CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 12, Issue 6, 2013

Sepsis-associated encephalopathy (SAE) is a neurological dysfunction induced by sepsis, which is associated with high morbidity and mortality. However, at present, the cellular and molecular mechanisms of SAE have remained elusive. The pathogenesis of SAE is complex and multifactorial, in which activated inflammation is recognized as a major factor. Pathological characteristics of SAE include blood- brain barrier (BBB) disruption, reduction of cerebral blood fluid (CBF) and glucose uptake, inflammatory response and activation of microglia and astrocytes. The BBB disruption induces the leakage of immune cells and inflammatory mediators, which trigger an inflammatory response in the brain. Inflammatory mediators released by activated microglia and astrocytes cause neuronal loss and brain function defect. In the review we describe the most recent findings in the pathogenesis of SAE and focus on summarizing the major mechanisms related to SAE pathogenesis.

Inflammation plays a critical role in the progression of neurodegenerative diseases. Microglia are the resident macrophages of the central nervous system (CNS) which actively take part in the neuronal development of CNS and are involved in clearance of pathogens as well as cellular debris from the system upon insult to this organization. Chronic activation of microglia in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) as well as inflammatory conditions of CNS such as multiple sclerosis (MS) results in overall upregulation of pro-inflammatory cytokines and chemokines in the brain parenchyma. This compromises the neuronal health which further activates microglia by releasing death associated molecules such as neuromelanin, Aβ peptides and cellular debris at the lesion site thereby forming a vicious cycle of disease advancement. Targeting microglial activation has proven to be a viable option in the treatment of inflammation related neurodegenerative diseases. This review will discuss the central position of inflammation and therapeutic strategies aiming to alleviate disease progression in some of the important inflammatory conditions of CNS.

Background: Despite the significant role microglia play in the pathology of multiple sclerosis (MS), medications that act within the central nervous system (CNS) to inhibit microglia have not yet been identified as treatment options. Objective: We screened 1040 compounds with the aim of identifying inhibitors of microglia to reduce neuroinflammation. Methods: The NINDs collection of 1040 compounds, where most are therapeutic medications, was tested at 10 μM final concentration on lipopolysaccharide (LPS)-activated human microglia. An ELISA was run on the media to measure the level of TNF-α as an indicator of microglia activity. For compounds that reduce LPS-activated TNF-α levels by over 50%, considered as a potential inhibitor of interest, toxicity tests were conducted to exclude non-specific cytotoxicity. Promising compounds were subjected to further analyses, including toxicity to other CNS cell types, and multiplex assays. Results: Of 1040 compounds tested, 123 reduced TNF-α levels of LPS-activated microglia by over 50%. However, most of these were cytotoxic to microglia at the concentration tested while 54 were assessed to be non-toxic. Of the latter, spironolactone was selected for further analyses. Spironolactone reduced TNF-α levels of activated microglia by 50-60% at 10 μM, and this concentration did not kill microglia, neurons or astrocytes. In multiplex assays, spironolactone reduced several molecules in activated microglia. Finally, during the screening, we identified 9 compounds that elevated further the TNF-α levels in LPS-activated microglia. Conclusion: Many of the non-toxic compounds identified in this screen as inhibitors of microglia, including spironolactone, may be explored as viable therapeutic options in MS.

Diffuse and unstoppable infiltration of brain and spinal cord tissue by neoplastic glial cells is the single most important therapeutic problem posed by the common glioma group of tumors: astrocytoma, oligoastrocytoma, oligodendroglioma, their malignant variants and glioblastoma. These neoplasms account for more than two thirds of all malignant central nervous system tumors. However, most glioma research focuses on an examination of the tumor cells rather than on host-specific, tumor micro-environmental cells and factors. This can explain why existing diffuse glioma therapies fail and why these tumors have remained incurable. Thus, there is a great need for innovation. We describe a novel strategy for the development of a more effective treatment of diffuse glioma. Our approach centers on gaining control over the behavior of the microglia, the defense cells of the CNS, which are manipulated by malignant glioma and support its growth. Armoring microglia against the influences from glioma is one of our research goals. We further discuss how microglia precursors may be genetically enhanced to track down infiltrating glioma cells.

In order to understand microglial senescence it is important to also understand neuroinflammation because the distinction between senescent and activated microglia is a fine one to make and not always made easily. Indeed, it is not easy to reliably identify activated microglia which is why we spend some effort here discussing intricacies associated with both acute and chronic neuroinflammation before addressing the subject of microglial senescence. The idea of microglial senescence in the context of aging-related neurodegenerative disease (NDD) pathogenesis represents a relatively recent idea that emerged largely because of the many caveats and inconsistencies found to be associated with the belief that neuroinflammation is a critical event in NDD pathogenesis. In this paper, we discuss most of these discrepancies and explain why microglial senescence can provide a better conceptual framework for understanding NDD mechanisms and for devising radically different pharmacological approaches to treatment.

Neuropathic pain is a serious consequence of injury or disease in the nervous system itself. Current treatment options for this condition are often unsatisfactory. From being originally viewed as a diseased caused by neuronal dysfunction, a growing body of evidence implicate activated microglia as a key player in the development of this pain condition. In this review, some of the evidence for this proposal is briefly discussed and placed in a translational context, pointing out the difficulties in translating commonly used animal models of neuropathic pain to the clinical condition, as well as emphasizing the broader role of activated microglia in the injured or diseased nervous system.

Expression of functional glutamate receptors (GluR) on glial cells in the developing and mature brain has been recently established. Over the last decade there has been physiological, molecular and biochemical evidence suggesting the presence of GluR on microglia. However, the significance of GluR activation in microglia remains largely unknown. In this review, we discuss the expression of GluR on microglia and the effect of GluR activation on microglial function. Microglia are the resident immune cells of the central nervous system, and activation of GluR in them has been shown to regulate their immunological response which may be either neuroprotective or neurotoxic. Microglial activation is known to initiate a myriad of molecular events such as nitric oxide production, free radicals generation, disruption of calcium regulation and release of proinflammatory cytokines, proteases, neurotransmitters, and excitatory amino acids, primarily glutamate. Since microglial activation has been implicated in several neuropathologies, an understanding of the pathway coupled to the various microglial GluR will help to develop therapeutic interventions for ameliorating microglia-mediated damage.

Iron is a vital element required by almost all cells for their normal functioning. The well-established role of iron in oxidative metabolism, myelination and synthesis of neurotransmitter makes it an indispensable nutrient required by the brain. Both iron deficiency and excess have been associated with numerous patho-physiologies of the brain, suggesting a need for iron homeostasis. Various studies have reported that the immune effector cells of the brain, the microglial cells, are involved in iron homeostasis in the brain. Microglial cells, which accumulate iron during the developmental period, have a role in myelination process. Along with the increased iron accumulation documented in neurodegenerative diseases, the striking finding is the presence of iron positive microglial cells at the foci of lesion. Though excess iron within activated microglia is demonstrated to enhance the release of pro-inflammatory cytokines and free radicals, a complete understanding of the role of iron in microglia is lacking. The present knowledge on iron mediated changes, in the functions of microglia is summarized in this review.

Inflammation in the central nervous system (CNS) may occur as a result of trauma, infection or neurodegenerative stimuli and is characterized by activation of microglia, the resident immune cells of the CNS. Activated microglia proliferate rapidly, migrate to the site of injury or infection and elicit immune response by phagocytosis of cell debris, production of cytokines, chemokines and reactive oxygen species, and presentation of antigens to other immune cells. In addition, microglia participate in tissue repair by producing neurotrophic factors. However, when microglia are chronically activated, they become neurotoxic to the surrounding CNS parenchyma. Chronic activation of microglia has been shown to augment neurodegeneration in Parkinson’s disease (PD), Alzheimer’s disease (AD), brain injury and number of other CNS pathologies. Identification of factors that control microglial activation, therefore, has become the major focus of recent research. A number of herbal and chemical compounds have been shown to attenuate microglial activation. However, these compounds exhibit non-specificity and produce unpleasant side-effects. Here, we provide a comprehensive review on some of the currently available drugs known to reduce microglial activation, their molecular targets and the subcellular signaling networks on which they act. We also review some of the newly emerging therapeutic avenues such as ‘epidrugs’ and finally emphasize on the importance of targeted drug delivery systems for alleviating microglia-mediated neurotoxicity.

Notch signaling pathway is a major player in normal development in neurons, oligodendrocytes and astrocytes as well as neurological disorders of the central nervous system (CNS). Microglia, one of the major types of glial cells in the CNS, partakes in diverse roles within the CNS mainly related to normal brain development and inflammatory diseases, yet the involvement of Notch signaling pathway in microglia has remained elusive and has only recently been recognized suggesting its putative role in microglial maturation and activation. Notch ligands and receptors are constitutively expressed by microglia in developing brain. Notch signaling pathway is important for the maintenance of microglial population during early development as in other glial cells in normal development. Remarkably, Notch signaling pathway is also involved in microglial activation and inflammation process in neuroinflammatory diseases in both postnatal and adult rats. Targeting Notch signaling is therefore a promising strategy for prevention of neurodevelopmental diseases and development of future therapies for the treatment of neuroinflammatory disorders. This review highlights some recent findings of Notch signaling in microglia, both in normal development and pathological conditions.

Chemokines may play a role in leukocyte migration across the blood-brain barrier (BBB) during neuroinflammation and other neuropathological processes, such as epilepsy. The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family that binds several chemokines, including CCL3 (macrophage inflammatory protein-1alpha, MIP-1alpha), CCL4 (macrophage inflammatory protein-1beta, MIP-1beta) and CCL5 (RANTES). The current review examines the relationship between CCR5 and the microglia in different neurological disorders and models of CNS injury. CCR5 expression is upregulated in different neurological diseases, where it is often immunolocalized in microglial cells. A multistep cascade couples CCR5 activation by chemokines to Ca(2+) increases in human microglia. Because changes in [Ca(2+)] (i) affect chemotaxis, secretion, and gene expression, pharmacologic modulation of this pathway may alter inflammatory and degenerative processes in the CNS. Consequently, targeting CCR5 by using CCR5 antagonists may attenuate critical aspects of neuroinflammation in different models of neurological disorders. To illustrate the interaction between CCR5 and microglia in the CNS, we used a model of excitotoxicity, and demonstrate the intimate involvement of CCR5 in neuron injury and inflammation attendant to kainic acid (KA)-induced neurotoxicity. CCR5 participates in neuronal injury caused by the excitotoxin, KA, brings inflammatory cells to the sites of KA-induced CNS injury, defines the extent of tissue loss after KA exposure and limits reparative responses. We used a SV40-derived vector carrying an interfering RNA (RNAi) that targets CCR5. Delivered directly to the bone marrow, this vector decreased CCR5 expression in circulating cells. Animals so treated showed greatly reduced expression of CCR5 and its ligands (MIP-1alpha and RANTES) in the CNS, including in the brain vasculature, decreased BBB leakage, demonstrated greater KA-stimulated neurogenesis and increased migration of bone marrow-derived cells to the brain to become neurons. Thus, therapeutic targeting of CCR5 may allow control of potentially injurious neuroinflammatory responses, including decrease in microglial cells activation and proliferation, and facilitate neurogenic repair in seizure-induced and, potentially, other forms of CNS injury.

Purslane (Portulaca oleraceae L.), a member of the Portulacaceae family, is widespread as a weed and has been ranked as the eighth most common plant in the world. In order to evaluate purslane herbal aqueous juice as a neuroprotective agent, the antioxidant activity of purslane juice was assessed in vitro and the neuroprotective effects of purslane (1.5 mL/Kg bwt) on rotenone (12 mg/Kg bwt for 12 days) induced biochemical changes and apoptosis in striatum of rats were also examined. The repeated administration of rotenone produced dramatic increases in intercellular content of calcium, dopamine metabolites and apoptosis in the striatum. In addition, rotenone administration caused significant decrease in complex I activity. These biochemical changes and apoptosis inductions were effectively counteracted by administration of purslane. Overall, the present study demonstrated the neuroprotective role of purslane in the striatum and proposes its prophylactic potential against developing brain damage and Parkinson's disease induction followed by rotenone administration, and that purslane may be considered as a potential neuroprotective agent against environmental factors affecting the function of the dopaminergic system.

Amyloid-β (Aβ) plays an important role in Alzheimer’s disease (AD) progression and is associated with synaptic damage and neuronal death. Epidemiological and experimental studies indicate that hypercholesterolemia and hyperhomocysteinemia increase susceptibility to AD; however, the exact impact and mechanisms involved are largely unknown. Few studies have addressed the combined effects of the above compounds, which are considered to be risk factors for developing AD, on Aβ-induced neurotoxicity. The aim of the present work was to analyze the relationships between homocysteine (Hcy) and cholesterol and their role in Aβ toxicity in human neuroblastoma cells, as well as the mechanisms associated with this neurotoxicity. In addition to finding that Hcy is involved in cholesterol homeostasis in neurons, we demonstrate that the combined effect of cholesterol and Hcy in the presence of copper significantly increases the levels of reactive oxygen species and may render neurons more vulnerable to Aβ.

The isocitrate dehydrogenase (IDH) enzymes were initially identified as essential components of the Krebs cycle. IDH mutations were thought to be incompatible with cell survival. However, 90% of glioblastomas were recently shown to be associated with somatic mutations in these enzymes, indicating a possible role for IDH in promoting cellular survival in hypoxic environments. Our proteomic analysis of rats given 10 minutes of middle cerebral artery occlusion to induce transient ischemia demonstrates a significant decrease in IDH expression. We have recapitulated this decrease in an in vitro model using primary cortical neurons exposed to acute oxygen and glucose deprivation. Given the role of IDHs in energy metabolism and antioxidant production, we hypothesize that the IDHs may serve as first-line, rapid-response enzymes that regulate survival in environments of energetic or oxidative stress. In order to identify the specific events that regulate IDH enzymes, HT-22 neural cells were subjected to either a selective energetic challenge or a pure oxidative stress. In response to the non-lethal energetic challenge induced by substituting galactose for glucose, we observed increased IDH1, 2, and 3 expression and cessation of cellular proliferation. No change in expression of any IDH isoform was observed when neural cells were subjected to subtoxic oxidative stress via glutathione depletion. Taken together, these data imply that IDH expression rapidly responds to changes in energetic status, but not to oxidative stress. These data also suggest that IDH enzymes respond not only to allosteric modulation, but can also change patterns of expression in response to moderate stress in an effort to maximize ATP production and survival.

Patients with schizophrenia exhibit various clinical symptoms including positive and negative symptoms, neurocognitive impairments and mood disturbances. Although a series of second generation antipsychotics (SGAs) (e.g., risperidone, olanzapine and quetiapine) have been developed in the past two decades, clinical reports do not necessarily show advantages over first generation antipsychotics (FGAs) in the treatment of schizophrenia, especially in their efficacy against cognitive impairment and ability to cause extrapyramidal side effects (EPS). Recently, several lines of studies have revealed therapeutic roles of 5-HT receptors in modulating cognitive impairments and extrapyramidal motor disorders. Specifically, inhibition of 5-HT1A, 5-HT3 and 5-HT6 receptors or activation of 5-HT4 receptors alleviates cognitive impairments (e.g., deficits in learning and memory). In addition, stimulation of 5-HT1A receptors or inhibition of 5-HT3 and 5-HT6 receptors as well as 5-HT2A/2C receptors can ameliorate extrapyramidal motor disorders. Thus, controlling the activity of 5-HT1A, 5-HT3 or 5-HT6 receptors seems to provide benefits by both alleviating cognitive impairments and reducing antipsychotic-induced EPS. This article reviews the functional roles and mechanisms of 5-HT receptors in the treatment of schizophrenia, focusing on the serotonergic modulation of cognitive and extrapyramidal motor functions, and illustrates future therapeutic strategies.

Vascular and metabolic dysfunctions and mitochondrial failure are now believed to be contributors to Alzheimer's disease (AD) pathogenesis. Vascular dysfunction includes reduced cerebral blood flow (CBF), blood-brain barrier (BBB) disturbances and cerebral amyloid angiopathy (CAA). Mitochondrial failure results in deregulation of Ca2+ homeostasis and elevated reactive oxygen species (ROS) generation, both of which are linked to neurotoxicity. Increased levels of ROS stimulate proinflammatory gene transcription and release of cytokines, such as IL-1, IL-6, and TNF-α, and chemokines, thereby inducing neuroinflammation. Conversely, inflammatory reactions activate microglia and astrocytes to generate large amounts of ROS, so neuroinflammation could be perceived as a cause and a consequence of chronic oxidative stress. The interaction between oxidative stress and neuroinflammation leads to amyloid-β (Aβ) generation. The deposition of Aβ peptide in the brain generates a cascade of pathological events, including the formation of neurofibrillary tangles (NFTs), inflammatory reactions, increased oxidative stress and mitochondrial dysfunction, which are causative factors of cell death and dementia. The purpose of this paper is to provide current evidence on vascular dysfunction and mitochondrial failure, both in neurons and glia and in brain vascular wall cells in the context of potential application for treatment of AD and other neurodegenerations.

Until now the overlapping and diverse pharmacological protective mechanisms of different compounds in the treatment of cerebral ischemia, both on the signaling pathway and network levels have not been revealed. In order to find differential pathway networks from gene expression profiles of hippocampus of ischemic mice treated with baicalin (BA), ursodeoxycholic acid (UA) and jasminoidin (JA), a microarray comprising 16,463 genes, FDA Arraytrack software and Ingenuity Pathway Analysis, was employed. A total of 5, 8, 11, 9 networks and 6, 7, 40, 16 pathways were found in vehicle (vs sham), BA, UA and JA (vs vehicle), respectively. Only 4 and 7 overlapping pathways were shared between BA and UA, UA and JA, accounting for 9.3% and 14.3% of the total number of all pathways, respectively. BA, UA and JA all acted on Ca2+-dependent signaling cascades in diverse links. BA intervened in arachidonic acid metabolism. UA affected eicosanoid, cyclin-dependent kinase 5, nuclear factor-κB, and T-helper 1 cell cytokine production. It was found that JA might decrease oxidative damage via nuclear factor erythroid 2-related factor 2-mediated antioxidant response. Compared to vehicle, no overlapping pathways were found among three groups. However, the total of 60 (71.4%) overlapping functions could be approximately divided into diseases and disorders, molecular and cellular functions, physiological system development and function as categories with ratio of 1:1:1. Analysis of network functions and known pathways may be two complementary paradigms for revealing potential pharmacological mechanisms based on the same phenotype variation.