Search Results (62)

Ethanol affects the central nervous system, with frequent use leading to memory impairment. This study aims to determine the effects of brivaracetam on ethanol-induced memory impairment and alterations in selected neurotransmitter levels, trace elements in the brain and serum oxidative stress parameters in rats. Brivaracetam was administered for three weeks (6 mg/kg b.w.) before behavioral tests. Ethanol was given as a forced model (5 g/kg b.w.). Spatial memory was evaluated with the Morris water maze test and recognition memory with the novel object recognition test. GABA and glutamate concentrations were evaluated in the cerebellum, hippocampus, and cerebral cortex, while superoxide dismutase (SOD) and catalase (CAT) activities and malondialdehyde (MDA) levels were measured in blood serum. The levels of copper, manganese, zinc, iron, and magnesium in the brain were also determined. Brivaracetam was found to negatively affect spatial and retrieval memory when administered with ethanol and during withdrawal; however, the drug improved ethanol-induced short-term recognition memory impairment. Furthermore, brivaracetam increased CAT activity, while MDA was decreased and SOD increased in all drug-treated animals. Brivaracetam may counteract ethanol-induced manganese brain concentration, but increases iron, magnesium, and copper concentrations. Hence, brivaracetam use induces various effects on the central nervous system. Full article

Compounds containing electron-withdrawing dicyanopyrazine and 1,2,5-chalcogenadiazole fragments are promising for the design of magnetic and optoelectronic materials. In this paper, bis([1,2,5]thiadiazolo)[3,4-f:3′,4′-h]quinoxaline-8,9-dicarbonitrile was prepared via Körner–Hinsberg condensation of benzo[1,2-c:3,4-c′]bis([1,2,5]thiadiazole)-4,5-dione with 2,3-diaminomaleonitrile in the presence of catalytic amounts of TsOH in refluxing ethanol. The structure of the newly synthesized compound was established via elemental analysis, mass spectrometry, ¹³C NMR, and IR spectroscopy. Full article

Noble metal nanostructures based on localized surface plasmon resonance (LSPR) can induce metal-enhanced fluorescence (MEF) and surface-enhanced Raman scattering (SERS), significantly improving trace detection sensitivity for biomedical and chemical analysis. While self-assembly of noble metal nanoparticles offers simplicity and low equipment dependence, achieving large-area, uniform, and controllable nanostructures remains challenging. In this study, angle-dependent dip coating (ADDC) technology was employed to achieve efficient, controllable self-assembly of silver nanoparticles (AgNPs) on glass slides, establishing a fabrication process for MEF/SERS dual-functional substrates. A stable AgNPs-anhydrous ethanol suspension was prepared and extracted from an inclined substrate reservoir using a microfluidic syringe pump, enabling large-area uniform nanostructure assembly. Systematic investigation revealed that substrate inclination angle provides better morphology and fluorescence enhancement control than withdrawal flow rate. The silver nanostructured surface fabricated under a withdrawal flow rate of 16 mL/h and a substrate inclination angle of 30° exhibited a Cy3 detection limit as low as ${10}^{-1}$ nM, with an enhancement factor ranging from 19.14 to 28.66, as well as an R6G SERS detection limit of ${10}^{-10}$ M with an enhancement factor of 4.07 × ${10}^8$. This study confirms that ADDC technology enables simple, efficient, large-area uniform AgNPs self-assembly for superior dual-function enhancement substrates, offering a cost-effective and efficient strategy for highly sensitive trace detection. Full article

Kratom (Mitragyna speciosa) is a botanical candidate for pain management with potentially reduced opioid-related risks, partly through modulation of neuroimmune pathways involving Toll-Like Receptor 4 (TLR4). This study aimed to characterize the phytochemical profile of kratom ethanol extract and evaluate its effects on TLR4 signalling, neuroinflammatory cytokines, analgesic activity, withdrawal behaviours, and organ safety in morphine-dependent mice. Metabolite profiling was conducted using UHPLC–Q-Exactive Orbitrap HRMS, followed by molecular docking of major constituents to the TLR4 complex. In vivo assessments included flow cytometry and gene expression analyses of TLR4-mediated cytokines (NF-κB, IL-1β, IL-6), behavioural assays for antinociception, endurance, and withdrawal symptoms, and histopathological and biochemical evaluation of liver, kidney, and spleen tissues. More than 100 metabolites were identified, including mitragynine and flavonoids such as rutin and isoquercetin, which showed interactions with key TLR4 residues. Selected fractions suppressed pro-inflammatory cytokine expression, increased tail-pinch latency comparable to morphine, reduced withdrawal manifestations, and demonstrated nephroprotective and immunomodulatory effects, although mild reversible hepatic alterations were observed in specific fractions. Overall, kratom ethanol extract exhibited fraction-dependent analgesic and anti-neuroinflammatory activities associated with TLR4 modulation, supporting its potential as a botanical analgesic candidate while emphasizing the importance of safety optimization and standardized fraction development. Full article

Buprenorphine (BUP) is widely used in the treatment of neonatal opioid withdrawal syndrome (NOWS). However, the most compounded formulation contains 30% ethanol, despite regulatory and clinical concerns regarding ethanol exposure in pediatric patients. Thus, this research aimed to develop an ethanol-free sublingual (SL) gel formulation of BUP that would be safe, stable, and suitable for NOWS. Multiple polymers were screened as gelling agents, with hydroxypropyl methylcellulose (HPMC) emerging as the ideal base polymer for the formulation due to its optimal pH, rheological characteristics, and stability. The formulated gels were stored at room temperature and refrigerated conditions for 30 days and evaluated for stability using pH, rheology, and liquid chromatography-mass spectrometry. BUP content was between 90–110% of the labeled amount of the dosage form (75 µg/mL) at all time-points, and the pH remained close to physiological values. Release studies demonstrated a drug release of 23–24% for SL gels without surfactants stored at room temperature and refrigerated conditions, respectively. Incorporation of non-ionic surfactants (Tween 20 and Tween 80) significantly increased drug release to 33% and 40%, respectively, reflecting enhanced solubilization and improved mucosal penetration. The ethanol-free formulation demonstrated physicochemical stability and favorable release characteristics suitable for neonatal administration. These findings represent a meaningful advance in the development of safer pediatric formulations for NOWS. Full article

Alcohol Use Disorder (AUD) profoundly impacts individuals and society, driven by neurobiological adaptations that sustain chronicity and relapse. Emerging research highlights neuroinflammation, particularly microglial activation, as a central mechanism in AUD pathology. Ethanol engages microglia—the brain’s immune cells—through key signaling pathways such as Toll-like receptor 4 (TLR4) and the NLRP3 inflammasome, triggering the release of proinflammatory cytokines (IL-1β, TNF-α, IL-6). These mediators alter synaptic plasticity in addiction-related brain regions, including the ventral tegmental area, nucleus accumbens, amygdala, and lateral habenula, thereby exacerbating cravings, withdrawal symptoms, and relapse risk. Rodent models reveal that microglial priming disrupts dopamine signaling, heightening impulsivity and anxiety-like behaviors. Human studies corroborate these findings, demonstrating increased microglial activation markers in postmortem AUD brains and neuroimaging analyses. Notably, sex differences influence microglial reactivity, complicating AUD’s neuroimmune landscape and necessitating sex-specific research approaches. Microglia-targeted therapies—including minocycline, ibudilast, GLP-1 receptor agonists, and P2X7 receptor antagonists—promise to mitigate neuroinflammation and reduce alcohol intake, yet clinical validation remains limited. Addressing gaps such as biomarker identification, longitudinal human studies, and developmental mechanisms is critical. Leveraging multi-omics tools and advanced neuroimaging can refine microglia-based therapeutic strategies, offering innovative avenues to break the self-sustaining cycle of AUD. Full article

Alcohol use disorder (AUD) is a widespread, multifaceted disorder involving overproduction of pro-inflammatory cytokines, oxidative liver injury, and dysfunction of the brain’s dopaminergic reward circuits. Korean red ginseng (KRG), an herbal supplement derived from Panax ginseng, has demonstrated qualities potentially useful to the treatment of AUD, including antioxidative, anti-inflammatory, neuroprotective, and anxiolytic effects. This review examines active constituents of KRG, their pharmacological actions, and evidence supporting KRG’s therapeutic potential in the context of AUD, while also assessing its safety profile, adverse effects, and potential drug interactions. KRG’s main bioactive constituents, ginsenosides, appear to have roles in modulating alcohol-metabolizing enzymes, ethanol-activated inflammatory cytokine cascades, and neurological systems disrupted by AUD, including GABAergic and dopaminergic pathways. Evidence from animal models and limited small-scale human trials suggests KRG may alleviate symptoms of alcohol withdrawal, enhance cognitive performance, and attenuate anxiety through these pathways. While generally safe for consumption, several case reports and animal studies have indicated KRG’s potential to pose a variety of risks in vulnerable populations at high, prolonged doses, including hepatotoxicity, cardiovascular changes, mood disturbances, and hormonal effects. Furthermore, KRG’s neuromodulating role and influence on cytochrome P450 enzymes make it liable to interact with several medications, including warfarin, midazolam, selegiline, and serotonergic agents. Overall, KRG shows promise as a complementary supplement in managing aspects of AUD, though current evidence is limited by low sample sizes, inconsistent reports regarding nuances of ginsenosides’ mechanisms, and a low number of human trials. Further human-focused research is needed to elucidate its safety, efficacy, and mechanism. Full article

Background: Ethanol intake leads to cognitive deficits. Recent research demonstrated that a dysregulation of synaptic vesicle glycoprotein 2A (SV2A) expression seems to be linked to anxiety and memory disorders. Levetiracetam and brivaracetam are two antiseizure drugs that affect the SV2A protein. This study aimed to assess the impact of these drugs on associative learning and anxiety-like behaviors in ethanol-treated rats. Methods: Adult male Wistar rats (n = 64) were given brivaracetam or levetiracetam via i.g. for three weeks at doses of 300 mg/kg or 6 mg/kg, respectively. Ethanol was administered as a 20% solution twice a day, via i.g., at a morning dose of 1.5 g/kg b.w. and an afternoon dose of 3.5 g/kg b.w. Additionally, 5% ethanol was available ad libitum between 4:00 p.m. and 8:00 a.m. Associative learning was evaluated using the passive avoidance test during the alcohol administration period, as well as the contextual fear conditioning and cued fear conditioning tests during the withdrawal period. The level of anxiety was determined using the elevated plus maze test in withdrawal rats. Results: Ethanol consumption resulted in impaired associative memory, and its withdrawal was linked to increased anxiety levels. Levetiracetam enhanced memory performance in the passive avoidance test, but brivaracetam disturbed memory associated with unpleasant stimuli in the contextual fear conditioning. Additionally, withdrawal-induced disturbance of locomotor activity persisted, particularly in animals receiving levetiracetam in the elevated plus maze. Conclusions: Levetiracetam appears to provide certain beneficial effects, whereas brivaracetam may worsen memory disturbances in rats. Full article

Adolescent binge drinking has lasting behavioral consequences by disrupting the endocannabinoid system (ECS) and depleting brain omega-3. The natural accumulation of omega-3 fatty acids in cell membranes is crucial for maintaining the membrane structure, supporting interactions with the ECS, and restoring synaptic plasticity and cognition impaired by prenatal ethanol (EtOH) exposure. However, it remains unclear whether omega-3 supplementation can mitigate the long-term effects on the ECS, endocannabinoid-dependent synaptic plasticity, and cognition following adolescent binge drinking. Here, we demonstrated that omega-3 supplementation during EtOH withdrawal increases CB1 receptors in hippocampal presynaptic terminals of male mice, along with the recovery of receptor-stimulated [³⁵S]GTPγS binding to Gαi/o proteins. These changes are associated with long-term potentiation (LTP) at excitatory medial perforant path (MPP) synapses in the dentate gyrus (DG), which depends on anandamide (AEA), transient receptor potential vanilloid 1 (TRPV1), and N-methyl-D-aspartate (NMDA) receptors. Finally, omega-3 intake following binge drinking reduced the time and number of errors required to locate the escape box in the Barnes maze test. Collectively, these findings suggest that omega-3 supplementation restores Barnes maze performance to levels comparable to those of control mice after adolescent binge drinking. This recovery is likely mediated by modulation of the hippocampal ECS, enhancing endocannabinoid-dependent excitatory synaptic plasticity. Full article

Background: Prenatal alcohol exposure (PAE) models can cause neurodevelopmental abnormalities like those observed in fetal alcohol spectrum disorder (FASD). Previous studies link experimental PAE effects in the brain to impaired signaling through insulin/IGF and Notch pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Importantly, concurrent administration of peroxisome proliferator-activated receptor agonists or dietary soy prevented many aspects of FASD due to their insulin-sensitizing, anti-inflammatory, and antioxidant properties. Objective: To determine if dietary soy interventions during pregnancy would be sufficient to normalize central nervous system structure and function, we examined the effects of maternal gestation-limited dietary soy on cerebellar postnatal development, motor function, and critical signaling pathways. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source. The ethanol and soy feedings were discontinued upon delivery. The offspring were subjected to rotarod motor function tests, and on postnatal day 35, they were sacrificed to harvest cerebella for histological and molecular studies. Results: Despite the postnatal cessation of alcohol exposure, chronic gestational exposure reduced brain weight, caused cerebellar hypoplasia, and impaired motor performance. Gestational dietary soy prevented the ethanol-associated reduction in brain weight and largely restored the histological integrity of the cerebellum but failed to normalize motor performance. Ethanol withdrawal abolished the impairments in insulin/IGF signaling that were previously associated with ongoing ethanol exposures, but ethanol’s inhibitory effects on Notch and Wnt signaling persisted. Soy significantly increased cerebellar expression of the insulin and IGF-1 receptors and abrogated several ethanol-associated impairments in Notch and Wnt signaling. Conclusions: Although gestation-restricted dietary soy has significant positive effects on neurodevelopment, optimum prevention of FASD’s long-term effects will likely require dietary soy intervention during the critical periods of postnatal development, even after alcohol exposures have ceased. Full article

The N-methyl-D-aspartate (NMDA) glutamate receptor is a major target of ethanol, and it is implicated in learning and memory formation, and other cognitive functions. Glycine acts as a co-agonist for this receptor. We examined whether Org24598, a selective inhibitor of glycine transporter1 (GlyT1), affects ethanol withdrawal-induced deficits in recognition memory (Novel Object Recognition (NOR) task) and spatial memory (Barnes Maze (BM) task) in rats, and whether the NMDA receptor glycine site participates in this phenomenon. Male Wistar rats were habituated to NOR or BM tasks, and then received binge-like intragastric ethanol administration (5 days, 5 g/kg). After ethanol withdrawal, Org24598 (0.1, 0.3, and 0.6 mg/kg) was administered 30 min before NOR (day 10 of withdrawal) or the reversal learning phase of BM (day 11–13 of withdrawal) task. The expression of GluN1 and GluN2B subunits of NMDA receptors were measured in the perirhinal cortex (PRC) and hippocampus (HIP) after termination of NOR. In the BM task, a glycine antagonist, L-701,324 (5 mg/kg), was administered 30 min before Org24598 to confirm the involvement of the NMDA receptor glycine site in the effects of Org24598. Our study showed that binge-like ethanol administration induced recognition and spatial memory impairments after withdrawal in rats. Additionally, an up-regulation of GluN1 and GluN2B subunits of the NMDA receptor was observed in the HIP and PRC on day 11 of abstinence. Org24598 ameliorated memory loss and normalized the expression of these subunits. L-701,324 reversed the effect of Org24598. Thus, NMDA receptor glycine sites are important in ethanol withdrawal-induced memory impairments. Full article

Adolescence is a critical period when the effects of ethanol and stress exposure are particularly pronounced. Argan oil (AO), a natural vegetable oil known for its diverse pharmacological benefits, was investigated for its potential to mitigate addictive-like behaviors and brain damage induced by adolescent intermittent ethanol intoxication (IEI) and unpredictable mild stress (UMS). From P30 to P43, IEI rats received a daily ip ethanol (3 g/kg) on a two-day on/two-day off schedule. On alternate days, the rats were submitted to UMS protocol. Next, a two-bottle free access paradigm was performed over 10 weeks to assess intermittent 20% ethanol voluntary consumption. During the same period, the rats were gavaged daily with AO (15 mL/kg). Our results show that IEI/UMS significantly increased voluntary alcohol consumption (from 3.9 g/kg/24 h to 5.8 g/kg/24 h) and exacerbated withdrawal signs and relapse-like drinking in adulthood. Although AO treatment slightly reduced ethanol intake, it notably alleviated withdrawal signs during abstinence and relapse-like drinking in adulthood. AO’s effects were associated with its modulation of the HPA axis (elevated serum corticosterone), restoration of amygdala oxidative balance, BDNF levels, and attenuation of neurodegeneration. These findings suggest that AO’s neuroprotective properties could offer a potential therapeutic avenue for reducing ethanol/stress-induced brain damage and addiction. Further research is needed to explore its mechanisms and therapeutic potential in alcohol use disorders. Full article

Alcohol use disorder (AUD) is the most common substance use disorder and poses a significant global health challenge. Despite pharmacological advances, no single drug effectively treats all AUD patients. This study explores the protective potential of hispidol, a 6,4′-dihydroxyaurone, for AUD using the Caenorhabditis elegans model system. Our findings demonstrate that hispidol-fed worms exhibited more pronounced impairments in thrashes, locomotory speed, and bending amplitude, indicating that hispidol exacerbated the detrimental effects of acute ethanol exposure. However, hispidol significantly improved ethanol withdrawal behaviors, such as locomotory speed and chemotaxis performance. These beneficial effects were absent in slo-1 worms (the ortholog of mammalian α-subunit of BK channel) but were restored with the slo-1(+) or hslo(+) transgene, suggesting the involvement of BK channel activity. Additionally, hispidol increased fluorescence intensity and puncta in the motor neurons of slo-1::mCherry-tagged worms, indicating enhanced BK channel expression and clustering. Notably, hispidol did not alter internal ethanol concentrations, suggesting that its action is independent of ethanol metabolism. In the mouse models, hispidol treatment also demonstrated anxiolytic activity against ethanol withdrawal. Overall, these findings suggest hispidol as a promising candidate for targeting the BK channel in AUD treatment. Full article

The stereoisomers (E)-2,2-dimethyl-4-(4-subsitutedstyryl)-2,3-dihydro-1H-[1,5]-benzodiazepine 3(a–d) were synthesized via the condensation reaction of 2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (BZD) 1 with the benzaldehyde derivatives 2(a–d) in ethanol. The chemical structure of the prepared products was confirmed by NMR (¹H and ¹³C), HRMS, and X-ray analysis of the crystal structure 3d. The condensation reaction was examined using DFT calculations at the theoretical level of B3LYP/6-31G(d) to elucidate the chemo-, regio-, and stereoselectivity and the reaction mechanism of the produced isomer. Furthermore, we identified each reagent’s reactive sites by the measurement of the reactivity indices. We also looked at how the electron-withdrawing groups (EWGs) of various aldehydes affected the reaction’s mechanism and the stability of products 3(a–d). Full article

Exercise has increasingly been recognized as an adjunctive therapy for alcohol-use disorder (AUD), yet our understanding of its underlying neurological mechanisms remains limited. This knowledge gap impedes the development of evidence-based exercise guidelines for AUD treatment. Chronic ethanol (EtOH) exposure has been shown to upregulate and sensitize kappa opioid receptors (KORs) in the nucleus accumbens (NAc), which is innervated by dopamine (DA) neurons in the midbrain ventral tegmental area (VTA), which may contribute to AUD-related behaviors. In this study, we investigated the impact of voluntary exercise in EtOH-dependent mice on EtOH consumption, KOR and delta opioid receptor (DOR) expression in the NAc and VTA, and functional effects on EtOH-induced alterations in DA release in the NAc. Our findings reveal that voluntary exercise reduces EtOH consumption, reduces KOR and enhances DOR expression in the NAc, and modifies EtOH-induced adaptations in DA release, suggesting a competitive interaction between exercise-induced and EtOH-induced alterations in KOR expression. We also found changes to DOR expression in the NAc and VTA with voluntary exercise but no significant changes to DA release. These findings elucidate the complex interplay of AUD-related neurobiological processes, highlighting the potential for exercise as a therapeutic intervention for AUD. Full article