The mutated cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2 S968F) regulates cocaine-induced reward behaviour and plasticity in the nucleus accumbens.

BACKGROUND AND PURPOSE: Cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2), as a component of the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex, is involved in actin polymerization, contributing to neuronal development and structural plasticity. Mutating serine-968 to phenylalanine (S968F) in CYFIP2 causes an altered cocaine response in mice. The neuronal mechanisms underlying this response remain unknown. EXPERIMENTAL APPROACH: We performed cocaine reward-related behavioural tests and examined changes in synaptic protein phenotypes and neuronal morphology in the nucleus accumbens (NAc), using CYFIP2 S968F knock-in mice to investigate the role of CYFIP2 in regulating cocaine reward. KEY RESULTS: CYFIP2 S968F mutation attenuated cocaine-induced behavioural sensitization and conditioned place preference. Cocaine-induced c-Fos was not observed in the NAc of CYFIP2 S968F knock-in mice. However, c-Fos induction was still evident in the medial prefrontal cortex (mPFC). CYFIP2 S968F mutation altered cocaine-associated CYFIP2 signalling, glutamatergic protein expression and synaptic density in the NAc following cocaine exposure. To further determine the role of CYFIP2 in NAc neuronal activity and the mPFC projecting to the NAc activity-mediating reward response, we used optogenetic tools to stimulate the NAc or mPFC-NAc pathway and observed that optogenetic activation of the NAc or mPFC-NAc pathway induced reward-related behaviours. This effect was not observed in the S968F mutation in CYFIP2. CONCLUSION AND IMPLICATIONS: These results suggest that CYFIP2 plays a role in controlling cocaine-mediated neuronal function and structural plasticity in the NAc, and that CYFIP2 could serve as a target for regulating cocaine reward.

The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents.

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.

Natural course of chronic subdural hematoma following surgical clipping of unruptured intracranial aneurysm by pterional approach.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a neurological complication following clipping surgery. However, the natural course and ideal approach for the treatment of clipping-related-CSDH (CR-CSDH) have not been clearly established. We aimed to investigate the course of CR-CSDH using chronological radiological findings. METHODS: We performed a retrospective analysis of 28 (3.8%) patients who developed CSDH among 736 patients who underwent surgical clipping using pterional approach for unruptured aneurysms at our institution between December 2010 and December 2018. Patients underwent follow-up CT scan 6-8 weeks after clipping surgery and decision to pursue surgical intervention rests upon the patient's symptom based on the Markwalder's grading scale (MGS) and numeric rating scale (NRS). RESULTS: Of the 28 patients, 3 patients (10.7%) underwent surgery, while 25 (89.2%) showed spontaneous resolution of CR-CSDH. Eighteen patients (64.2%) had mild headache with MGS of 0-1. The mean maximum hematoma volume was 41.9±30.9 ml (5.8-135 ml), and 26 patients (92.8%) had homogeneous hematoma. The mean time to hematoma resolution was 126.7±52.9 days (46-228 days). Comparing group of CR-CSDH volume ≥43 ml or a midline shift ≥5 mm, the difference in presence of linear low-density area (p=0.002) and age (p=0.026) between the conservative and operative groups were found to be statistically significant. CONCLUSIONS: Most CR-CSDH cases spontaneously resolved within 4 months. Therefore, we suggest that close observation should be performed if patient's symptoms are mild and special radiologic findings are present, despite its relatively large volume and midline shifting.

In Vitro Comparison of Differences in Setting Time of Premixed Calcium Silicate-Based Mineral Trioxide Aggregate According to Moisture Content of Gypsum.

Recently, a paste-type premixed calcium silicate-based mineral trioxide aggregate (MTA) product that quickly solidifies through a pozzolanic reaction was introduced to replace existing MTA, which has the disadvantage of a long setting time. In this study, we evaluated the effect of moisture content in the root canal on the setting time of premixed calcium silicate-based MTA in a simulated root canal environment using Endoseal MTA and Well-Root ST, among commercially available products. The setting time was measured according to ISO 6876/2012. A mold made using grades 2, 3, and 4 dental gypsum according to the classification of ISO 6873/2013 was used to reproduce the difference in moisture environment. Differences in moisture content were measured using micro-computed X-ray tomography (micro-CT). The micro-CT results showed that the moisture content was the highest and lowest in the grade 2 and 4 gypsum molds, respectively. Moreover, the setting time indicated by the manufacturer was the shortest for the grade 2 gypsum mold. Hence, the differences in moisture content significantly affect the setting time of MTA. This result can help set future experimental conditions and develop premixed calcium silicate-based MTA products.

The importance of compression time in stapled hemorrhoidopexy: is patience a virtue?

Purpose: The aim of this study was to evaluate whether longer compression time before firing the stapler reduced the postoperative complications related to staple line formation in stapled hemorrhoidopexy. Methods: This retrospective case-control study was conducted at a colorectal-anal specialty hospital. Consecutive patients with grade III and IV hemorrhoids who underwent stapled hemorrhoidopexy between January 2016 and November 2019 were included. According to the compression time, patients were assigned to the long compression time group (2 minutes) or the typical compression time group (30 seconds). The primary outcome measure was incidence of staple line complications such as dehiscence, bleeding, and stenosis. Results: A total of 348 patients treated with stapled hemorrhoidopexy were evaluated. Seventy-three and 275 patients were included in the long compression time group and the typical compression time group, respectively. No significant differences were observed in patient characteristics between the groups. However, additional procedures were performed more frequently in the typical compression time group (78.1% vs. 92.0%, P=0.001). Bleeding occurred more frequently in the typical compression time group (1.4% vs. 8.4%, P=0.030). The rates of dehiscence and stenosis were not significantly different between the groups. Fecal urgency developed more frequently in the typical compression time group (0% vs. 5.1%, P=0.040). In logistic regression analysis, typical compression time (30 seconds) was the only risk factor for bleeding (odds ratio, 8.496; P=0.040). Conclusion: Longer compression time was associated with a decreased incidence of postoperative bleeding after stapled hemorrhoidopexy.

SAMM50 Regulates Thermogenesis of Beige Adipocytes Differentiated from Human Adipose-Derived Stem Cells by Balancing Mitochondrial Dynamics.

Brown/beige adipocyte thermogenesis is a process that is important for energy balance. The thermogenesis of brown/beige adipocytes occurs in the mitochondria, which is modulated by the dynamic balance between mitochondrial fusion and fission. Mitophagy is also involved in mitochondrial dynamics. The sorting and assembly machinery (SAM) complex protein, SAMM50, plays a key role in mitochondrial dynamics and quality control through regulating mitophagy. However, the roles of SAMM50 in the thermogenesis of beige adipocytes remain unknown. Thus, the objective of this study was to conduct functional analyses of SAMM50. The expression of mitochondrial fusion genes was repressed by SAMM50 knockdown but was not altered by SAMM50 overexpression. These results agreed with the distribution of the fluorescence-stained mitochondria and an mtDNA copy number. In contrast, the expression of mitochondrial fission genes showed an opposite outcome. As a result, suppression by the SAMM50 shRNA inhibited the expression of thermogenic genes (UCP1, PPARGC1A, DIO2, ELOVL3, CIDEA, and CIDEC) and mitochondrial-related genes (CYCS, COX7A1, TFAM, CPT1B, and CPT2). Conversely, SAMM50 overexpression promoted the expression of the thermogenic genes and mitochondrial genes. Thus, SAMM50 links the balance between the mitochondrial dynamics and thermogenesis of beige adipocytes.

Extract of Ephedra sinica Stapf Induces Browning of Mouse and Human White Adipocytes.

Browning of adipocytes using herbal extracts is an attractive and realistic strategy for obesity treatment. Ephedra sinica Stapf (E. sinica) is an Asian traditional medicine known to activate brown adipocytes. To evaluate the effect of E. sinica (EEs) on the browning of white adipocytes, expression levels of browning markers, including uncoupling protein 1 (UCP1), were determined using qPCR, Western blot, and immunocytochemistry after mature mouse inguinal preadipocyte (mIPA) and human adipose-derived stem cells (hADSCs) were treated with EEs. In addition, mitochondrial activity was determined by analyzing MitoTracker staining, mtDNA copy number, and oxygen consumption rate (OCR). Treatment with EEs suppressed lipid accumulation and expression levels of adipogenic markers, including Pparg, during mIPA differentiation. In mature mIPA and hADSCs browning markers, including Ucp1, were up-regulated by EEs. In addition, EEs increased expression of mitochondrial genes, mtDNA copy number, and OCR. EEs showed a dual function: inhibiting adipogenesis in immature preadipocytes, and promoting thermogenesis via browning in mature white adipocytes. Therefore, E. sinica is a potential herb for regulating energy metabolism by inducing the browning process.

Korean Red Ginseng inhibits methamphetamine addictive behaviors by regulating dopaminergic and NMDAergic system in rodents.

BACKGROUND: Methamphetamine (METH) is the most widely used psychostimulant and has been known to exhibit reinforcing effects even after long abstinence. We showed the inhibitory effect of Korean Red Ginseng extract (RGE) on METH-induced addictive behaviors in animal models mimicking the human drug-use pattern. METHODS: We first investigated the effect of RGE on the acquisition of METH-induced dependence using self-administration and conditioned place preference (CPP) tests. Additionally, further experiments such as METH-induced motivational behavior and seeking behavior were conducted. To study the underlying mechanism, dopamine receptor, dopamine transporter, and N-methyl-D-aspartate receptor were assessed through Western blot analysis. RESULTS: Treatment with RGE significantly reduced METH-induced self-administration on a fixed-ratio 1 schedule of reinforcement. It could be also decreased a progressive ratio schedule, and inhibited METH-primed reinstatement. In CPP, RGE significantly prevented the development of METH-induced CPP. Moreover, RGE not only shortened the withdrawal period clearly, but also prevented the reinstatement of CPP. RGE treatment also reversed METH-induced overexpression of dopamine transporter, dopamine receptor D1, and NMDA receptor in the nucleus accumbens. CONCLUSION: Our findings reflect that RGE has therapeutic potential to suppress METH-induced addictive behaviors by regulating dopaminergic and NMDAergic system.

Efficacy of 3D-Printed Titanium Mesh-Type Patient-Specific Implant for Cranioplasty.

OBJECTIVE: Autologous bone grafting for cranioplasty is associated with a high infection rate and bone absorption. Synthetic implant materials for cranioplasty have been developed. In this study, we evaluated the efficacy of titanium mesh-type patient-specific implants (PSIs) for patients with skull defects using the dice similarity coefficient (DSC), clinical outcomes, and artifacts caused by implants. METHODS: This retrospective study included 40 patients who underwent cranioplasty with a titanium mesh PSI at our institution. Based on preoperative and postoperative computed tomography scans, we calculated DSC and artifacts. RESULTS: The calculated DSC of 40 patients was 0.75, and the noise was 13.89% higher in the region of interest (ROI) near the implanted side (average, 7.64 hounsfield unit [HU]±2.62) than in the normal bone (average, 6.72 HU±2.35). However, the image signal-to-noise ratio did not significantly differ between the ROI near the implanted side (4.77±1.78) and normal bone (4.97±1.88). The patients showed no significant perioperative complications that required a secondary operation. CONCLUSION: Titanium mesh-type PSIs for cranioplasty have excellent DSC values with lower artifacts and complication rates.

Direct Pattern Growth of Carbon Nanomaterials by Laser Scribing on Spin-Coated Cu-PI Composite Films and Their Gas Sensor Application.

The excellent physical and chemical properties of carbon nanomaterials render them suitable for application in gas sensors. However, the synthesis of carbon nanomaterials using high-temperature furnaces is time consuming and expensive. In this study, we synthesize a carbon nanomaterial using local laser-scribing on a substrate coated with a Cu-embedded polyimide (PI) thin film to reduce the processing time and cost. Spin coating using a Cu-embedded PI solution is performed to deposit a Cu-embedded PI thin film (Cu@PI) on a quartz substrate, followed by the application of a pulsed laser for carbonization. In contrast to a pristine PI solution-based PI thin film, the laser absorption of the Cu-embedded PI thin film based on Cu@PI improved. The laser-scribed carbon nanomaterial synthesized using Cu@PI exhibits a three-dimensional structure that facilitates gas molecule absorption, and when it is exposed to NO2 and NH3, its electrical resistance changes by -0.79% and +0.33%, respectively.

Association between tumor size and peritumoral brain edema in patients with convexity and parasagittal meningiomas.

BACKGROUND AND PURPOSE: Peritumoral brain edema (PTBE) is a common complication in meningioma and disruption of the tumor-brain barrier in meningioma is crucial for PTBE formation. To evaluate the association between meningioma size and PTBE, we measured meningioma volumes using the 3D slicer in patients with convexity and parasagittal meningiomas. METHODS: Receiver operating characteristic curve analysis was used to determine the optimal cut-off meningioma volume values for predicting PTBE occurrence. Logistic regressions were used to estimate the odds ratios for PTBE occurrence in patients with convexity and parasagittal meningiomas according to several predictive factors. RESULTS: A total of 205 convexity or parasagittal meningioma patients with no other brain disease who underwent one or more contrast-enhanced brain MRIs were enrolled in this 10-year analysis in two hospitals. The optimal cut-off meningioma volume value for prediction of PTBE in all study patients was 13.953 cc (sensitivity = 76.1%; specificity = 92.5%). If a meningioma is assumed to be a complete sphere, 13.953 cc is about 2.987 cm in diameter. CONCLUSIONS: Our study suggests a cut-off value of 3 cm meningioma diameter for prediction of PTBE in patients with convexity and parasagittal meningiomas. We believe that we have revealed why the meningioma diameter of 3 cm is clinically meaningful.

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.

Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia-related behaviours based on an imbalance of neurochemicals in the brain.

BACKGROUND AND PURPOSE: Methoxphenidine is a dissociative-based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action. EXPERIMENTAL APPROACH: Addictive potential of methoxphenidine was examined using intravenous self-administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests (open field test, elevated plus maze test, novel object recognition test, social interaction test and tail suspension test) performed to assess whether methoxphenidine caused schizophrenia-related symptoms in mice. Additionally, neurotransmitter enzyme-linked immunosorbent assay and western blot were used to confirm methoxphenidine-induced neurochemical changes in specific brain regions related to abnormal behaviours. KEY RESULTS: Methoxphenidine caused addictive behaviours via reinforcing and rewarding effects. Consistently, methoxphenidine induced over-activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, methoxphenidine caused all categories of schizophrenia-related symptoms, including positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression) and cognitive impairment. Consistently, methoxphenidine led to the disruption of the hippocampal-prefrontal cortex pathway that is considered to be pathological involved in schizophrenia. CONCLUSIONS AND IMPLICATIONS: We demonastrate that methoxphenidine causes addictive and schizophrenia-like behaviours and induces neurochemical changes in brain regions associated with these behaviours. We propose that methoxphenidine could be used in developing useful animal disease models and that it also requires legal restrictions on its recreational use.

Extracellular Vesicles From a Three-Dimensional Culture of Perivascular Cells Accelerate Skin Wound Healing in a Rat.

BACKGROUND: Soluble proteins and extracellular vesicles (EVs) are crucial wound repair mediators in cell-based therapy. Previous studies reported that EVs of perivascular cells stimulated migration and proliferation of cell types involved in the dermatological wound healing process. However, these studies only show effects of EVs from perivascular cells (PVCs) for in vitro models. METHODS: EVs were collected from 3D-cultured PVC (PVC-3D-EV) and compared with EVs from 2D-culture PVC (PVC-2D-EV) to investigate effects on wound contraction, angiogenesis, activation of myofibroblast, and collagen deposition. RESULTS: PVC-3D-EV was significantly improved in terms of wound contraction compared with PVC-2D-EV and the control. Activation of myofibroblast and collagen deposition in a rat skin wound model was significantly stimulated by PVC-3D-EV. In addition, angiogenesis and vascular endothelial growth factor expression were also highly stimulated by PVC-3D-EV. These results suggest that PVC-3D-EV was regulated in granulation tissue formation, angiogenesis, and wound contraction in healing of a rat skin wound. These results indicate a pivotal role of PVC-3D-EV in wound healing through multiple mechanisms. CONCLUSIONS: 3D-culture using a polystyrene scaffold is demonstrated to be a better system for providing better physiological conditions than the 2D-culture system, and EVs from 3D-cultured PVC could be a promising option for healing skin wound. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Korean Red Ginseng reduces chronic social defeat stress-induced mood disorders via N-methyl-D-aspartate receptor modulation in mice.

BACKGROUND: A chronic social defeat stress (CSDS) model has been proposed as relevant to stress-induced behavioral change in humans. In this study, we examined the effect of Korean Red Ginseng (KRG) on CSDS-induced mood disorders and protein expression in an animal model. METHODS: To evaluate the effect of KRG on social defeat stress, test mice were exposed in the resident aggressor's home cage compartment for 14 days beginning 1 h after KRG treatment (10, 20, and 40 mg/kg, per oral (p.o.)). After the exposure, behavioral tests to measure anxiety, social interaction, and depression-like behavior were performed. To investigate the underlying mechanism, N-methyl-D-aspartate receptor expression levels in CSDS-induced mice were evaluated using Western blot analysis. RESULTS: CSDS induced anxiety-like behaviors by decreasing central activity in the open-field test and open-arm approach in the elevated plus maze test and led to social avoidance behavior in the social interaction test. CSDS mice showed upregulated NR1, NR2A, and NR2B expression in the hippocampus. KRG 20 and 40 mg/kg ameliorated anxiety-like activities and KRG 20 mg/kg alleviated social avoidance by decreasing time in the corner zone. KRG treatment recovered CSDS-induced NR1, NR2A, and NR2B protein levels in the hippocampus. CONCLUSION: These results indicate that KRG has a therapeutic effect on CSDS-induced mood disorder by alleviating N-methyl-D-aspartate receptor overexpression in the hippocampus.

Fabrication of Carbon Nanomaterials Using Laser Scribing on Copper Nanoparticles-Embedded Polyacrylonitrile Films and Their Application in a Gas Sensor.

Carbon nanomaterials have attracted significant research attention as core materials in various industrial sectors owing to their excellent physicochemical properties. However, because the preparation of carbon materials is generally accompanied by high-temperature heat treatment, it has disadvantages in terms of cost and process. In this study, highly sensitive carbon nanomaterials were synthesized using a local laser scribing method from a copper-embedded polyacrylonitrile (CuPAN) composite film with a short processing time and low cost. The spin-coated CuPAN was converted into a carbonization precursor through stabilization and then patterned into a carbon nanomaterial of the desired shape using a pulsed laser. In particular, the stabilization process was essential in laser-induced carbonization, and the addition of copper promoted this effect as a catalyst. The synthesized material had a porous 3D structure that was easy to detect gas, and the resistance responses were detected as -2.41 and +0.97% by exposure to NO2 and NH3, respectively. In addition, the fabricated gas sensor consists of carbon materials and quartz with excellent thermal stability; therefore, it is expected to operate as a gas sensor even in extreme environments.

Interfacial Reactions and Mechanical Properties of Sn-58Bi Solder Joints with Ag Nanoparticles Prepared Using Ultra-Fast Laser Bonding.

The effects of Ag nanoparticle (Ag NP) addition on interfacial reaction and mechanical properties of Sn-58Bi solder joints using ultra-fast laser soldering were investigated. Laser-assisted low-temperature bonding was used to solder Sn-58Bi based pastes, with different Ag NP contents, onto organic surface preservative-finished Cu pads of printed circuit boards. The solder joints after laser bonding were examined to determine the effects of Ag NPs on interfacial reactions and intermetallic compounds (IMCs) and high-temperature storage tests performed to investigate its effects on the long-term reliabilities of solder joints. Their mechanical properties were also assessed using shear tests. Although the bonding time of the laser process was shorter than that of a conventional reflow process, Cu-Sn IMCs, such as Cu6Sn5 and Cu3Sn, were well formed at the interface of the solder joint. The addition of Ag NPs also improved the mechanical properties of the solder joints by reducing brittle fracture and suppressing IMC growth. However, excessive addition of Ag NPs degraded the mechanical properties due to coarsened Ag3Sn IMCs. Thus, this research predicts that the laser bonding process can be applied to low-temperature bonding to reduce thermal damage and improve the mechanical properties of Sn-58Bi solders, whose microstructure and related mechanical properties can be improved by adding optimal amounts of Ag NPs.

New designer phenethylamines 2C-C and 2C-P have abuse potential and induce neurotoxicity in rodents.

2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.

Antineuroinflammatory Effects of 7,3',4'-Trihydroxyisoflavone in Lipopolysaccharide-Stimulated BV2 Microglial Cells through MAPK and NF-κB Signaling Suppression.

Neuroinflammation-a common pathological feature of neurodegenerative disorders such as Alzheimer's disease-is mediated by microglial activation. Thus, inhibiting microglial activation is vital for treating various neurological disorders. 7,3',4'-Trihydroxyisoflavone (THIF)-a secondary metabolite of the soybean compound daidzein-possesses antioxidant and anticancer properties. However, the effects of 7,3',4'-THIF on microglial activation have not been explored. In this study, antineuroinflammatory effects of 7,3',4'-THIF in lipopolysaccharide (LPS)-stimulated BV2 microglial cells were examined. 7,3',4'-THIF significantly suppressed the production of the proinflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) as well as of the proinflammatory cytokine interleukin-6 (IL-6) in LPS-stimulated BV2 microglial cells. Moreover, 7,3',4'-THIF markedly inhibited reactive oxygen species (ROS) generation. Western blotting revealed that 7,3',4'-THIF diminished LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), glycogen synthase kinase-3ß (GSK-3ß), and nuclear factor kappa B (NF-κB). Overall, 7,3',4'-THIF exerts antineuroinflammatory effects against LPS-induced microglial activation by suppressing mitogen-activated protein kinase (MAPK) and NF-κB signaling, ultimately reducing proinflammatory responses. Therefore, these antineuroinflammatory effects of 7,3',4'-THIF suggest its potential as a therapeutic agent for neurodegenerative disorders.