Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4′-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death.

The use of synthetic cannabinoid receptor agonists (SCRAs) poses major psychiatric risks. We previously showed that repeated exposure to the prototypical SCRA JWH-018 induces alterations in dopamine (DA) transmission, abnormalities in the emotional state, and glial cell activation in the mesocorticolimbic DA circuits of rats. Despite growing evidence suggesting the relationship between substance use disorders (SUD) and neuroinflammation, little is known about the impact of SCRAs on the neuroimmune system. Here, we investigated whether repeated JWH-018 exposure altered neuroimmune signaling, which could be linked with previously reported central effects. Adult male Sprague-Dawley (SD) rats were exposed to JWH-018 (0.25 mg/kg, i.p.) for fourteen consecutive days, and the expression of cytokines, chemokines, and growth factors was measured seven days after treatment discontinuation in the striatum, cortex, and hippocampus. Moreover, microglial (ionized calcium-binding adaptor molecule 1, IBA-1) and astrocyte (glial fibrillary acidic protein, GFAP) activation markers were evaluated in the caudate-putamen (CPu). Repeated JWH-018 exposure induces a perturbation of neuroimmune signaling specifically in the striatum, as shown by increased levels of cytokines [interleukins (IL) -2, -4, -12p70, -13, interferon (IFN) γ], chemokines [macrophage inflammatory protein (MIP) -1α, -3α], and growth factors [macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF)], together with increased IBA-1 and GFAP expression in the CPu. JWH-018 exposure induces persistant brain region-specific immune alterations up to seven days after drug discontinuation, which may contribute to the behavioral and neurochemical dysregulations in striatal areas that play a role in the reward-related processes that are frequently impaired in SUD.

Aging is a progressive physiological degeneration associated with a decline in chemosensory processes and cognitive abilities and a reduction in synaptic plasticity. The biological bases of ageing are still not completely understood, and many theories have been proposed. This study aimed to evaluate the occurrence of age-related changes affecting the chemosensory function (gustatory and olfactory) and general cognitive abilities and their potential associations in women. To this aim, 319 women (the age ranging from 18 to 92 years) were recruited and divided into four different age groups: 18–34 years, 35–49 years, 50–64 years, and ≥65 years. Our results confirmed that in women, gustatory, olfactory, and cognitive functions decline, though in a different manner during aging. Olfactory and cognitive function showed a slight decline along the first three age classes, with a dramatic decrease after age 65 years, while gustatory function decreased more gradually. Olfactory and gustatory deficits may have a high degree of predictivity for general cognitive function as well as for specific cognitive subdomains such as visuospatial/executive abilities, language, memory, and attention. Our study highlighted the importance of using chemosensory assessments for the early diagnosis of cognitive decline and for the development of appropriate personalized risk prevention strategies.

Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor‐α (PPARα), with the clinically available agonist fenofibrate, attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 hours after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/CTRL group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1 levels were lower than in veh/CTRL group. Notably, MIP-1, TNF-, GRO/KC, GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, indicating the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate the consequences of MIA.