Current Neuropharmacology - Online First

Methcathinone, a synthetic cathinone derivative similar to amphetamine, has transitioned from a 1920s ephedrine precursor and Soviet-era antidepressant to a recreationally used substance since the 1970s-1980s, raising public health concerns due to its addiction potential and neurotoxicity-related health risks.

This review comprehensively analyzes methcathinone's impact on adult offspring, synthesizing recent advancements and critiquing literature to pinpoint key findings, challenges, and future research directions.

The systematic review adhered to PRISMA guidelines and encompassed case series, prospective and retrospective studies, as well as short communications published in English. An electronic search was conducted on PubMed, Elsevier, and CNKI. The focus was on methcathinone and its neuropsychological disorders and physical health complications, specifically in adult offspring.

A total of 8 studies met the inclusion criteria, resulting in a dataset of methcathinone on neurobehavioral and cognitive functions. These studies mainly found that prenatal methcathinone exposure in rats led to delayed physical development and induced anxiety-like behavior in offspring, with changes observed in neurobehavioral tests and the concentration of serotonin and dopamine. Furthermore, neurochemical effects were identified, showing dose- and time-dependent increases in extracellular dopamine and serotonin concentrations, and neurotoxic potential towards brain dopamine neurons.

This study concludes that methcathinone poses severe risks, including neurotoxicity for users and developmental harm for offspring, necessitating ongoing research to comprehend associated risks and inform public health interventions.

Inflammation is linked to the pathophysiology of schizophrenia. The neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammation, has been reported to be associated with schizophrenia. However, few studies have examined the sex-specific association between neutrophil-to-lymphocyte ratio (NLR) and clinical symptoms in schizophrenia. This study aimed to explore sex differences in NLR and its correlation with symptoms in first-episode schizophrenia (FES) patients.

Ninety-seven FES patients and 65 control subjects were recruited. The severity of clinical symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS), and white blood cells were calculated. We performed a cross-sectional analysis comparing NLR in males and females in the patient and control groups. We explored its sex-specific associations with clinical symptoms in the patient group.

We found that neutrophil (NEU) counts and NLR were higher in male patients compared to female patients with schizophrenia. There were no significant differences in white blood cell counts and NLR in healthy controls. Linear regression analysis showed that NEU counts were associated with clinical symptoms in male patients, and NLR correlated with symptoms in female patients after controlling for age, onset age, and years of education.

Our study suggests that NLR values and NEU counts were higher in male patients compared with female patients with schizophrenia and that the association between NLR or NEU and clinical symptoms was sex-specific.

The gasotransmitter hydrogen sulfide (H2S) modulates various brain functions, including neuron excitability, synaptic plasticity, and Ca²⁺ dynamics. Furthermore, H2S may stimulate nitric oxide (NO) release from cerebrovascular endothelial cells, thereby regulating NO-dependent endothelial functions, such as angiogenesis, vasorelaxation, and cerebral blood flow (CBF). However, the signaling pathway by which H2S induces NO release from cerebrovascular endothelial cells is still unclear.

Herein, we exploited single-cell imaging of intracellular Ca²⁺, H2S, and NO levels to assess how H2S induces Ca²⁺-dependent NO release from the human cerebrovascular endothelial cell line, hCMEC/D3.

Administration of the H2S donor, sodium hydrosulfide (NaHS), induced a dose-dependent increase in (Ca²⁺)i only in the presence of extracellular Ca²⁺. NaHS-induced extracellular Ca²⁺ entry was mediated by the Ca²⁺-permeable TRPA1 channel, as shown by pharmacological and genetic manipulation of the TRPA1 protein. Furthermore, NaHS-dependent TRPA1 activation led to NO release that was abolished by buffering the concomitant increase in (Ca²⁺)i and inhibiting eNOS. Furthermore, the endothelial agonist, adenosine trisphosphate (ATP), caused a long-lasting elevation in (Ca²⁺)i that was driven by cystathionine g-lyase (CSE)-dependent H2S production and by TRPA1 activation. Consistent with this, ATP-induced NO release was strongly reduced either by blocking CSE or by inhibiting TRPA1.

These findings demonstrate for the time that H2S stimulates TRPA1 to induce NO production in human brain microvascular endothelial cells. Additionally, they show that this signaling pathway can be recruited by an endothelial agonist to modulate NO-dependent events at the human neurovascular unit.

Glucagon-Like Peptide-1 Receptor (GLP1R) agonists have become widespread anti-obesity/diabetes pharmaceuticals in the United States.

This article aimed to provide our current knowledge on the plausible mechanisms linked to the role of Ozempic (Semaglutide), which is generalized as one of the anti-addiction compounds.

The effects of GLP1R agonists in Alcohol Use Disorder (AUD) and substance use disorder (SUD) are mediated, in part, through the downregulation of dopamine signaling. We posit that while GLP1R agonism could offer therapeutic advantages in hyperdopaminergia, it may be detrimental in patients with hypodopaminergia, potentially leading to long-term induction of Suicidal Ideation (SI). The alleged posit of GLP1 agonists to induce dopamine homeostasis is incorrect. This study refined 31 genes based on the targets of Ozempic, GLP1R, and related enzymes for SI and 10 genes of the Genetic Addiction Risk Score (GARS) test. STRING-MODEL refined 29 genes, and further primary analyses indicated associations of GLP1R with DRD3, BDNF, CREB1, CRH, IL6, and DPP4.

In-depth silico enrichment analysis revealed an association between candidate genes and depressive phenotypes linked with dopaminergic signaling. Finally, through primary and in-depth silico analyses, we demonstrated multiple findings supporting that GLP1R agonists can induce depression phenotypes.

Our findings suggest that associated polymorphisms seem to have overlapping effects with addictive behaviors of Reward Deficiency Syndrome (RDS) and dopamine regulation. Consequently, GLP1R agonists may represent a double-edged sword, potentially triggering both anti-addictive effects and SI by exacerbating depressive phenotypes. Thus, we encourage the scientific community to perform further empirical clinical studies to confirm this proposed pathway.

The study demonstrates that pharmacological blockade of type 3 metabotropic glutamate (mGlu3) receptors at the time of tumor induction significantly reduces the incidence of brain gliomas in rats. The overall survival of patients with high-grade brain gliomas is 14-20 months after current multimodal therapy, including surgery, radiotherapy, and adjuvant chemotherapy.

To demonstrate in this experimental model that pharmacological blockade of group II metabotropic glutamate receptors reduces the incidence of brain tumors induced by prenatal exposure to N- ethyl-N-nitrosourea (ENU) in rats.

Dams received a single injection of ENU (40 mg/kg, e.v.) at day 20 of pregnancy, combined with 5 daily injections of either saline or the mGlu2/3 receptor antagonist, LY341495 (10 mg/kg) (from day 15 to day 21 of pregnancy). Assessment of brain tumors in the offspring at 5 months of age showed the presence of mixed gliomas (astrocytomas/oligodendrogliomas) in 70% of the ENU + saline group of rats and only in 30% of the ENU + LY341495 group.

Tumors in both groups of rats showed a moderate/high expression of the astrocyte marker, GFAP, and the oligodendrocyte marker, OLIG-2, and a low expression of the proliferation marker, Ki-67. However, tumors of the ENU + LY341495 group showed a reduced density of Iba-1⁺ cells, suggesting a lower extent of neuroinflammation in the tumor microenvironment. These findings strengthen the hypothesis that mGlu3 receptors are candidate drug targets for the treatment of malignant gliomas.