Search Results (104)

Background and objectives: Duloxetine is widely used for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and various types of neuropathic pain. While its efficacy is well documented in clinical trials, less is known about how it is perceived and utilized in routine psychiatric practice. To address this knowledge gap, we conducted a cross-sectional observational study involving 80 psychiatrists from Spain to assess real-world clinical attitudes toward duloxetine. Methods: Participants completed a 20-item multiple-choice questionnaire that examined familiarity, perceived efficacy in multiple conditions (MDD, GAD, neuropathic pain, somatization, and quality of life), and perspectives on tolerability, safety, adherence, and overall satisfaction. Results: Survey results indicated that a large majority of psychiatrists frequently prescribe duloxetine, particularly for patients with MDD and comorbid chronic pain. Notably, 94% rated it as either “more effective” or “much more effective” for diabetic peripheral neuropathic pain. Psychiatrists reported a high perceived efficacy of duloxetine: 94% rated it as “more effective” or “much more effective” for diabetic peripheral neuropathy, and 93% gave similarly positive ratings for general neuropathic pain. For somatization, 70% found it “effective” or “very effective”, and 83% observed improvements in quality of life for many of their patients. Psychiatrists generally reported favorable perceptions of duloxetine’s tolerability profile: 97.5% rated it as the antidepressant associated with the least weight gain, and 82.5% perceived fewer sexual side effects compared to other options. Sedation and gastrointestinal side effects were generally considered mild or less severe. In terms of treatment adherence, 69% rated it as “better” or “much better” than other antidepressants, and 80% found its combination with other antidepressants to be “favorable” or “very favorable”. Overall satisfaction was high, with 99% of psychiatrists reporting being either “satisfied” or “very satisfied” with its use. The side effect profile was generally viewed as manageable, with low perceived rates of weight gain, sedation, and sexual dysfunction. Furthermore, 96% of respondents expressed a willingness to recommend duloxetine to their colleagues. Conclusions: Psychiatrists reported highly favorable attitudes toward duloxetine, viewing it as a flexible treatment option in routine care. However, these findings reflect clinicians’ subjective perceptions rather than objective clinical outcomes and should be interpreted accordingly. Full article

Diabetic neuropathy (DN) remains a major clinical burden, characterized by progressive sensory dysfunction, pain, and impaired quality of life. Despite the available symptomatic treatments, there is a pressing need for disease-modifying therapies. In recent years, preclinical research has highlighted the potential of repurposed pharmacological agents, originally developed for other indications, to target key mechanisms of DN. This narrative review examines the main pathophysiological pathways involved in DN, including metabolic imbalance, oxidative stress, neuroinflammation, ion channel dysfunction, and mitochondrial impairment. A wide array of repurposed drugs—including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)—have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN. Full article

Neuropathic pain is a persistent and exhausting condition which results from damage to the nervous system and is often accompanied by emotional and cognitive impairments. In this study, we investigated dynamic changes in pain-related behaviors over 8 weeks using a spared nerve injury (SNI) model in male C57Bl/6 mice. We examined behavioral outcomes in conjunction with glial activation, neurogenesis, and glutamatergic signaling in the hippocampus to elucidate the mechanisms underlying cognitive and affective alterations associated with chronic pain. Our findings demonstrate that SNI-induced neuropathic pain progressively increases anxiety-like behavior and impairs both working and long-term memory. These behavioral deficits are accompanied by significant activation of microglia and astrocytes, a reduction in hippocampal neurogenesis, and a decrease in the expression of NMDA and AMPA glutamate receptor subunits and the scaffolding protein PSD-95. Taken together, our results suggest that hippocampal neuroinflammation and associated synaptic dysfunction contribute to the affective and cognitive disturbances observed in chronic pain, providing insight into potential molecular targets for therapeutic intervention. Full article

Background/Objectives: Dry eye disease (DED) is a multifactorial condition with complex pathophysiology involving tear film instability, ocular surface inflammation, and nerve dysfunction. This review summarizes current evidence on the different available therapies targeting these mechanisms. Methods: A review of clinical studies evaluating treatment outcomes for therapies targeting aqueous tear deficiency, Meibomian gland dysfunction, ocular surface inflammation, and ocular pain was conducted, with an emphasis on randomized controlled trials and meta-analyses where available. Results: Artificial tears provide symptomatic relief with limited impact on tear film stability. Punctal plugs improve tear retention but show variable efficacy across studies. Treatments targeting MGD—such as lipid-based lubricants, eyelid hygiene, thermal pulsation (LipiFlow, iLux), and intense pulsed light (IPL)—demonstrate improvements in gland function, though outcomes vary. Anti-inflammatory agents including cyclosporine, lifitegrast, and short-term corticosteroids improve ocular surface signs, with mixed symptom relief. Biologic therapies like autologous serum tears and platelet-rich plasma show promise for both signs and symptoms, but data remain inconsistent. Nerve-targeted therapies, including oral neuromodulators (gabapentin, antidepressants), botulinum toxin, and transcutaneous nerve stimulation, have shown potential for managing neuropathic ocular pain, although randomized data are limited. Overall, variability in study designs, patient populations, and outcome measures highlights the need for more rigorous research. Conclusions: Personalized, mechanism-based treatment strategies are essential for optimizing outcomes in DED. Future research should prioritize well-designed, controlled studies to clarify the role of emerging therapies and guide the individualized management of this heterogeneous condition. Full article

During periods of exercise, the primary cause of metabolic acidosis is the accumulation of lactate from anaerobic metabolism, whereas a transient increase in CO₂ triggers a mild respiratory acidosis through the production of carbonic acid (H₂CO₃). The combined effects of these reactions result in a slight acidifying shift in arterial blood pH. Proton-sensing G protein-coupled receptors (including GPR68, GPR4, GPR132, and GPR65) represent the primary receptors within the body for detecting alterations in extracellular proton concentrations. These receptors have been demonstrated to possess potential roles in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Recent studies have shown that the activation or inhibition of these receptors modulates a number of arterial functions, including angiogenesis, arterial relaxation, and arterial inflammation. It is well established that moderate exercise has a beneficial effect on the regulation of arterial function. This study examines the effect of exercise on proton concentrations in the microenvironment of the organism and its influence on proton-sensing G protein-coupled receptors located on cell membranes, as well as possible mechanisms involved in the regulation of arterial function. The objective is to present novel perspectives for the exploration of potential drug targets for the prevention and treatment of arterial dysfunction and the development of exercise regimens. Full article

Background: Primary ciliary dyskinesia (PCD) is a rare hereditary disorder caused by defective motile cilia, predominantly affecting the respiratory system. Conductive hearing loss (CHL) due to chronic otitis media with effusion (OME) is a typical feature of PCD, particularly in childhood. However, the underlying mechanisms contributing to sensorineural hearing loss (SNHL) in patients with PCD remain unclear. Methods: We present the case of a 52-year-old male with a clinical diagnosis of PCD, confirmed by the presence of situs inversus, chronic respiratory symptoms, and ultrastructural ciliary defects. Results: Despite a history of recurrent acute otitis media (AOM), the patient developed severe bilateral SNHL, a relatively uncommon and poorly understood manifestation of PCD. Genetic testing revealed a pathogenic SH3TC2 variant, a gene classically associated with Charcot–Marie–Tooth disease type 4C (CMT4C), raising the possibility of an alternative or contributory genetic etiology for the patient’s auditory dysfunction. Conclusions: This case highlights the importance of comprehensive audiological and genetic evaluations in PCD patients, particularly those presenting with progressive or atypical HL. The presence of a pathogenic SH3TC2 mutation suggests a potential neuropathic component to the patient’s HL, underscoring the need for further research into the intersection between ciliary dysfunction and genetic neuropathies. Early identification and intervention are critical to optimizing auditory outcomes and quality of life in affected individuals. Full article

TNF-α is a pro-inflammatory cytokine that plays a pivotal role in the regulation of immune responses. It is predominantly produced by activated macrophages, although other cell types, such as T lymphocytes and NK cells, also contribute to its secretion. TNF-α participates in various physiological processes, including cell proliferation and differentiation. Moreover, TNF-α has been implicated in the pathogenesis of numerous inflammatory and autoimmune disorders. Recent studies have highlighted the important role of TNF-α in neuropathic pain, a complex and frequently disabling condition caused by nerve injury or dysfunction. Increased TNF-α levels in the nervous system have been associated with the onset of neuropathic pain, contributing to neuronal sensitization and alterations in pain signaling pathways. This study supports the idea that TNF-α connects the immune system with the nervous system, thereby supporting our understanding of the neuroimmune interface of pain and bringing a potential treatment against neuropathic pain: targeting TNF-α. Anti-TNF-α antibody administration reduces pain behaviors and neuroinflammation in preclinical animal models. Simultaneously, clinical trials are evaluating the safety and efficacy of anti-TNF-α treatments, with preliminary results indicating promising outcomes in patients experiencing neuropathic pain. Here, targeting TNF-α goes beyond its conventional spectrum of inflammatory pathologies and initiates a new mechanism-based approach to defining neuropathic pain, thereby improving the quality of life of the individuals affected and bringing together an area of colossal unmet clinical need. Full article

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the small intestine upon food intake. GLP-1 enhances insulin secretion, suppresses glucagon release, and promotes satiety, resulting in reduced food consumption and subsequent weight loss. Endogenous GLP-1 has a very short half-life and is rapidly degraded by the enzyme dipeptidyl-peptidase-IV (DPP-4). To address this limitation, GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors (DPP-4is) were developed and have demonstrated potency in clinical practice. In recent years, GLP-1RA and DPP4-i therapies are known to have pleiotropic effects, such as a reduction in oxidative stress, autophagy regulation, metabolic reprogramming, enhancement of anti-inflammatory signaling, regulation of gene expression, and being neuroprotective. These effects imply a therapeutic perspective for GLP-1RA and DPP-4i therapies in neuropathic pain treatment. Preclinical and clinical studies increasingly support the hypothesis that these therapies may alleviate neuropathic pain by targeting multiple mechanisms that induce neuropathic pain, such as inflammation, oxidative stress, and mitochondrial dysfunction. This review explores the mechanisms by which GLP-1RAs and DPP-4is alleviate neuropathic pain. It also highlights current advancements in incretin research, focusing on the therapeutic effects of GLP-1RAs and DPP-4-is for neuropathic pain. Full article

Neuropathic pain is a chronic condition resulting from injury or dysfunction in the somatosensory nervous system, which leads to persistent pain and a significant impairment of quality of life. Research has highlighted the complex molecular mechanisms that underlie neuropathic pain and has begun to delineate the roles of microRNAs (miRNAs) in modulating pain pathways. miRNAs, which are small non-coding RNAs that regulate gene expression post-transcriptionally, have been shown to influence key cellular processes, including neuroinflammation, neuronal excitability, and synaptic plasticity. These processes contribute to the persistence of neuropathic pain, and miRNAs have emerged as critical regulators of pain behaviors by modulating signaling pathways that control pain sensitivity. miRNAs can influence neuropathic pain by targeting genes that encode protein kinases involved in pain signaling. This review focuses on miRNAs that have been demonstrated to modulate neuropathic pain behavior through their effects on protein kinases or their immediate upstream regulators. The relationship between miRNAs and neuropathic pain behaviors is characterized as either an upregulation or a downregulation of miRNA levels that leads to a reduction in neuropathic pain. In the case of miRNA upregulation resulting in an alleviation of neuropathic pain behaviors, protein kinases exhibit a positive correlation with neuropathic pain, whereas decreased protein kinase levels correlate with diminished neuropathic pain behaviors. The only exception is GRK2, which shows an inverse correlation with neuropathic pain. In the case of miRNA downregulation resulting in a reduction in neuropathic pain behaviors, protein kinases display mixed relationships to neuropathic pain, with some kinases exhibiting positive correlation, while others exhibit negative correlation. By exploring how protein kinases mediate miRNA modulation of neuropathic pain, valuable insight may be gained into the pathophysiology of neuropathic pain, offering potential therapeutic targets for developing more effective strategies for pain management. Full article

This study investigates the role of p38 mitogen-activated protein kinase (MAPK) activation in dorsal root ganglion (DRG) neurons in the development and progression of chemotherapy-induced peripheral neuropathy (CIPN). This research evaluates whether inhibiting activation of p38 MAPK could reduce neuropathic outcomes in a transgenic breast cancer mouse model (C3TAg) and wild-type mice (FVB/N) treated with cisplatin. Cisplatin treatment stimulated p38 MAPK phosphorylation and nuclear translocation in DRG neurons. Neflamapimod, a specific inhibitor of p38 MAPK alpha (p38α), proven to be safe in clinical trials, inhibited neuronal cisplatin-induced p38 MAPK phosphorylation in vitro and in vivo. Neflamapimod also reduced cisplatin-induced oxidative stress, mitochondrial dysfunction, and cleaved caspase-3 expression in DRG neurons in vitro, protecting neuronal integrity and preventing axonal damage. Functionally, neflamapimod improved mechanical and musculoskeletal hyperalgesia, and cold sensitivity in cisplatin-treated mice, reversing neuropathic pain and neurotoxicity. This study identifies p38 MAPK activation as a critical driver of CIPN and highlights its potential as a therapeutic target for CIPN. Targeting p38 MAPK activation with neflamapimod offers a promising strategy to mitigate neurotoxicity and hyperalgesia without exacerbating cancer progression, positioning it as a novel intervention for CIPN. Full article

Diabetes mellitus is characterized by a state of hyperglycemia, which can lead to severe complications if left untreated or poorly managed. Diabetic peripheral neuropathy (DPN) is one common complication. This condition is characterized by damage to the nerves that supply the legs and feet as well as problems with blood vessels, the heart, or urinary tract. To alleviate pain for patients, clinicians resort to long-term treatment regimens of nerve pain medications, which are usually either anticonvulsants or antidepressants. However, little is understood about the underlying mechanisms of DPN. Many pathogenic pathways have been proposed, one of which is mitochondrial dysfunction. Mitochondrial dysfunction includes a range of possible deficiencies given the number of functions controlled by or located in mitochondria, including their core function of bioenergetics. This review focuses on mitochondrial bioenergetics, including respiration/ATP synthesis and reactive oxygen species (ROS) production, as well as calcium homeostasis and apoptosis, and their potential as targets for the effective treatment of diabetic peripheral neuropathy. Full article

Neuropathic pain (NP) is a type of chronic pain resulting from injury or dysfunction of the nerves or spinal cord. Previous studies have shown that the combination of ligustrazine (LGZ) and sinomenine (SIN) exerts a synergistic antinociceptive effect in peripheral and central NP models. On this basis, a comprehensive analgesic evaluation was performed in a chronic constriction injury (CCI)-induced NP model in rats. Sciatic nerve histopathological changes were observed, and 22 cytokines and chemokines levels were analyzed. We also combined network pharmacology and metabolomics to explore their molecular mechanisms. Results showed that the combination of LGZ and SIN significantly alleviated the pain-like behaviors in CCI rats in a time- and dose-dependent manner, demonstrating superior therapeutic effects compared to LGZ or SIN alone. It also improved pathological damage to sciatic nerves and regulated inflammatory cytokine levels. Network pharmacology identified shared and distinct pain-related targets for LGZ and SIN, while metabolomics revealed 54 differential metabolites in plasma, and 17 differential metabolites in CSF were associated with the combined intervention of LGZ and SIN. Finally, through an integrated analysis of the core targets and differential metabolites, tyrosine metabolism, phenylalanine metabolism, and arginine and proline metabolism were identified as potential key metabolic pathways underlying the therapeutic effects of LGZ and SIN in CCI treatment. In conclusion, our study provides evidence to support the clinical application of LGZ and SIN in the treatment of NP. Full article

Diabetic peripheral neuropathy (DPN) is a prevalent and disabling complication of diabetes, with painful diabetic peripheral neuropathy (PDPN) being its most severe subtype due to chronic pain and resistance to treatment. Satellite glial cells (SGCs), critical for maintaining dorsal root ganglion (DRG) homeostasis, undergo significant structural and functional changes under pathological conditions. This study investigated the role of galactosylceramide (GalCer), a key sphingolipid, in SGC dysfunction and neuron–glia interactions during DPN progression. Using a rat model of PDPN, we employed single-cell RNA sequencing (scRNA-seq), targeted mass spectrometry, and immunofluorescence analysis. The PDPN group exhibited transcriptional activation and structural reorganization of SGCs, characterized by increased SGC abundance and glial activation, evidenced by elevated Gfap expression. Functional enrichment analyses revealed disruptions in sphingolipid metabolism, including marked reductions in GalCer levels. Subclustering identified vulnerable SGC subsets, such as Cluster a, with dysregulated lipid metabolism. The depletion of GalCer impaired SGC-neuron communication, destabilizing DRG homeostasis and amplifying neurodegeneration and neuropathic pain. These findings demonstrate that GalCer depletion is a central mediator of SGC dysfunction in PDPN, disrupting neuron–glia interactions and exacerbating neuropathic pain. This study provides novel insights into the molecular mechanisms of DPN progression and identifies GalCer metabolism as a potential therapeutic target. Full article

Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus, characterized by progressive nerve damage driven by chronic hyperglycemia and systemic inflammation. The pathophysiology of DPN is significantly influenced by pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These cytokines promote oxidative stress, vascular dysfunction, and neuronal degeneration by activating important signaling pathways including NF-κB and MAPK. While IL-6 promotes a pro-inflammatory microenvironment, increasing neuronal damage and neuropathic pain, TNF-α and IL-1β worsen Schwann cell failure by compromising axonal support and causing demyelination. Immune cell infiltration and TLR activation increase the inflammatory cascade in DPN, resulting in a persistent neuroinflammatory state that sustains peripheral nerve injury. The main characteristics of DPN are axonal degeneration, decreased neurotrophic support, and Schwann cell dysfunction, which weaken nerve transmission and increase susceptibility to damage. Advanced glycation end-products, TNF-α, and CXCL10 are examples of biomarkers that may be used for early diagnosis and disease progression monitoring. Additionally, crucial molecular targets have been found using proteomic and transcriptome techniques, enabling precision medicine for the treatment of DPN. This review emphasizes the importance of cytokine signaling in the pathogenesis of DPN and how cytokine-targeted treatments might reduce inflammation, restore nerve function, and improve clinical outcomes for diabetic patients. Full article

Neuropathic pain, a debilitating condition arising from somatosensory system damage, significantly impacts quality of life, leading to anxiety, self-mutilation, and depression. Oxidative and nitrosative stress, an imbalance between reactive oxygen and nitrogen species (ROS/RNS) and antioxidant defenses, plays a crucial role in its pathophysiology. While reactive species are essential for physiological functions, excessive levels can cause cellular component damage, leading to neuronal dysfunction and pain. This review highlights the complex interactions between reactive species, antioxidant systems, cell signaling, and neuropathic pain. We discuss the physiological roles of ROS/RNS and the detrimental effects of oxidative and nitrosative stress. Furthermore, we explore the potential of manganese porphyrins, compounds with antioxidant properties, as promising therapeutic agents to mitigate oxidative stress and alleviate neuropathic pain by targeting key cellular pathways involved in pain. Further research is needed to fully understand their therapeutic potential in managing neuropathic pain in human and non-human animals. Full article