It is well established that the neuroprotective effects of these antioxidant compounds involve their radical scavenging and metal chelating activity andor the regulation of antioxidant enzymes.Most interestingly, however, emerging evidence suggest that various intracellular signalling pathways, in addition to free radical scavenging properties, play a central role in the neuroprotection induced by natural products.These signalling molecules include the mitogenactivated protein, protein kinase C, and the transcription factor NF? B. These multiple mechanisms of actions that may be synergistic or additive likely explain the variability of their clinical efficacy.JAMA. Stroke. Stroke. Lancet. Neurology. Stroke. JAMA. No: ext, Fax No, Email: View publication stats View publication stats The user has requested enhancement of the downloaded file.Increasing evidence indicates that microglial activation in the central nervous system is heterogeneous, which can be categorized into two opposite types: M phenotype and M phenotype.Depending on the Tasosartan phenotypes activated, microglia can produce either cytotoxic or neuroprotective effects.In this review, we focus on the potential role of M and M microglia and the dynamic changes of MM phenotypes that are critically associated with the neurodegenerative diseases.Generally, M microglia predominate at the injury site at the end stage of disease, when the immunoresolution and repair Tasosartan process of M microglia are dampened.This phenotype transformation is very complicated in AD due to the phagocytosis of regionally distributed amyloid plaque and tangles that are released into the extracellular space.The endogenous stimuli including aggregated synuclein, mutated superoxide dismutase, A, and tau oligomers exist in the milieu that may persistently activate M proinflammatory responses and finally lead to irreversible neuron loss.The changes of microglial phenotypes depend on the disease stages and severity; mastering the stagespecific switching of MM phenotypes within appropriate time windows may provide better therapeutic benefit.Microglial activation is the principal component of neuroinflammation in the central nervous system, which provides the first line of defense whenever injury or disease occurs. The molecular and clinical evidences from postmortem analysis and positron emission tomography imaging have shown an increase of microglial activation and an increasing accumulated inflammatory mediators during the pathogenesis of neurodegenerative diseases. Neuroinflammation is now considered as a doubleedged sword that executes both detrimental and beneficial effects on the neurons, whereas others indicate that neuroinflammation is actually beneficial in certain circumstances to stimulate myelin repair, remove toxic aggregated proteins and cell debris from the CNS, as well as secretion of neurotrophic factors to prevent neural injury. Immune cells within the CNS milieu such as microglia appear to be heterogeneous with diverse functional phenotypes that range from proinflammatory M phenotypes to immunosuppressive M phenotypes.In recent years, MM paradigm of microglial activation has been increasingly studied in several neurodegenerative diseases in attempt to uncover the mechanisms of immunopathogenesis.In this review, we focus on the roles of microglial phenotypes and their switch in multiple neurodegenerative diseases.In the normal condition, the immune responses are fineregulated in the process of either initiation or resolution, so as to keep tissue homeostasis.In the pathological condition, however, the immune responses are uncontrolled and skew to either extreme of the immune balance that highly integrates with cell loss or cell dysfunction occurred within the inflammatory processes.

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