such as microglia and astrocytes participate as first line defenders against infections or inflammation. However, during chronic inflammation they can participate in perpetuating the self-destructive environment by secretion of inflammatory factors and/or presentation of myelin epitopes to autoreactive T cells. Dendritic cells (DC) are also participants in the presentation of antigen to T cells, even within the CNS. While the APCs alone are not solely responsible for mediating the destruction to the myelin sheath, they are critical players in perpetuating the inflammatory milieu. This review will highlight relevant studies which have provided insight to the roles played by microglia, DCs and astrocytes in the context of CNS autoimmunity.     

综述: 大脑新皮层和神经发育疾病

哺乳动物进化过程中,大脑皮层逐渐增大增厚和脑容量增大,从而构成了脑神经环路复杂性的细胞生物学基础.皮层出现皱褶是非人类灵长类演化的重要特征.成体人脑大约由近860多亿个神经细胞组成,其中,在人脑神经发生高峰,每小时有近400多万个兴奋性神经细胞产生.如此高速的神经生成过程需要精确的细胞与分子调控机制.本文主要讨论调控大脑皮层增大增厚的细胞与分子机制和相关的脑发育疾病.     

Demyelination-Induced Inflammation Attracts Newly Born Neurons to the White Matter

There is compelling evidence that microglial activation negatively impacts neurogenesis. However, microglia have also been shown to promote recruitment of newly born neurons to injured areas of the gray matter. In the present study, we explored whether demyelination-triggered inflammation alters the process of neurogenesis in the white matter. A 2-μl solution of 0.04 % ethidium bromide was stereotaxically injected into the corpus callosum of adult male rats. Brain inflammation was dampened by daily injections of progesterone (5 mg/kg, s.c.) for 14 days. Control rats received oil (s.c.). Newly born neurons (DCX and Tbr2), microglia (Iba-1), astrocytes (vimentin or GFAP), oligodendrocyte progenitor cells (OPCs; NG2), and mature oligodendrocytes (CC-1) were monitored in the vicinity of demyelination site using immunofluorescent staining. Western blot was used to explore microglial polarization using M1 (iNOS) and M2 (arginase-1) markers. Focal demyelination elicited strong microglial and astroglial activation and reduced the number of OPCs at the site of demyelination. This inflammatory response was associated with enhanced number of newly born neurons in the white matter and the subventricular zone (SVZ). A proportion of newly born neurons within the white matter showed features of OPCs. Interestingly, blunting brain inflammation led to reduced neurogenesis around the demyelination area and in the SVZ. These data suggest that the white matter inflammation creates a conducive environment for the recruitment of newly born neurons. The fact that a sizable fraction of these newly born neurons adopt OPC features suggests that they could contribute to the remyelination process.     

HDAC6 regulates LPS-tolerance in astrocytes

Inflammatory tolerance is a crucial mechanism that limits inflammatory responses in order to avoid prolonged inflammation that may damage the host. Evidence that chronic inflammation contributes to the neuropathology of prevalent neurodegenerative and psychiatric diseases suggests that inflammatory tolerance mechanisms are often inadequate to control detrimental inflammation in the central nervous system. Thus, identifying mechanisms that regulate neuroinflammatory tolerance may reveal opportunities for bolstering tolerance to reduce chronic inflammation in these diseases. Examination of tolerance after repeated lipopolysaccharide (LPS) treatment of mouse primary astrocytes demonstrated that histone deacetylase (HDAC) activity promoted tolerance, opposite to the action of glycogen synthase kinase-3 (GSK3), which counteracts tolerance. HDAC6 in particular was found to be critical for tolerance induction, as its deacetylation of acetyl-tubulin was increased during LPS tolerance, this was enhanced by inhibition of GSK3, and the HDAC6 inhibitor tubacin completely blocked tolerance and the promotion of tolerance by inhibition of GSK3. These results reveal opposing interactions between HDAC6 and GSK3 in regulating tolerance, and indicate that shifting the balance between these two opposing forces on inflammatory tolerance can obliterate or enhance tolerance to LPS in astrocytes.     

Tetramethylpyrazine induces the release of BDNF from BM-MSCs through activation of the PI3K/AKT/CREB pathway

Compelling evidences suggest that transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) can be therapeutically effective for central nervous system (CNS) injuries and neurodegenerative diseases. The therapeutic effect of BM-MSCs mainly attributes to their differentiation into neuron-like cells which replace injured and degenerative neurons. Importantly, the neurotrophic factors released from BM-MSCs can also rescue injured and degenerative neurons, which plays a biologically pivotal role in enhancing neuroregeneration and neurological functional recovery. Tetramethylpyrazine (TMP), the main bioactive ingredient extracted from the traditional Chinese medicinal herb Chuanxiong, has been reported to promote the neuronal differentiation of BM-MSCs. This study aimed to investigate whether TMP regulates the release of neurotrophic factors from BM-MSCs. We examined the effect of TMP on brain-derived neurotrophic factor (BDNF) released from BM-MSCs and elucidated the underlying molecular mechanism. Our results demonstrated that TMP at concentrations of lower than 200 μM increased the release of BDNF in a dose-dependent manner. Furthermore, the effect of TMP on increasing the release of BDNF from BM-MSCs was blocked by inhibiting the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/cAMP-response element binding protein (CREB) pathway. Therefore, we concluded that TMP could induce the release of BDNF from BM-MSCs through activation of the PI3K/AKT/CREB pathway, leading to the formation of neuroprotective and proneurogenic microenvironment. These findings suggest that TMP possesses novel therapeutic potential to promote neuroprotection and neurogenesis through improving the neurotrophic ability of BM-MSCs, which provides a promising nutritional prevention and treatment strategy for CNS injuries and neurodegenerative diseases via the transplantation of TMP-treated BM-MSCs.     

Effects of neuroinflammation on the regenerative capacity of brain stem cells

In the adult brain, neurogenesis under physiological conditions occurs in the subventricular zone and in the dentate gyrus. Although the exact molecular mechanisms that regulate neural stem cell proliferation and differentiation are largely unknown, several factors have been shown to affect neurogenesis. Decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. Furthermore, in pathological conditions of the central nervous system associated with neuroinflammation, inflammatory mediators such as cytokines and chemokines can affect the capacity of brain stem cells and alter neurogenesis. In this review, we summarize the state of the art on the effects of neuroinflammation on adult neurogenesis and discuss the use of the lipopolysaccharide-model to study the effects of inflammation and reactive-microglia on brain stem cells and neurogenesis. Furthermore, we discuss the possible causes underlying reduced neurogenesis with normal aging and potential anti-inflammatory, pro-neurogenic interventions aimed at improving memory deficits in normal and pathological aging and in neurodegenerative diseases.     

p38 MAPK signalling cascades in inflammatory disease.

Inflammatory mediators released during acute and chronic diseases activate multiple intracellular signalling cascades including the mitogen-activated protein kinase (MAPK) signal transduction pathway, which plays a significant role in the recruitment of leukocytes to sites of inflammation. Stimulation of leukocytes by pro-inflammatory cytokines is known to result in the activation of the MAPK isoform p38. However, the functional consequences of p38 MAPK activation during leukocyte recruitment, including adhesion, migration and effector functions such as oxidative burst and degranulation, are only just beginning to be elucidated. Specific p38 inhibitors aimed at reducing the production of inflammatory mediators are now being developed, and might in the future provide more effective treatment for inflammatory diseases.     

3,6'-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ(1-42) intracerebroventricular injection on hippocampal neurogenesis and memory deficit

J. Neurochem. (2012) 122, 1181-1192. ABSTRACT: Evidence indicates altered neurogenesis in neurodegenerative diseases associated with inflammation, including Alzheimer's disease (AD). Neuroinflammation and its propagation have a critical role in the degeneration of hippocampal neurons, cognitive impairment, and altered neurogenesis. Particularly, tumor necrosis factor (TNF)-α plays a central role in initiating and regulating the cytokine cascade during an inflammatory response and is up-regulated in brain of AD patients. In this study, we investigated the effects of a novel thalidomide-based TNF-α lowering drug, 3,6'-dithiothalidomide, on hippocampal progenitor cell proliferation, neurogenesis and, memory tasks after intracerebroventricular injection of β-amyloid (A?)(1-42) peptide. Seven?days after Aβ(1-42) injection, a significant proliferation of hippocampal progenitor cells and memory impairment were evident. Four?weeks after Aβ(1-42) peptide injection, elevated numbers of surviving 5-bromo-2'-deoxyuridine cells and newly formed neurons were detected. Treatment with 3,6'-dithiothalidomide attenuated these Aβ(1-42) provoked effects. Our data indicate that although treatment with 3,6'-dithiothalidomide in part attenuated the increase in hippocampal neurogenesis caused by Aβ(1-42) -induced neuroinflammation, the drug prevented memory deficits associated with increased numbers of activated microglial cells and inflammatory response. Therefore, 3,6'-dithiothalidomide treatment likely reduced neuronal tissue damage induced by neuroinflammation following Aβ(1-42) injection. Understanding the modulation of neurogenesis, and its relationship with memory function could open new therapeutic interventions for AD and other neurodegenerative disorders with an inflammatory component.     

Abrogated inflammatory response promotes neurogenesis in a murine model of Japanese encephalitis

Background

Japanese encephalitis virus (JEV) induces neuroinflammation with typical features of viral encephalitis, including inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The detrimental effects of inflammation on neurogenesis have been reported in various models of acute and chronic inflammation. We investigated whether JEV-induced inflammation has similar adverse effects on neurogenesis and whether those effects can be reversed using an anti-inflammatory compound minocycline.

Methodology/Principal Findings

Here, using in vitro studies and mouse models, we observed that an acute inflammatory milieu is created in the subventricular neurogenic niche following Japanese encephalitis (JE) and a resultant impairment in neurogenesis occurs, which can be reversed with minocycline treatment. Immunohistological studies showed that proliferating cells were replenished and the population of migrating neuroblasts was restored in the niche following minocycline treatment. In vitro, we checked for the efficacy of minocycline as an anti-inflammatory compound and cytokine bead array showed that production of cyto/chemokines decreased in JEV-activated BV2 cells. Furthermore, mouse neurospheres grown in the conditioned media from JEV-activated microglia exhibit arrest in both proliferation and differentiation of the spheres compared to conditioned media from control microglia. These effects were completely reversed when conditioned media from JEV-activated and minocycline treated microglia was used.

Conclusion/Significance

This study provides conclusive evidence that JEV-activated microglia and the resultant inflammatory molecules are anti-proliferative and anti-neurogenic for NSPCs growth and development, and therefore contribute to the viral neuropathogenesis. The role of minocycline in restoring neurogenesis may implicate enhanced neuronal repair and attenuation of the neuropsychiatric sequelae in JE survivors.