Centro Of Ingegneria Genetica Biotecnologie Avanzate

Napoli, Italy

Centro Of Ingegneria Genetica Biotecnologie Avanzate

Napoli, Italy
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De Chiara V.,NeuroLogica | Angelucci F.,Fondazione Santa Lucia | Rossi S.,NeuroLogica | Musella A.,NeuroLogica | And 13 more authors.
Journal of Neuroscience | Year: 2010

The role of brain-derived neurotrophic factor (BDNF) in emotional processes suggests an interaction with the endocannabinoid system. Here, we addressed the functional interplay between BDNF and cannabinoid CB1 receptors (CB1Rs) in the striatum, a brain area in which both BDNF and CB1s play a role in the emotional consequences of stress and of rewarding experiences. BDNF potently inhibited CB1R function in the striatum, through a mechanism mediated by altered cholesterol metabolism and membrane lipid raft function. The effect of BDNF was restricted to CB1Rs controlling GABA-mediated IPSCs (CB1R(GABA)), whereas CB1Rs modulating glutamate transmission and GABAB receptors were not affected. The action of BDNF on CB1R (GABA) function was tyrosine kinase dependent and was complete even after receptor sensitization with cocaine or environmental manipulations activating the dopamine (DA)-dependent reward system. In mice lacking one copy of the BDNF gene (BDNF+/-), CB1R(GABA) responses were potentiated and were preserved from the action of haloperidol, a DA D2 receptor (D2R) antagonist able to fully abolish CB1R (GABA) function in rewarded animals. Haloperidol also enhanced BDNF levels in the striatum, suggesting that this neurotrophin may act as a downstream effector of D2Rs in the modulation of cannabinoid signaling. Accordingly, 5 d cocaine exposure both reduced striatal BDNF levels and increased CB1R(GABA) activity, through a mechanism dependent on D2Rs. The present study identifies a novel mechanism of CB1R regulation mediated by BDNF and cholesterol metabolism and provides some evidence that DA D2R-dependent modulation of striatal CB1R activity is mediated by this neurotrophin. Copyright © 2010 the authors.


PubMed | Centro Of Ingegneria Genetica Biotecnologie Avanzate
Type: Journal Article | Journal: Clinical & experimental metastasis | Year: 2013

Dipyridamole is a widely prescribed drug in ischemic disorders, and it is here investigated for potential clinical use as a new treatment for breast cancer. Xenograft mice bearing triple-negative breast cancer 4T1-Luc or MDA-MB-231T cells were generated. In these in vivo models, dipyridamole effects were investigated for primary tumor growth, metastasis formation, cell cycle, apoptosis, signaling pathways, immune cell infiltration, and serum inflammatory cytokines levels. Dipyridamole significantly reduced primary tumor growth and metastasis formation by intraperitoneal administration. Treatment with 15 mg/kg/day dipyridamole reduced mean primary tumor size by 67.5 % (p = 0.0433), while treatment with 30 mg/kg/day dipyridamole resulted in an almost a total reduction in primary tumors (p = 0.0182). Experimental metastasis assays show dipyridamole reduces metastasis formation by 47.5 % in the MDA-MB-231T xenograft model (p = 0.0122), and by 50.26 % in the 4T1-Luc xenograft model (p = 0.0292). In vivo dipyridamole decreased activated -catenin by 38.64 % (p < 0.0001), phospho-ERK1/2 by 25.05 % (p = 0.0129), phospho-p65 by 67.82 % (p < 0.0001) and doubled the expression of IkB (p = 0.0019), thus revealing significant effects on Wnt, ERK1/2-MAPK and NF-kB pathways in both animal models. Moreover dipyridamole significantly decreased the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in primary tumors (p < 0.005), and the inflammatory cytokines levels in the sera of the treated mice. We suggest that when used at appropriate doses and with the correct mode of administration, dipyridamole is a promising agent for breast-cancer treatment, thus also implying its potential use in other cancers that show those highly activated pathways.

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