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Journal ArticleDOI

Microglial activation and its implications in the brain diseases.

01 May 2007-Current Medicinal Chemistry (Curr Med Chem)-Vol. 14, Iss: 11, pp 1189-1197
TL;DR: A comprehensive review of recent findings of mechanisms and signaling pathways by which microglial cells are activated in CNS inflammatory diseases and various forms of potential therapeutic options to inhibit the microglia activation which amplifies the inflammation-related neuronal injury in neurodegenerative diseases are summarized.
Abstract: An inflammatory process in the central nervous system (CNS) is believed to play an important role in the pathway leading to neuronal cell death in a number of neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, prion diseases, multiple sclerosis and HIV-dementia. The inflammatory response is mediated by the activated microglia, the resident immune cells of the CNS, which normally respond to neuronal damage and remove the damaged cells by phagocytosis. Activation of microglia is a hallmark of brain pathology. However, it remains controversial whether microglial cells have beneficial or detrimental functions in various neuropathological conditions. The chronic activation of microglia may in turn cause neuronal damage through the release of potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. Therefore, suppression of microglia-mediated inflammation has been considered as an important strategy in neurodegenerative disease therapy. Several anti-inflammatory drugs of various chemical ingredients have been shown to repress the microglial activation and to exert neuroprotective effects in the CNS following different types of injuries. However, the molecular mechanisms by which these effects occur remain unclear. In recent years, several research groups including ours have attempted to explain the potential mechanisms and signaling pathways for the repressive effect of various drugs, on activation of microglial cells in CNS injury. We provide here a comprehensive review of recent findings of mechanisms and signaling pathways by which microglial cells are activated in CNS inflammatory diseases. This review article further summarizes the role of microglial cells in neurodegenerative diseases and various forms of potential therapeutic options to inhibit the microglial activation which amplifies the inflammation-related neuronal injury in neurodegenerative diseases.
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Journal ArticleDOI
TL;DR: Obesity is associated with neuronal injury in a brain area crucial for body weight control in both humans and rodent models, and evidence of increased gliosis in the mediobasal hypothalamus of obese humans is found.
Abstract: Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.

1,432 citations

Journal ArticleDOI
TL;DR: Current understanding of the involvement of cytokines in neurodegenerative disorders and their potential signaling mechanisms are summarized to suggest that microglial activation and pro-inflammatory cytokines merit interest as targets in the treatment of neurodegnerative disorders.

760 citations


Cites background from "Microglial activation and its impli..."

  • ...ctivation results in a transition in microglial morphology to an meboid state facilitating the migration of these cells to the site f insult [41]....

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  • ...Microglial response to CNS pathology also results n initiation of a number of immune functions including phagoytosis, antigen processing and presentation, and production of oth cytotoxic and neurotrophic factors [41,180]....

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Journal ArticleDOI
TL;DR: The current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein–Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease and multiple sclerosis are summarized.
Abstract: Histone deacetylases (HDACs)--enzymes that affect the acetylation status of histones and other important cellular proteins--have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Pharmacological manipulations using small-molecule HDAC inhibitors--which may restore transcriptional balance to neurons, modulate cytoskeletal function, affect immune responses and enhance protein degradation pathways--have been beneficial in various experimental models of brain diseases. Although mounting data predict a therapeutic benefit for HDAC-based therapy, drug discovery and development of clinical candidates face significant challenges. Here, we summarize the current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease and multiple sclerosis.

703 citations


Cites background from "Microglial activation and its impli..."

  • ...Inflammation and apoptosis Studies of the neuroprotective roles of HDAC inhibitors, which are known to broadly affect gene expression within the immune system, have been extended to other diseases that involve inflammation and neuronal apoptosis, such as multiple sclerosi...

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Journal ArticleDOI
TL;DR: The plasticity of these signatures of microglia in health and disease is discussed and the mechanisms underlying their establishment, maintenance and regulation are considered.
Abstract: Microglia are the primary innate immune cells in the CNS In the healthy brain, they exhibit a unique molecular homeostatic 'signature', consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment

485 citations

Journal ArticleDOI
TL;DR: The role of inflammation in the pathophysiology of psychiatric disorders, such as MDD, BD, schizophrenia, and autism will be highlighted and the role of microglial activation and associated molecular cascades will be discussed as a means by which these neuroinflammatory mechanisms take place.

467 citations


Cites background from "Microglial activation and its impli..."

  • ...However, although activation of microglia is a typical hallmark of brain pathology, the extent to which it has beneficial or detrimental functions in the brain in different psychiatric disorders remains to be elucidated (Dheen et al., 2007)....

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