The Designer Drug αPHP Affected Cell Proliferation and Triggered Deathly Mechanisms in Murine Neural Stem/Progenitor Cells
Author:
Roda Elisa1, De Luca Fabrizio2ORCID, Priori Erica Cecilia2ORCID, Ratto Daniela2, Pinelli Silvana3, Corradini Emilia3, Mozzoni Paola3, Poli Diana4ORCID, Mazzini Giuliano25, Bottone Maria Grazia2ORCID, Gatti Anna Maria1, Marti Matteo67ORCID, Locatelli Carlo Alessandro1ORCID, Rossi Paola2, Bottai Daniele8ORCID
Affiliation:
1. Laboratory of Clinical & Experimental Toxicology, Pavia Poison Centre, National Toxicology Information Centre, Toxicology Unit, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy 2. Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy 3. Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy 4. INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Via Fontana Candida, 1, 00078 Monte Porzio Catone, Italy 5. Institute of Molecular Genetics—CNR (National Research Council), 27100 Pavia, Italy 6. Department of Translational Medicine, Section of Legal Medicine, LTTA Center and University Center of Gender Medicine, University of Ferrara, 44121 Ferrara, Italy 7. Collaborative Centre for the Italian National Early Warning System, Department of Anti-Drug Policies, Presidency of the Council of Ministers, 44121 Ferrara, Italy 8. Department of Pharmaceutical Sciences, Section of Pharmacology and Biosciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy
Abstract
Increasing reports of neurological and psychiatric outcomes due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the understanding of neurotoxic mechanisms is still lacking, particularly for the under-investigated αPHP, one of the major MDPV derivatives. In particular, its effects on neural stem/progenitor cell cultures (NSPCs) are still unexplored. Therefore, in the current in vitro study, the effects of increasing αPHP concentrations (25–2000 μM), on cell viability/proliferation, morphology/ultrastructure, genotoxicity and cell death pathways, have been evaluated after exposure in murine NSPCs, using a battery of complementary techniques, i.e., MTT and clonogenic assay, flow cytometry, immunocytochemistry, TEM, and patch clamp. We revealed that αPHP was able to induce a dose-dependent significant decrease of the viability, proliferation and clonal capability of the NSPCs, paralleled by the resting membrane potential depolarization and apoptotic/autophagic/necroptotic pathway activation. Moreover, ultrastructural alterations were clearly observed. Overall, our current findings demonstrate that αPHP, damaging NSPCs and the morpho-functional fundamental units of adult neurogenic niches may affect neurogenesis, possibly triggering long-lasting, irreversible CNS damage. The present investigation could pave the way for a broadened understanding of SCs toxicology, needed to establish an appropriate treatment for NPS and the potential consequences for public health.
Funder
Ricerca Corrente funding scheme (Istituti Clinici Scientifici Maugeri IRCCS) of the Ministry of Health Anti-Drug Policies Department, Presidency of the Council of Ministers, Italy University of Ferrara
Subject
General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology
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