The Designer Drug αPHP Affected Cell Proliferation and Triggered Deathly Mechanisms in Murine Neural Stem/Progenitor Cells

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.

α-Pyrrolidinohexanophenone (α-PHP) and α-Pyrrolidinoisohexanophenone (α-PiHP): A Review

“…The cardiovascular effects include palpitation, tachycardia, and hypertension; the psychological effects are agitation, dysphoria, anxiety, panic, paranoia, hallucinations and depression; and the neurologic effects encompass aggressiveness, memory loss, headache, irreversible central nervous system damage, dizziness, tremors, and seizures. Moreover, there are also reported ophthalmologic effects, such as blurred vision and mydriasis, gastrointestinal symptoms like nausea, vomiting, and abdominal pain, and others such as fever and hyponatremia [8,28,[90][91][92]. In particular, the use of α-PHP can lead to associated adverse effects such as agitation and compulsive behaviour, pronounced paranoia and anxiety, hallucinations, unconsciousness, hypertension, tachycardia and cardiac arrest, dehydration, nausea and vomiting, seizures, the suppression of physiological functions (e.g., urination), and rhabdomyolysis, and in some cases can cause death, as reported above [19,28,74,77].…”

Exploring the role of eosinophil cationic protein (ECP) in schizophrenia: Insights and implications

“…ECP’s cytotoxic properties, including its ability to induce cell membrane damage and trigger apoptosis, raise questions about its potential neurotoxic effects within the CNS. [16] ECP’s interactions with neural cells might disrupt synaptic integrity, neuronal signaling pathways, or contribute to oxidative stress, potentially impacting neural function and neuronal viability relevant to schizophrenia pathology.…”

“…Several assays are used to measure ECP, and standardization becomes particularly important for accurate interpretation and meaningful comparisons. [16] Here are some commonly used assays:…”

“…ECP’s multifaceted functions contribute to various facets of immune regulation, impacting both innate and adaptive immune mechanisms. [16] ECP exhibits antimicrobial properties by disrupting microbial cell membranes, making it effective against bacteria, viruses, fungi, and parasites. [17] Its cationic nature allows interaction with negatively charged microbial surfaces, leading to membrane permeabilization and subsequent microbe destruction, thereby contributing to the innate immune defense against invading pathogens.…”

“…While crucial for combating pathogens, excessive ECP release can exacerbate tissue injury and inflammation in certain conditions. [16]…”