The MDPV Derivative α-PHP Regulates Cellular Differentiation and Triggers Apoptotic Cell Death and Ultrastructural Changes in Murine 3D Neurospheres

Cumulative reports of psychiatric and neurological outcomes due to synthetic cathinones continue to raise public concern. However, the understanding of the neurotoxic mechanism of action is still poorly understood, particularly for the under-explored αPHP, one of the main MDPV derivatives. In particular, the effects of this synthetic drug on neural stem/progenitor cell cultures are still unknown. Therefore, in the proposed in vitro study, the effects of increasing αPHP concentrations (50–2000 μM) on cell morphology, neuronal/glial differentiation, cell death pathways, and ultrastructure have been evaluated after exposure in murine 2D NSPCs and 3D neurospheres using complementary techniques, i.e., phase contrast microscopy, immunocytochemistry, confocal microscopy, and transmission electron microscopy. We observed that αPHP was able to induce a dose-dependent neurotoxic and neuromodulatory effect in murine 2D NSPC cultures and a 3D neurosphere model, affecting neuronal/glial differentiation, activating the apoptotic pathway, and inducing morphological and ultrastructural changes. The present study could pave the way for a broadened knowledge of synthetic cathinone (SCs) toxicology, needed to establish the right treatment for novel psychoactive substance (NPS) exposure and the possible consequences for public health.