Glia
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Neurosteroids are synthesized either by glial cells, by neurons, or within the context of neuron-glia cross-talk. Various studies suggested neurosteroid involvement in the control of neurodegeneration but there is no evidence showing that the natural protection of nerve cells against apoptosis directly depends on their own capacity to produce neuroprotective neurosteroids. Here, we investigated the interactions between neurosteroidogenesis and apoptosis occurring in sensory structures of rats subjected to neuropathic pain generated by sciatic nerve chronic constriction injury (CCI). ⋯ Consistently, immunohistochemical investigations localized aromatase (estradiol-synthesizing enzyme) in DRG neurons but not in SGC. Pharmacological inhibition of aromatase caused apoptosis of CCI rat DRG neurons. Altogether, our results suggest that endogenously produced neurosteroids such as estradiol may be pivotal for the protection of DRG sensory neurons against sciatic nerve CCI-induced apoptosis.
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Cathepsin B (CB) is a cysteine lysosomal protease implicated in a number of inflammatory diseases. Although it is now evident that caspase-1, an essential enzyme for maturation of interleukin-1beta (IL-1beta), can be activated through the inflammasome, there is still evidence suggesting the existence of lysosomal-proinflammatory caspase pathways. In the present study, a marked induction of pro-IL-1beta, its processing to the mature form and secretion were observed in the primary cultured microglia prepared from wild-type mice after stimulation with chromogranin A (CGA). ⋯ Inconsistent with these in vitro observations, the immunoreactivity for the cleaved IL-1beta was markedly observed in microglia of the hippocampus from aged wild-type but not CB-deficient mice. These observations strongly suggest that CB plays a key role in the pro-IL-1beta maturation through the caspase-1 activation in enlarged lysosomes of CGA-treated microglia. Therefore, either pharmacological or genetic inhibition of CB may provide therapeutic intervention in inflammation-associated neurological diseases.