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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.
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Trastornos del Conocimiento , Síndromes de Neurotoxicidad , Enfermedad de Parkinson , Masculino , Animales , Ratones , Ratones Endogámicos ICR , Dopamina , EncéfaloRESUMEN
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.
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Drogas de Diseño/toxicidad , Síndromes de Neurotoxicidad/etiología , Fenetilaminas/toxicidad , Animales , Drogas de Diseño/administración & dosificación , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Inflamación/inducido químicamente , Inflamación/patología , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Síndromes de Neurotoxicidad/fisiopatología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Fenetilaminas/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The use of new psychoactive substances (NPSs) as a substitute for illegal drugs is increasing rapidly and is a serious threat to public health. 25C-NBF is a newly synthesized phenethylamine-type NPS that acts as a 5-hydroxyindoleacetic acid (5-HT) receptor agonist, but little is known about its pharmacological effects. Considering that NPSs have caused unexpected harmful effects leading to emergency and even death, scientific confirmation of the potential adverse effects of 25C-NBF is essential. In the present study, we investigated whether 25C-NBF has addictive and neurotoxic potential and causes neurochemical changes. In addictive potential assessments, high conditioned place preference (CPP) scores and stable self-administration (SA) were observed in the 25C-NBF groups (CPP [3 mg kg-1]; SA [0.01, 0.03, 0.1 mg kg-1]), suggesting the addictive liability of 25C-NBF. In neurotoxic potential assessments, 25C-NBF treatment (single super-high dose [1 × 15, 30, 40 mg kg-1]; repeated high dose [4 × 8, 15, 30 mg kg-1]) resulted in reduced motor activity (open field test), abnormal motor coordination (rota-rod test) and impaired recognition memory (novel object recognition test), suggesting that 25C-NBF is neurotoxic leading to motor impairment and memory deficits. Subsequently, immunohistochemistry showed that 25C-NBF treatment decreased tyrosine hydroxylase (TH) expression and increased ionized calcium-binding adapter molecule 1 (Iba-1) expression in the striatum. Taken together, our results clearly demonstrate the dangers of recreational use of 25C-NBF, and we suggest that people stop using 25C-NBF and other NPSs whose pharmacological effects are not precisely known.
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Conducta Adictiva/inducido químicamente , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Fenetilaminas/toxicidad , Psicotrópicos/toxicidad , Trastornos Relacionados con Sustancias/etiología , Animales , Conducta Adictiva/metabolismo , Conducta Adictiva/psicología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Proteínas de Unión al Calcio/metabolismo , Condicionamiento Psicológico/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Proteínas de Microfilamentos/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/fisiopatología , Prueba de Campo Abierto/efectos de los fármacos , Ratas Sprague-Dawley , Prueba de Desempeño de Rotación con Aceleración Constante , Trastornos Relacionados con Sustancias/metabolismo , Trastornos Relacionados con Sustancias/psicología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Lespedeza bicolor, a traditional herbal medicine widely used in Australia, North America, and Eastern Asia, has various therapeutic effects on inflammation, nephritis, hyperpigmentation, and diuresis. In this study, to evaluate the effects of L. bicolor on cognitive function, we examined whether L. bicolor improved amyloid beta-induced memory impairment and assessed the possible mechanisms in mice. Catechin, rutin, daidzein, luteolin, naringenin, and genistein were identified in the powdered extract of L. bicolor by HPCL-DAD analyses. In behavioral experiments, L. bicolor (25 and 50 mg/kg, p.âo.) significantly improved amyloid beta25â-â35 (6 nmol, intracerebroventricular)-induced cognitive dysfunction in the Y-maze, novel recognition, and passive avoidance tests. Our molecular studies showed L. bicolor (25 and 50 mg/kg, p.âo.) significantly recovered the reduced glutathione content as well as increased thiobarbituric acid reactive substance and acetylcholinesterase activities in the hippocampus. Furthermore, we found that L. bicolor significantly increased the expression of brain-derived neurotrophic factor, and phospho-Akt, extracellular signal-regulated kinase, and cAMP response element binding caused by amyloid beta25â-â35 in the hippocampus. In conclusion, L. bicolor exerts a potent memory-enhancing effect on cognitive dysfunction induced by amyloid beta25â-â35 in mice.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Lespedeza/química , Trastornos de la Memoria/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Péptidos beta-Amiloides , Animales , Cognición/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Trastornos de la Memoria/inducido químicamente , Ratones , Fragmentos de Péptidos , Transducción de Señal/efectos de los fármacos , Regulación hacia ArribaRESUMEN
The development of silicon-based anodes with high capacity and good cycling stability for next-generation lithium-ion batteries is a very challenging task due to the large volume changes in the electrodes during repeated cycling, which results in capacity fading. In this work, we synthesized silicon alloy as an active anode material, which was composed of silicon nanoparticles embedded in Cu-Al-Fe matrix phases. Poly(amide imide)s, (PAI)s, with different thermal treatments were used as polymer binders in the silicon alloy-based electrodes. A systematic study demonstrated that the thermal treatment of the silicon alloy electrodes at high temperature made the electrodes mechanically strong and remarkably enhanced the cycling stability compared to electrodes without thermal treatment. The silicon alloy electrode thermally treated at 400 °C initially delivered a discharge capacity of 1084 mAh g(-1) with good capacity retention and high Coulombic efficiency. This superior cycling performance was attributed to the strong adhesion of the PAI binder resulting from enhanced secondary interactions, which maintained good electrical contacts between the active materials, electronic conductors, and current collector during cycling. These findings are supported by results from X-ray photoelectron spectroscopy, scanning electron microscopy, and a surface and interfacial cutting analysis system.
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Metal-organic frameworks (MOFs) are porous materials assembled using metal and organic linkers, showing a high specific surface area and a tunable pore size. Large portions of metal open sites in MOFs can be exposed to electrolyte ions, meaning they have high potential to be used as electrode materials in energy storage devices such as supercapacitors. Also, they can be easily converted into porous metal oxides by heat treatment. In this study, we obtained high energy storage performance by preparing electrode materials through applying heat treatment to manganese MOFs (Mn-MOFs) under air. The chemical and structural properties of synthesized and thermally treated Mn-MOFs were measured by Fourier-transform infrared spectroscopy (FTIR), Raman spectroscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM). The surface area and porosity were investigated by nitrogen adsorption/desorption isotherms. The electrochemical properties were studied by cyclic voltammetry (CV) and galvanostatic charge-discharge (GCD) using a three-electrode cell. It was found that Mn-MOF electrodes that underwent heat treatment at 400 °C under air consisted of Mn2O3 with high specific surface area and porosity. They also showed a superior specific capacitance of 214.0 F g-1 and an energy density value of 29.7 Wh kg-1 (at 0.1 A g-1) compared to non-treated Mn-MOFs.
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BACKGROUND AND PURPOSE: Cytoplasmic fragile X messenger ribonucleoprotein 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.
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Proteínas Adaptadoras Transductoras de Señales , Cocaína , Ratones Endogámicos C57BL , Plasticidad Neuronal , Núcleo Accumbens , Recompensa , Animales , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Cocaína/farmacología , Plasticidad Neuronal/efectos de los fármacos , Ratones , Masculino , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Mutación , Conducta Animal/efectos de los fármacosRESUMEN
BACKGROUND AND PURPOSE: Methamphetamine (METH) use disorder has risen dramatically over the past decade, and there are currently no FDA-approved medications due, in part, to gaps in our understanding of the pharmacological mechanisms related to METH action in the brain. EXPERIMENTAL APPROACH: Here, we investigated whether transient receptor potential ankyrin 1 (TRPA1) mediates each of several METH abuse-related behaviours in rodents: self-administration, drug-primed reinstatement, acquisition of conditioned place preference, and hyperlocomotion. Additionally, METH-induced molecular (i.e., neurotransmitter and protein) changes in the brain were compared between wild-type and TRPA1 knock-out mice. Finally, the relationship between TRPA1 and the dopamine transporter was investigated through immunoprecipitation and dopamine reuptake assays. KEY RESULTS: TRPA1 antagonism blunted METH self-administration and drug-primed reinstatement of METH-seeking behaviour. Further, development of METH-induced conditioned place preference and hyperlocomotion were inhibited by TRPA1 antagonist treatment, effects that were not observed in TRPA1 knock-out mice. Similarly, molecular studies revealed METH-induced increases in dopamine levels and expression of dopamine system-related proteins in wild-type, but not in TRPA1 knock-out mice. Furthermore, pharmacological blockade of TRPA1 receptors reduced the interaction between TRPA1 and the dopamine transporter, thereby increasing dopamine reuptake activity by the transporter. CONCLUSION AND IMPLICATIONS: This study demonstrates that TRPA1 is involved in the abuse-related behavioural effects of METH, potentially through its modulatory role in METH-induced activation of dopaminergic neurotransmission. Taken together, these data suggest that TRPA1 may be a novel therapeutic target for treating METH use disorder.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Metanfetamina , Ratones Endogámicos C57BL , Ratones Noqueados , Canal Catiónico TRPA1 , Animales , Metanfetamina/farmacología , Metanfetamina/administración & dosificación , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Canal Catiónico TRPA1/metabolismo , Canal Catiónico TRPA1/genética , Canal Catiónico TRPA1/antagonistas & inhibidores , Masculino , Ratones , Trastornos Relacionados con Anfetaminas/metabolismo , Autoadministración , Ratas Sprague-Dawley , Estimulantes del Sistema Nervioso Central/farmacologíaRESUMEN
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.
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Núcleo Accumbens , Psicotrópicos , Receptores de Dopamina D1 , Recompensa , Transducción de Señal , Animales , Masculino , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/agonistas , Ratones , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Transducción de Señal/efectos de los fármacos , Ratas , Psicotrópicos/farmacología , Ratas Sprague-Dawley , Ratones Endogámicos C57BL , Fenetilaminas/farmacología , Autoadministración , Dopamina/metabolismoRESUMEN
Adinazolam (ADZ) is a benzodiazepine-type new psychoactive substance (NPS) with anxiolytic, anticonvulsant, and antidepressant effects. High ADZ doses have been reported to impair psychomotor performance and memory; however, the abuse potential and drug dependence of ADZ have not yet been fully investigated. In this study, we evaluated whether ADZ has abuse potential and leads to drug dependence and withdrawal symptoms. The intravenous self-administration (IVSA) test revealed that ADZ (0.01, 0.03, and 0.1 mg/kg/infusion) was self-administered significantly above vehicle levels, suggesting the reinforcing effect of ADZ. Furthermore, we revealed that treatment discontinuation following chronic ADZ administration (3 and 6 mg/kg) caused several somatic withdrawal symptoms in mice, including body tremor. Moreover, it induced motivational withdrawal signs, such as anxiety-related behavior in the elevated plus maze (EPM) test and memory deficits in the Y-maze test. After the IVSA test, an enzyme-linked immunosorbent assay (ELISA) showed that ADZ administration significantly increased the dopamine contents in the thalamus, nucleus accumbens (NAc), and ventral tegmental area (VTA). This finding was also supported by the results of the Western blot. Taken together, our results suggest that ADZ has abuse potential and can lead to drug dependence and withdrawal syndrome.
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Roedores , Síndrome de Abstinencia a Sustancias , Animales , Ratones , Benzodiazepinas , Fármacos del Sistema Nervioso CentralRESUMEN
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.
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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.
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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.
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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.
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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.
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Conducta Adictiva , Esquizofrenia , Animales , Conducta Adictiva/inducido químicamente , Encéfalo , Ratones , Piperidinas , RatasRESUMEN
Emotional disorders such as anxiety and depression are widespread psychological diseases that affect up to 20% of the world's population. There are many approaches to the discovery of novel agents for the treatment of depressive- and anxiety-like symptoms. However, the efficacy of existing drugs for emotional disorders is only exerted after a few weeks of treatment and have serious side effects. Due to this, new strategies to find suitable and safe options are being sought by many researchers. Among them, a lot of interest has been attracted by plant-derived natural compounds due to their wide range of beneficial effects for new agent development. Flavonoids are natural polyphenol-like compounds found commonly in plants, fruits, vegetables, and medicinal herbs. A diverse range of flavonoids have been studied to investigate their potential therapeutic activities for the treatment of brain-associated disorders, including anxiety and depression. The main aim of this review is to understand the associations between the various flavonoids and the emotional disorders and discuss the therapeutic effects of these natural compounds that were demonstrated during the conduction of recent studies. The current work shows advances in the latest research of some flavonoids as a potential candidate for the treatment of emotional disorders. We summarize their behavioral, molecular, physiological, and neurochemical effects in various in vitro and in vivo models. Therefore, in the present work, the latest studies were collected on the most important flavonoid compounds and their underlying mechanisms of action in emotion-related disorders were discussed.
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Afecto/efectos de los fármacos , Ansiolíticos/uso terapéutico , Antidepresivos/uso terapéutico , Ansiedad/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Depresión/tratamiento farmacológico , Emociones/efectos de los fármacos , Flavonoides/uso terapéutico , Animales , Ansiolíticos/efectos adversos , Ansiolíticos/farmacocinética , Antidepresivos/efectos adversos , Antidepresivos/farmacocinética , Ansiedad/metabolismo , Ansiedad/fisiopatología , Ansiedad/psicología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Depresión/metabolismo , Depresión/fisiopatología , Depresión/psicología , Flavonoides/efectos adversos , Flavonoides/farmacocinética , HumanosRESUMEN
7,3',4'-Trihydroxyisoflavone (THIF) is a secondary metabolite derived from daidzein and is abundantly present in soybeans. Daidzein and 7,3',4'-THIF exhibit several pharmacological activities, including antioxidant and anti-atopic properties. However, the effects of 7,3',4'-THIF on cognitive function have not been fully investigated. Here, we evaluated the effects of 7,3',4'-THIF on memory using Y-maze and passive avoidance tests. The positive control groups were given donepezil (5 mg/kg, p.o.) or piracetam (200 mg/kg, i.p.) and the treated groups were given 7,3',4'-THIF (0.25, 0.5 and 1 mg/kg, p.o.). 7,3',4'-THIF at 1 mg/kg and donepezil at 5 mg/kg effectively ameliorated memory impairments induced by scopolamine (0.5 mg/kg, i.p.) in mice. In addition, 7,3',4'-THIF at 1 mg/kg and piracetam at 200 mg/kg significantly enhanced memory in intact mice. To examine the underlying mechanisms of 7,3',4'-THIF on cognition following behavioral experiments, biochemical tests were performed in the whole hippocampus. 7,3',4'-THIF (1 mg/kg, p.o.) significantly recovered scopolamine-induced cholinergic impairments. Moreover, brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), and synaptophysin, along with phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element binding (CREB), were significantly increased by 7,3',4'-THIF (1 mg/kg, p.o.). Our findings indicate that 7,3',4'-THIF improves cognitive function by regulating cholinergic system and BDNF signaling.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Isoflavonas/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Memoria/efectos de los fármacos , Nootrópicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/química , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Homólogo 4 de la Proteína Discs Large/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/química , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Fosforilación/efectos de los fármacos , Escopolamina , Sinaptofisina/metabolismoRESUMEN
Daidzein isolated from soybean (Glycine max) has been widely studied for its antioxidant and anti-inflammatory activities. However, the protective effects of 7,8,4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, on 6-hydroxydopamine (OHDA)-induced neurotoxicity are not well understood. In the current study, 7,8,4'-THIF significantly inhibited neuronal cell death and lactate dehydrogenase (LDH) release induced by 6-OHDA in SH-SY5Y cells, which were used as an in vitro model of Parkinson' disease (PD). Moreover, pretreatment with 7,8,4'-THIF significantly increased the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) and decreased malondialdehyde (MDA) activity in 6-OHDA-induced SH-SY5Y cells. In addition, 7,8,4'-THIF significantly recovered 6-OHDA-induced cleaved caspase-3, cleaved caspase-9, cleaved poly-ADP-ribose polymerase (PARP), increased Bax, and decreased Bcl-2 levels. Additionally, 7,8,4'-THIF significantly restored the expression levels of phosphorylated c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), phosphatidylinositol 3-kinases (PI3K)/Akt, and glycogen synthase kinase-3 beta (GSK-3ß) in 6-OHDA-induced SH-SY5Y cells. Further, 7,8,4'-THIF significantly increased the reduced tyrosine hydroxylase (TH) level induced by 6-OHDA in SH-SY5Y cells. Collectively, these results suggest that 7,8,4'-THIF protects against 6-OHDA-induced neuronal cell death in cellular PD models. Also, these effects are mediated partly by inhibiting activation of the MAPK and PI3K/Akt/GSK-3ß pathways.
RESUMEN
Daidzein, one of the important isoflavones, is extensively metabolized in the human body following consumption. In particular, 6,7,4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, has been the focus of recent investigations due to its various health benefits, such as anti-cancer and anti-obesity effects. However, the protective effects of 6,7,4'-THIF have not yet been studied in models of Parkinson's disease (PD). Therefore, the present study aimed to investigate the protective activity of 6,7,4'-THIF on 6-hydroxydopamine (OHDA)-induced neurotoxicity in SH-SY5Y human neuroblastoma cells. Pretreatment of SH-SY5Y cells with 6,7,4'-THIF significantly inhibited 6-OHDA-induced neuronal cell death, lactate dehydrogenase release, and reactive oxygen species production. In addition, 6,7,4'-THIF significantly attenuated reductions in 6-OHDA-induced superoxide dismutase activity and glutathione content. Moreover, 6,7,4'-THIF attenuated alterations in Bax and Bcl-2 expression and caspase-3 activity in 6-OHDA-induced SH-SY5Y cells. Furthermore, 6,7,4'-THIF significantly reduced 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase 1/2. Additionally, 6,7,4'-THIF effectively prevented 6-OHDA-induced loss of tyrosine hydroxylase. Taken together, these results suggest that 6,7,4'-THIF, a major metabolite of daidzein, may be an attractive option for treating and/or preventing neurodegenerative disorders such as PD.