Neurotoxicity due to excessive exposure to manganese (Mn) has been described as early as 1837 (Couper, Br Ann Med Pharm Vital Stat Gen Sci 1:41-42, 1837). Extensive research over the past two decades has revealed that Mn-induced neurological injury involves complex pathophysiological signaling mechanisms between neurons and glial cells. Glial cells are an important target of Mn in the brain, both for sequestration of the metal, as well as for activating inflammatory signaling pathways that damage neurons through overproduction of numerous reactive oxygen and nitrogen species and inflammatory cytokines. Understanding how these pathways are regulated in glial cells during Mn exposure is critical to determining the mechanisms underlying permanent neurological dysfunction stemming from excess exposure. The subject of this review will be to delineate mechanisms by which Mn interacts with glial cells to perturb neuronal function, with a particular emphasis on neuroinflammation and neuroinflammatory signaling between distinct populations of glial cells.
Predicting seizurogenic properties of pharmacologically active compounds is difficult due to the complex nature of the mechanisms involved and because of the low sensitivity and high variability associated with current behavioral-based methods. To identify early neuronal signaling events predictive of seizure, we exposed transgenic NF-κB/EGFP reporter mice to multiple low doses of kainic acid (KA), postulating that activation of the stress-responsive NF-κB pathway could be a sensitive indicator of seizurogenic potential. The sub-threshold dose level proximal to the induction of seizure was determined as 2.5 mg/Kg KA, using video EEG monitoring. Subsequent analysis of reporter expression demonstrated significant increases in NF-κB activation in the CA3 and CA1 regions of the hippocampus 24 hrs after a single dose of 2.5 mg/Kg KA. This response was primarily observed in pyramidal neurons with little non-neuronal expression. Neuronal NF-κB/EGFP expression was observed in the absence of glial activation, indicating a lack of neurodegeneration-induced neuroinflammation. Protein expression of the immediate-early gene, Nurr1, increased in neurons in parallel to NF-κB activation, supporting that the sub-threshold doses of KA employed directly caused neuronal stress. Lastly, KA also stimulated NF-κB activation in organotypic hippocampal slice cultures established from NF-κB/EGFP reporter mice. Collectively, these data demonstrate the potential advantages of using genetically encoded stress pathway reporter models in the screening of seizurogenic properties of new pharamacologically active compounds.
Neurotoxicity due to excessive exposure to manganese (Mn) has been described as early as 1837. Despite extensive study over the past century, it is only now becoming clear that Mn neurotoxicity involves complex pathophysiological signaling mechanisms between neurons and glial cells. Glial cells are an important target of Mn in the brain, where high levels of the metal accumulate, activating inflammatory signaling pathways that damage neurons through overproduction of numerous reactive oxygen and nitrogen species and inflammatory cytokines. Understanding how these pathways are regulated in glial cells during Mn exposure is critical to determining the mechanisms underlying permanent neurological dysfunction stemming from excess exposure. Neuroinflammatory activation of glial cells is an important mechanism in Mn neurotoxicity and in other degenerative conditions of the central nervous system. Recent studies have redefined the importance of astrocytes and microglia to neuronal development, homeostasis, and survival, transforming our understanding of the role of these cells from inert structural components to important components of brain physiology and pathology. This chapter will describe the role of microglia and astrocytes in the neurotoxicity of Mn and outline how Mn-dependent neuroinflammatory signaling mechanisms are regulated at a molecular level in these cell types. In addition, methods for studying interactions between glial cell types will also be discussed in context of deciphering which inflammatory signaling molecules are critical to neuronal injury during Mn exposure.
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