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MIRIAM CIANI
Assegnista di ricerca Dipartimento di Scienze della Vita sede ex-Scienze Biomediche
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Pubblicazioni
2023
- ADOLESCENCE AS A CRITICAL TIME-WINDOW FOR NEUROINFLAMMATION IN THE MOUSE: WHY SEX
MATTERS
[Abstract in Rivista]
Toscano, Ylenia; Benatti, Cristina; Alboni, Silvia; Ciani, Miriam; Rigillo, Giovanna; Tascedda, Fabio; Blom, Johanna Maria Catharina; Brunello, Nicoletta
abstract
2023
- VORTIOXETINE ATTENUATES NEUROINFLAMMATION BY MODULATING THE NOD-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3 INFLAMMASOME ACTIVATION IN MICROGLIA: IMPLICATIONS FOR COGNITIVE FUNCTION
[Abstract in Rivista]
Rigillo, G.; Ciani, M.; Benatti, C.; Blom, J. M. C.; Tascedda, F.; Pani, L.; Alboni, S.; Brunello, N.
abstract
Vortioxetine (VTX) is a multimodal antidepressant with an
extensive pharmacological profile that includes modulation of various neurotransmitter
systems, neuroprotective activity, and beneficial effects on cognitive
functions. Recent research has revealed a novel aspect of VTX's activity - its antiinflammatory
effects - that suggests an intriguing molecular mechanism may
underpin its therapeutic benefits. Neuroinflammation, dysfunctional neurogenesis
and neurotransmission, and dysregulation of the hypothalamus–
pituitary–adrenal (HPA) axis are all pivotal in the onset and progression of
depression. One particular immune-inflammatory pathway overactivated in
brain disorders is the NOD-like receptor family pyrin domain containing 3
(NLRP3) inflammasome, a multiprotein complex. This complex's activation is
mediated by NF-kB and reactive oxygen species (ROS) signalling pathways,
leading to caspase-1-dependent release of the proinflammatory cytokines, IL-1β
and IL-18. Mounting evidence implicates NLRP3 inflammasome in neuroinflammation-
related disorders, with its activation associated with cognitive
function impairment. Of note, microglia, the resident immune cells crucial for
brain plasticity, express high levels of the NLRP3-inflammasome components.
Our initial findings indicate that VTX exerts a region-dependent modulatoryeffect on the NLRP3-inflammasome system in a LPS-induced memory impairment
in vivo model. Furthermore, VTX's ability to modulate immune response
suggests that microglia could be a direct target of the drug.
AIM: In light of the compelling evidence surrounding the role of the NLRP3
inflammasome in cognitive dysfunctions and the recent discovery of VTX's anti-inflammatory
activity, we aimed to investigate the molecular effects induced by
VTX pre-treatment in the presence or absence of the inflammasome-inducer LPS
in a well-established in vitro model of mouse microglia: BV2 cells.
METHODS: To dissect the influence of VTX pre-treatment (24h) on the NLRP3
inflammasome signaling pathway and microglial polarization, we analyzed gene
and protein expression in BV2 cells stimulated with LPS or vehicle for 6h. We also
scrutinized the activation/translocation of NF-kB and ROS release under these
conditions. We applied one-way or two-way ANOVA followed by Tukey’s post
hoc test for statistical analysis based on the experimental design.
RESULTS: Our data demonstrate that short-term exposure to LPS significantly
induces the activation/translocation of NF-kB signaling and ROS release in BV2
cells. We observed a time-dependent transcriptional upregulation of the
inflammasome complex, IL-1β and IL-18, and microglial pro-inflammatory targets
post-LPS stimulation, alongside a downregulation of the anti-inflammatory
factors. Interestingly, a pre-treatment with VTX (10 nM) for 24h effectively
modulated the LPS-induced NF-kB translocation and ROS production compared
to control cells. Cells pre-treated with VTX exhibited lower levels of LPS-induced
NLRP3 inflammasome- and microglia pro-inflammatory-related targets. However,
VTX did not influence the expression of anti-inflammatory factors in both
unstimulated and LPS-stimulated BV2 cells.
CONCLUSIONS: Our findings reinforce the emerging evidence that supports
VTX's anti-inflammatory activity. This activity is mediated via modulation of the
inflammasome signaling pathway, which plays a pivotal role in the inflammatory
response of microglia cells.
2022
- Deciphering the central immunomodulatory effects of a vortioxetine pretreatment on the LPS-induced inflammatory cascade
[Abstract in Atti di Convegno]
Ciani, M.; Toscano, Y.; Benatti, C.; Blom, J. M. C.; Tascedda, F.; Alboni, S.; Brunello, N.
abstract