Mepirapim, a novel synthetic cannabinoid, induces Parkinson's disease-related behaviors by causing maladaptation of the dopamine system in the brain.

Mepirapim is a novel synthetic cannabinoid that first appeared on the illicit drug market in 2013. In recent years, recreational abuse of Mepirapim has caused serious emergencies, posing a threat to public health. However, there are no legal regulations to prohibit the use of Mepirapim, as there is no scientific evidence for the dangerous pharmacological effects of the drug. In the present study, we investigated the dangerous neurotoxic effects of Mepirapim through behavioral and molecular experiments in mice (ICR/CD1, male, 25-30 g). In particular, based on a previous study that Mepirapim activates the dopamine system, we evaluated whether high-dose Mepirapim [single (15, 30, or 60 mg·kg-1, i.p.) or multiple (8, 15, or 30 mg·kg-1, i.p. × 4 at 2 h intervals)] treatment causes Parkinson's disease-related symptoms through damage to the dopamine system. In the result, we found that Mepirapim treatment caused comprehensive Parkinson's disease-related symptoms, including motor impairment, cognitive deficits and mood disorders. Furthermore, we confirmed the maladaptation in dopamine-related neurochemicals, including decreased dopamine levels, decreased tyrosine hydroxylase expression, and increased α-synuclein expression, in the brains of mice treated with Mepirapim. Taken together, these results indicate that Mepirapim has dangerous neurotoxic effects that induces Parkinson's disease-related behaviors by causing maladaptation of the dopamine system in the brain. Based on these findings, we propose the strict regulation of recreational abuse and therapeutic misuse of Mepirapim.

Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents.

Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.

Mosloflavone-Resveratrol Hybrid TMS-HDMF-5z Exhibits Potent In Vitro and In Vivo Anti-Inflammatory Effects Through NF-κB, AP-1, and JAK/STAT Inactivation.

TMS-HDMF-5z is a hybrid of the natural products mosloflavone and resveratrol. It was discovered to show potent inhibitory effects against lipopolysaccharide (LPS)-induced production of inflammatory mediators in RAW 264.7 macrophages. However, its mechanism of action is unknown. Hence this study aimed to demonstrate and explore in vitro and in vivo anti-inflammatory effects of TMS-HDMF-5z and its mechanism of action employing RAW 264.7 macrophages and carrageenan-induced hind paw edema. This work revealed that TMS-HDMF-5z suppressed the LPS-induced inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein, mRNA, and promoter binding levels and tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6, and interferon-ß (IFN-ß) at the mRNA expression in RAW 264.7 macrophages. The results showed that TMS-HDMF-5z reduced the transcription and DNA binding activities of nuclear factor-κB (NF-κB) through inhibiting nuclear translocation of p65 and phosphorylation of κB inhibitor α (IκBα), IκB kinase (IKK), and TGF-ß activated kinase 1 (TAK1). Additionally, TMS-HDMF-5z attenuated the LPS-induced transcriptional and DNA binding activities of activator protein-1 (AP-1) by suppressing nuclear translocation of phosphorylated c-Fos, c-Jun, and activating transcription factor 2 (ATF2). TMS-HDMF-5z also reduced the LPS-induced phosphorylation of Janus kinase 1/2 (JAK1/2), signal transducers and activators of transcription 1/3 (STAT1/3), p38 mitogen-activated protein kinase (MAPK), and MAPK-activated protein kinase 2 (MK2). In rats, TMS-HDMF-5z alleviated carrageenan-induced hind paw edema through the suppressing iNOS and COX-2 via NF-κB, AP-1, and STAT1/3 inactivation. Collectively, the TMS-HDMF-5z-mediated inhibition of NF-κB, AP-1, and STAT1/3 offer an opportunity for the development of a potential treatment for inflammatory diseases.

Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani.

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

Abuse Potential of Synthetic Cannabinoids: AM-1248, CB-13, and PB-22.

Currently, the expanding recreational use of synthetic cannabinoids (SCBs) threatens public health. SCBs produce psychoactive effects similar to those of tetrahydrocannabinol, the main component of cannabis, and additionally induce unexpected pharmacological side effects. SCBs are falsely advertised as legal and safe, but in reality, SCB abuse has been reported to cause acute intoxication and addictive disorders. However, because of the lack of scientific evidence to elucidate their dangerous pharmacological effects, SCBs are weakly regulated and continue to circulate in illegal drug markets. In the present study, the intravenous self-administration (IVSA) paradigm was used to evaluate the abuse potential of three SCBs (AM-1248, CB-13, and PB-22) in rats. All three SCBs maintained IVSA with a large number of infusions and active lever presses, demonstrating their reinforcing effects. The increase of active lever presses was particularly significant during the early IVSA sessions, indicating the reinforcementenhancing effects of the SCBs (AM-1248 and CB-13). The number of inactive lever presses was significantly higher in the SCB groups (AM-1248 and CB-13) than that in the vehicle group, indicating their impulsive effects. In summary, these results demonstrated that SCBs have distinct pharmacological properties and abuse potential.

1-Phenylcyclohexan-1-amine hydrochloride (PCA HCl) alters mesolimbic dopamine system accompanied by neuroplastic changes: A neuropsychopharmacological evaluation in rodents.

The recreational use of N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) and ketamine have grown rapidly due to their psychotomimetic properties. These compounds induce both non-fatal and fatal adverse effects and despite the enhanced regulation, they are continuously synthesized and are being sold in the illegal drug market, including 1-phenylcyclohexan-1-amine hydrochloride (PCA). Therefore, we evaluated its abuse potential through the conditioned-place preference (CPP), self-administration, and locomotor sensitization paradigms. Pretreatment with SCH 2 3390 and haloperidol was also performed during a CPP test. We used ELISA to measure dopamine (DA) levels and western blotting to determine effects on the DA-related proteins as well as on phosphorylated CREB, deltaFosB, and brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) and nucleus accumbens (NAc). Finally, we examined the effects on brain wave activity using electroencephalography (EEG). PCA induced CPP in mice and was self-administered by rats, suggesting that PCA has rewarding and reinforcing properties. PCA increased locomotor of mice on the first treatment and challenge days. SCH 23390 and haloperidol blocked the CPP. PCA altered the DA, tyrosine hydroxylase, dopamine D1 and D2 receptors as well as p-CREB and deltaFosB. Also, PCA altered the delta and gamma waves in the brain, which were then normalized by SCH 2 3390 and haloperidol. The present findings indicate that PCA may induce abuse potential through the dopaminergic system and probably accompanied with alterations in brain wave activity which is similar to that of other psychotomimetic NMDA antagonists. We advocate thorough monitoring of PCP analogs as they pose potential harm to public health.