Search Results (509)

Chronic neuropathic pain, particularly diabetic neuropathic pain and postherpetic neuralgia, severely impairs patients’ quality of life due to their complex mechanisms and recurrent, long-term nature, making treatment challenging. This study aimed to evaluate the analgesic efficacy of α-conotoxin GeXIVA[1,2], a selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR), in rat models of diabetic neuropathic pain and postherpetic neuralgia and investigate its associated physiological and pathological effects. GeXIVA[1,2] was administered continuously for three weeks, with mechanical hypersensitivity assessed through pain sensitivity tests, and behavioral assessments conducted to examine motor coordination and gait. Additionally, neural tissue structure and inflammation were analyzed. The results demonstrated that GeXIVA[1,2] significantly alleviated mechanical hypersensitivity in both diabetic neuropathic pain and postherpetic neuralgia models, with greater efficacy than gabapentin and no signs of tolerance. Behavioral tests indicated no significant effects on motor coordination or gait. Further analysis revealed that GeXIVA[1,2] reduced pro-inflammatory cytokine levels, decreased immune cell infiltration, and promoted repair of damaged nerve fibers. Overall, these findings suggest that GeXIVA[1,2] exerts analgesic effects through anti-inflammatory and neuroprotective mechanisms, providing a potential new therapeutic strategy for diabetic neuropathic pain and postherpetic neuralgia. Full article

Background/Objectives: Statins are currently one of the most commonly used cholesterol-lowering drugs. In recent years, in addition to their well-known effects on the cardiovascular system, statins have been shown to exert beneficial effects in the progression of various neuropsychiatric and neurodegenerative diseases. Methods: In this study, the effects of lovastatin on the function of α7-nicotinic acetylcholine (nACh) receptors expressed in rat hippocampus and Xenopus oocytes were investigated. Results: In whole-cell patch clamp studies in hippocampal neurons, 21-day chronic (20 mg/kg), but not acute (20 min), lovastatin treatment caused significant potentiation of choline (a selective agonist for α7 nACh receptors)-induced currents and choline-induced increases in GABA_A receptor-mediated currents. Further studies in Xenopus oocytes expressing human α7-nACh receptors indicated that 72 h pretreatment with lovastatin caused a significant increase in α7-nACh receptor function with an EC₅₀ value of 296 nM. Other statins, such as simvastatin and pravastatin, also potentiated α7-nACh receptors. Potentiation by lovastatin treatment was associated with a significant decrease in oocyte cholesterol content and was diminished by Go6983, an inhibitor of protein kinase C (PKC), suggesting that both decreased cholesterol levels and activation of PKC are involved in statin potentiation of α7-nACh receptors. Conclusions: In conclusion, our findings indicate that chronic lovastatin treatment potentiates the function of α7-nACh receptors in hippocampal neurons and in Xenopus oocytes expressing human α7-nACh receptors and provides important insights that could guide future efforts to design novel drugs targeting α7-nACh receptors. Full article

Acetylcholine (ACh) is an evolutionarily conserved neurotransmitter that is widely distributed in the central and peripheral nervous systems and plays essential roles in multiple physiological processes. This review summarizes the full biological cycle of ACh, including its synthesis, vesicular storage, release, degradation, and reuptake, and discusses the regulatory mechanisms underlying its functions in the nervous system and peripheral organs. Through nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs), ACh is involved in central nervous system functions such as cognition, learning and memory, attention, arousal, reward, and decision-making, as well as peripheral processes including motor control, autonomic regulation, and immune modulation. In addition, ACh plays a pivotal role in the brain–body axis. At the central level, the nervous system regulates peripheral organ function through autonomic and neuroendocrine pathways. At the peripheral level, cholinergic signals derived from the enteric nervous system and immune cells convey information about the body’s internal state to the central nervous system through vagal and other afferent pathways, forming an important bottom-up regulatory network. Collectively, these findings indicate that ACh is not only a classical neurotransmitter but also a key molecular mediator of brain–body communication. A more comprehensive understanding of cholinergic signaling may provide new insights into physiological regulation and the pathogenesis of neurological, psychiatric, cardiovascular, and inflammatory diseases. Full article

Background: Peripheral neuropathy is a common and clinically heterogeneous neurological condition caused by metabolic, inflammatory, toxic, or traumatic factors and is associated with sensory deficits, neuropathic pain, motor impairment, and reduced functional capacity. Management remains challenging and often requires multimodal therapeutic approaches, as pharmacological monotherapy frequently provides incomplete symptom control. Objective: This narrative review explores the conceptual rationale for combining galantamine with iontophoresis and Black Sea brine-based therapy as a potential multimodal strategy for peripheral neuropathy management. Main Findings: Galantamine, a reversible acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, has demonstrated neuroprotective, neuromodulatory, and anti-inflammatory properties in experimental settings. Iontophoresis may provide a non-invasive method for targeted local drug delivery while reducing systemic exposure. Black Sea brine, widely used in Bulgarian balneological and rehabilitation practice, has been associated with improved circulation, pain reduction, and neuromuscular support. The reviewed evidence suggests biologically plausible complementary mechanisms; however, no direct clinical studies evaluating the combined intervention were identified. Limitations: Current evidence is indirect and derived from separate investigations of galantamine, iontophoresis, and brine-based therapy, as well as heterogeneous historical and regional sources. Therefore, the proposed combination should be considered hypothesis-generating rather than evidence-established. Conclusions: The combination of galantamine, iontophoresis, and Black Sea brine represents a potentially interesting multimodal concept for peripheral neuropathy rehabilitation. Well-designed preclinical and clinical studies are required to determine safety, feasibility, optimal treatment parameters, and therapeutic efficacy. Full article

Alkaloids are structurally diverse, nitrogen-containing plant secondary metabolites with well-documented insecticidal activity. This review examines alkaloid-based insecticides, focusing on their chemical diversity, biosynthetic origins, plant distribution, and physicochemical properties relevant to pest control on farms. The principal molecular targets and modes of action are discussed, including interactions with nicotinic acetylcholine receptors, acetylcholinesterase, ryanodine receptors, and GABAergic signaling. Another focus is key metabolic enzymes, together with their activity spectra against major agricultural pests. Recent advances in rational structural modification, supported by crystallographic data, computational modeling, and structure–activity relationship studies, are highlighted as strategies to enhance the potency, selectivity, and stability of these compounds. Toxicological profiles, food residue behavior, analytical challenges, and regulatory considerations are critically assessed, emphasizing that natural origin does not equate to inherent safety. The review further evaluates the role of alkaloid-based insecticides within integrated pest management systems and identifies key research gaps related to environmental safety, non-target effects, and regulatory development and harmonization. It concludes that alkaloids are positioned as potentially valuable tools for sustainable agriculture when deployed within science-based regulatory frameworks and integrated control strategies. Full article

Hearing loss is detrimental to human health, and currently, more than 1.5 billion people are affected by hearing loss. Active military personnel and construction workers are examples of individuals in the workplace who are exposed to loud noise and are at serious risk of hearing loss. While there is currently no therapy for hearing loss, evidence supports investigating the enhancement of the Medial Olivocochlear (MOC) system, an efferent pathway for hearing that serves as a gain-control for hearing loss protection. Selectively modulating the α9α10 nicotinic acetylcholine receptor (nAChRs) found within this pathway is promising for the development of a new drug class. In this review article, we present the most current findings related to the therapeutic targeting of α9α10 nAChRs for hearing loss. We discuss the loss- or gain-of-function of the receptor, evaluate the known modulators of the receptor, examine their clinical relevance, and discuss their chemical and physical properties. Investigation of this novel pathway may aid in the development of a therapeutic for hearing loss. Full article

Kynurenic acid (KYNA), a metabolite of the L-kynurenine pathway of L-tryptophan degradation, is an endogenous blocker of glutamate ionotropic excitatory amino acid (EAA) receptors and nicotinic acetylcholine receptors (nAChRs). KYNA plays a significant role in various neuropsychiatric disorders and the aging process. Some researchers have suggested that KYNA may contribute to memory impairment. In this study, we examined the impact of L-kynurenine (a KYNA substrate) and the anti-dementia drugs D-cycloserine and Cerebrolysin on kynurenine aminotransferase (KAT) activity, an enzyme forming KYNA, in liver homogenates of Helix pomatia snails. Furthermore, a memory model was established using these snails, wherein tentacle shortening served as an indicator of learning activity. In vitro experiments on Helix pomatia demonstrated the significant impact of L-kynurenine and anti-dementia drugs on KYNA synthesis. KYNA levels increased significantly in the presence of L-kynurenine in liver homogenate. However, KYNA formation decreased when anti-dementia drugs, including Cerebrolysin or D-cycloserine, were administered to the snails’ liver homogenate. L-kynurenine has been shown to impair the learning process in vivo in snails, but an anti-dementia drug has been demonstrated to reverse this effect. Significant inhibition of tentacle lowering was observed in response to L-kynurenine treatment, which corresponded with elevated KYNA levels in the central nervous system. Administering D-cycloserine or Cerebrolysin alongside L-kynurenine reversed its effects. The Helix pomatia memory model is a valuable tool for studying learning and memory formation in various conditions and in the presence of different pharmacological agents. A drug or natural extract that blocks KYNA synthesis has the ability to increase tentacle lowering and could be considered an anti-dementia agent. Furthermore, this metabolite may also protect against aging and delay damage to the central nervous system related to memory. Full article

Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by persistent drug seeking and impaired behavioral control. Dopaminergic signaling has long been recognized as a central regulator of reinforcement learning, motivation, and habit formation. Addictive substances profoundly alter dopamine transmission through multiple mechanisms. These drug-induced changes contribute to the initiation, escalation, and persistence of addictive behaviors. In addition to dopamine, the cholinergic system has emerged as an important modulator of striatal circuit function. Acetylcholine and its receptors interact extensively with dopaminergic pathways, shaping striatal signaling dynamics and influencing learning and action selection, with particularly strong relevance for nicotine dependence. In this review, we discuss how striatal dopamine and acetylcholine contribute to learning, habit formation, and addiction-related behaviors, as well as how these systems interact at the circuit level. By integrating these findings, we propose a framework for understanding how dopamine–acetylcholine interactions may influence behavioral regulation relevant to substance use disorders. Full article

The clinical renaissance of psychedelic medicine has highlighted the therapeutic potential of rapid-acting neuroplastogens, or “psychoplastogens,” for psychiatric disorders. However, the widespread application of classical psychedelics—such as psilocybin and LSD—and the atypical dissociative ibogaine is severely limited by their hallucinogenic properties and, particularly in the case of ibogaine, life-threatening cardiotoxicity. Addressing these limitations, Tabernanthalog (TBG) has emerged as a frontrunner in the field. This non-hallucinogenic analog of ibogaine was rationally designed to eliminate interactions with the human ether-à-go-go-related gene (hERG, KCNH2) potassium channel, thereby mitigating cardiotoxic risks. While initially characterized for its anti-addictive and antidepressant-like properties, recent data from 2024–2025 have significantly expanded its therapeutic horizon. TBG demonstrates robust efficacy in preclinical models of neuropathic and visceral pain, as well as in the rescue of cognitive deficits associated with cancer-related cognitive impairment (CRCI). TBG has shown efficacy in reversing cognitive impairments induced directly by the presence of a tumor in preclinical models, rather than by chemotherapy-specific neurotoxicity. Crucially, emerging evidence suggests that TBG’s mechanism extends beyond simple 5-HT2A receptor agonism. New findings point to a multi-target profile involving the inhibition of nicotinic acetylcholine receptors (nAChRs), positive modulation of NMDA receptors, and functional crosstalk with mGlu2 receptors. Furthermore, TBG appears to induce structural neuroplasticity without the widespread induction of immediate early genes (IEGs) seen with classical hallucinogens, suggesting a decoupling of therapeutic rewiring from the subjective psychedelic experience. This review synthesizes current preclinical evidence to discuss TBG as a promising chemical scaffold for next-generation neurotherapeutics targeting the intersection of psychiatry and neurology. Full article

In 2024 and 2025, field populations of Aphis gossypii were collected from eight regions in Xinjiang to monitor their resistance levels to five commonly used insecticides: sulfoxaflor, acetamiprid, imidacloprid, abamectin, and chlorpyrifos. The mutation frequencies of five sites in the acetylcholinesterase (AChE) gene (S431F, V332A, A302S, G221A, F139L) and three sites in the β1 subunit of the nicotinic acetylcholine receptor (nAChR) (R81T, V62I, K264E) were also analyzed. The results showed that from 2024 to 2025, the eight A. gossypii field populations exhibited the highest resistance to imidacloprid (primarily moderate to high resistance), followed by acetamiprid (all moderate resistance). Resistance to abamectin and sulfoxaflor was relatively low, but sulfoxaflor resistance increased rapidly (from low resistance in 2024 to moderate resistance in 2025). All populations remained consistently susceptible to chlorpyrifos. Gene analysis revealed that the mutation rate of S431F in the AChE gene was nearly 100%, while that of V332A remained stable at approximately 30%. The mutation rates of A302S and G221A showed a slight increase, whereas the F139L mutation rate was extremely low (<1.00%). In the β1 subunit of nAChR, the mutation rates of R81T and V62I remained stable at around 50%, and the K264E mutation rate was extremely low (<1.00%). This study clarifies the resistance evolution patterns of A. gossypii to different insecticides and the variation characteristics of key resistance genes in Xinjiang, providing a scientific basis for the integrated resistance management of A. gossypii and the rational selection of effective insecticides. Full article

Background: Three-finger toxins (3FTxs) are a major axis of functional diversification in advanced snake venoms, with canonical paralytic activity mediated through muscle-type nicotinic acetylcholine receptors (nAChRs) and a broader set of non-nicotinic targets. This review integrates evidence bearing on coevolution between 3FTxs and target receptors, spanning toxin origin, diversification, receptor evolution, and ecological context. Methods: The synthesis draws on comparative genomic and transcriptomic studies of 3FTx gene-family evolution, codon-model analyses of selection, structural characterisation of toxin–receptor interfaces, and functional assays (including receptor-mimicking peptide binding) that link sequence variation to binding and toxicity. Results: Across lineages, 3FTx diversification is repeatedly structured by strong constraint on the disulphide-rich scaffold with accelerated change concentrated in solvent-exposed loops, alongside birth–death dynamics and exon/segment-level innovation that expand binding specificity. On the receptor side, resistance-associated variation is most intensively characterised for the nAChR α₁ orthosteric site and includes convergent, mechanistically distinct solutions such as electrostatic repulsion and glycosylation-mediated steric interference. Within the predominantly elapid systems currently examined, integrative datasets indicate that prey-selective binding and geographically variable susceptibility can arise from modest substitutions at toxin–receptor interfaces, but they also reveal substantial taxonomic and target-specific biases. Conclusions: Current evidence supports adaptive diversification in both toxins and receptors, while broader evolutionary interpretations are limited by uneven sampling and the frequent lack of matched toxin and receptor variants analysed within a common evolutionary framework. Development of predictive models will require joint pipelines linking genomics, structure-informed evolutionary inference, scalable functional assays, and explicit ecological network context. Full article

Face wrinkles caused by skin aging can be classified into dynamic wrinkles, which are caused by repetitive contraction of facial expression muscles, and static wrinkles, which are related to extracellular matrix damage and collagen breakdown caused by ultraviolet and oxidative stress. These two mechanisms are closely related, and prolonged, repetitive muscle contractions act as mechanical stress that promotes extracellular matrix degradation within the dermis, accelerating wrinkle formation. In this study, we used phage display to develop a novel peptide, Medipep-6PN, that targets both muscle-type nicotinic acetylcholine receptor (muscle nAChR), a major cause of dynamic wrinkles, and matrix metalloproteinase-1 (MMP-1), a cause of static wrinkles. In this study, the kinetic analysis of Medipep-6PN using surface plasmon resonance analysis showed that the equilibrium dissociation constant (K_D) for muscle nAChR α1 was 9.56 × 10⁻⁶ M, and the K_D for MMP-1 was 1.25 × 10⁻⁶ M. Calcium imaging analysis in TE671 cells expressing the muscle nAChR pentamer determined that Medipep-6PN inhibited muscle nAChR channel activity in a concentration-dependent manner, and in particular, it was confirmed that about 80% of muscle nAChR channel activity was inhibited under 30 μM of Medipep-6PN. In addition, in an in vitro test performed to evaluate MMP-1 activity, Medipep-6PN inhibited MMP-1 activity in a concentration-dependent manner, and the IC₅₀ was 4.2 ppm. When measuring MMP-1 gene expression in UVB-induced human fibroblasts, 1 ppm of Medipep-6PN showed a 52.3% decrease compared to UVB irradiation alone. When measuring type I procollagen synthesis in human fibroblasts, Medipep-6PN increased procollagen Iα1 production in a concentration-dependent manner, and concentrations between 5 and 10 ppm of Medipep-6PN significantly increased collagen I production. No significant toxicity was observed in cytotoxicity tests, demonstrating its safety. Furthermore, in a clinical study evaluating wrinkle improvement efficacy in 25 adults over a four-week period, the Medipep-6PN group demonstrated statistically significant reductions in wrinkle depth (by 10.16%) and wrinkle volume (by 13.00%), demonstrating efficacy comparable to that of commercially available functional anti-wrinkle ingredients. In conclusion, this study demonstrates that Medipep-6PN, developed to target two mechanisms—the relaxation of muscle contraction and the inhibition of collagen degradation—is a functional peptide effective in improving skin wrinkles, confirmed through in vitro evaluation and clinical studies. Full article

Nicotinic acetylcholine receptors (nAChRs) are membrane-bound proteins that mediate fast synaptic transmission throughout the nervous system. A functional nAChR subtype is formed by the combination of multiple subunits arranged as homomeric or heteromeric pentamers, each with a distinct pharmacological profile. Disruption of their neurotransmission contributes to various neuropathologies, emphasizing the need for detailed knowledge of receptor structure, function, subunit composition, dynamics, and potential ligand-binding sites. However, their structural complexity as integral membrane proteins has hindered expression in mammalian cell lines and proven even more challenging to crystallize, limiting insights into ligand interactions. Understanding the molecular determinants governing nAChRs function is essential for the rational design of selective therapeutics targeting neurological disorders. The emergence of a chimeric receptor approach has dramatically improved the ability to study these important proteins and opened new avenues for high-throughput screening in drug discovery efforts. This review explains how the design of chimera constructs using soluble homologs, such as AChBP, provides researchers with an immense opportunity to investigate receptor structure–function relationships and subtype-specific properties, thereby facilitating the development of more effective treatments. Full article

Nicotine is the main substance responsible for the development of tobacco addiction. The α3β4 nicotinic acetylcholine receptors (nAChRs) are a potential key target for mitigating nicotine reward. Preliminary studies in our laboratory suggest that α-conotoxin [S9K]TxID serves as a selective and potent antagonist targeting α3β4 nAChRs, which may be beneficial in addressing nicotine addiction. However, the mechanisms of [S9K]TxID treatment in nicotine addiction are still to be determined. This study aimed to identify the differential metabolic profiles of [S9K]TxID treatment in nicotine addiction using an untargeted metabolomic profiling method. As demonstrated by behavioral experiments, [S9K]TxID effectively attenuated nicotine-induced conditioned place preference (CPP) expression without exerting inhibitory effects on the central nervous system (CNS). The results of untargeted metabolomics revealed that eight metabolites were significantly altered after [S9K]TxID treatment, particularly phenylalanine. [S9K]TxID also attenuated nicotine-induced metabolic disorders by regulating phenylalanine, tyrosine and tryptophan biosynthesis. In conclusion, our findings suggest that [S9K]TxID could be a potential therapeutic compound for nicotine addiction. Full article

Plasticity is fundamental to the development, strengthening, and maintenance of healthy synaptic connections and recovery from injury in both the central and peripheral nervous systems. Yet, the processes involved are poorly understood. Herein, using a combination of patch-clamp electrophysiology and immuno-fluorescence confocal microscopy in adult mice, it is shown that blockade of synaptic transmission at submandibular ganglion junctions exposed to botulinum neurotoxin type A was accompanied by a rapid and striking decline in the abundance of synaptic vesicle markers—SV2, vesicle-associated membrane protein 2, and vesicular acetylcholine transporter—plus SNAP-25 (cleaved and intact) and postsynaptic α7 nicotinic acetylcholine receptors. Such alterations by the neurotoxin of parasympathetic synapses contrast starkly with the stability of postsynaptic proteins at nearby skeletal neuromuscular junctions. Both neurotransmission and the expression of SV2 and α7 nicotinic acetylcholine receptors remained depressed for 4 weeks, with full recovery of synaptic function delayed for more than 8 weeks. These novel findings may explain the relatively slow recovery of autonomic function after botulism or following therapeutic injections to alleviate hypersecretory disorders. Full article