MicroRNAs: Key Players in Microglia and Astrocyte Mediated Inflammation in CNS Pathologies.

The significance of microglia and astrocytes in neural development, in maintaining synaptic connections and homeostasis in the healthy brain is well established. Microglia are dynamic immune cells of the brain that elicit an immune response during brain damage and also participate in tissue repair and regeneration, while astrocytes contribute to the local inflammatory response by producing proinflammatory cytokines and resolving neuronal damage through production of anti-inflammatory cytokines and neurotrophic factors. Recent efforts have focused on elucidating the epigenetic mechanisms which regulate glial cell behavior in normal and pathologic states. An important class of epigenetic regulators is microRNAs (miRNAs) which are small non-coding RNA molecules that regulate gene expression posttranscriptionally. Certain dysregulated miRNAs contribute to chronic microglial inflammation in the brain, thereby leading to progression of neurological diseases like Alzheimer's disease, traumatic injury, amyotrophic lateral sclerosis and stroke. Further, several miRNAs are differentially expressed in astrocytes after ischemia and spinal cord injury. Despite knowledge about miRNAs in neuroinflammation, little is known about effective delivery routes and pharmacokinetic data for miRNA based therapeutics. This review summarizes the current research on the role of miRNAs in promoting and inhibiting inflammatory response of microglia and astrocytes in a disease-specific manner. In addition, miRNA delivery as a therapeutic strategy to treat neuroinflammation is discussed.

Potential drugs targeting microglia: current knowledge and future prospects.

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.