| Autor: |
Polini B; Department of Pathology, University of Pisa, 56100 Pisa, Italy., Zallocco L; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy., Gado F; Department of Pharmaceutical Sciences, University of Milan, 20133 Milano, Italy.; Department of Pharmacy, University of Pisa, 56126 Pisa, Italy., Ferrisi R; Department of Pharmaceutical Sciences, University of Milan, 20133 Milano, Italy.; Department of Pharmacy, University of Pisa, 56126 Pisa, Italy., Ricardi C; Department of Pathology, University of Pisa, 56100 Pisa, Italy., Zuccarini M; Department of Medical, Oral and Biotechnological Sciences, University G. D'Annunzio of Chieti-Pescara, 66100 Chieti, Italy., Carnicelli V; Department of Pathology, University of Pisa, 56100 Pisa, Italy., Manera C; Department of Pharmacy, University of Pisa, 56126 Pisa, Italy., Ronci M; Department of Medical, Oral and Biotechnological Sciences, University G. D'Annunzio of Chieti-Pescara, 66100 Chieti, Italy.; Interuniversitary Consortium for Engineering and Medicine (COIIM), 86100 Campobasso, Italy., Lucacchini A; Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy., Zucchi R; Department of Pathology, University of Pisa, 56100 Pisa, Italy., Giusti L; School of Pharmacy, University of Camerino, 62032 Camerino, Italy., Chiellini G; Department of Pathology, University of Pisa, 56100 Pisa, Italy. |
| Abstrakt: |
Neurodegenerative diseases (NDDs) are progressive multifactorial disorders of the nervous system sharing common pathogenic features, including intracellular misfolded protein aggregation, mitochondrial deficit, and inflammation. Taking into consideration the multifaceted nature of NDDs, development of multitarget-directed ligands (MTDLs) has evolved as an attractive therapeutic strategy. Compounds that target the cannabinoid receptor type II (CB2R) are rapidly emerging as novel effective MTDLs against common NDDs, such as Alzheimer's disease (AD). We recently developed the first CB2R bitopic/dualsteric ligand, namely FD22a, which revealed the ability to induce neuroprotection with fewer side effects. To explore the potential of FD22a as a multitarget drug for the treatment of NDDs, we investigated here its ability to prevent the toxic effect of β-amyloid (Aβ 25-35 peptide) on human cellular models of neurodegeneration, such as microglia (HMC3) and glioblastoma (U87-MG) cell lines. Our results displayed that FD22a efficiently prevented Aβ 25-35 cytotoxic and proinflammatory effects in both cell lines and counteracted β-amyloid-induced depression of autophagy in U87-MG cells. Notably, a quantitative proteomic analysis of U87-MG cells revealed that FD22a was able to potently stimulate the autophagy-lysosomal pathway (ALP) by activating its master transcriptional regulator TFEB, ultimately increasing the potential of this novel CB2R bitopic/dualsteric ligand as a multitarget drug for the treatment of NDDs. |
