Despite its widespread use, the underlying mechanisms of high frequency stimulation (HFS), as used in deep brain stimulation (DBS) therapy, remain unknown. HFS has been shown to directly modulate astrocyte activation, contributing to HFS beneficial effects. In this context, astrocytes may be considered key players in promoting the wide range of observed HFS therapeutic effects. Reactive astrocytes may have a dual role in neurological diseases, displaying neurotoxic or neuroprotective phenotypes depending on the nature of the immune or inflammatory microenvironments or insults. These phenotypes are defined by its polarization state. While the A1 subtype might be pro-inflammatory, the A2 subtype has been shown to be anti-inflammatory and neuroprotective. Given the importance of understanding the mechanisms of action of HFS to improve therapeutic efficacy, as well as the relevant role of astrocytes in this response, we have decided to address the following question: Can HFS change the astrocytic phenotype from a neurotoxic pro-inflammatory (subtype A1) to a neuroprotective anti-inflammatory phenotype (subtype A2) and consequently reestablish adequate neurophysiological conditions in patients with advanced neurological diseases? To test this hypothesis, we will evaluate the ability of HFS to alter the polarization phenotype of astrocytes in vitro. Astrocytes will be first actived by a TNF-± treatment and then stimulated with HFS at 130 Hz for 1 min. The mRNA expression of cytokines, neurotrophic factors, C3 component complement, as well as the immunofluorescence against the astrocyte marker GFAP, will be evaluated at different time points following the stimulation. Findings from our experiments will generate data on the potential effects of HFS on astrocytic phenotypes and may help us to uncover novel targets for anti-inflammatory drugs.
News published in Agência FAPESP Newsletter about the scholarship: