Neuropharmacology[JOURNAL]
Sun
200 papers
Purinergic signaling and cancer neuroscience.
Hu JQ, Zhou XD, Ren QL … +1 more , Han Y
Neuropharmacology · 2026 May · PMID 42214458 · Publisher ↗
The emerging field of cancer neuroscience has revealed that the nervous system plays an important role in tumor initiation, progression, metastasis, and therapeutic resistance. Purinergic signaling has been recognized as...
The emerging field of cancer neuroscience has revealed that the nervous system plays an important role in tumor initiation, progression, metastasis, and therapeutic resistance. Purinergic signaling has been recognized as a critical regulatory system in neuroscience and cancer, respectively. This review collected current understandings of purinergic signaling in cancer and neuroscience and pointed out that why purinergic signaling could work in cancer neuroscience and how to work in cancer neuroscience. It also proposed that purinergic signaling represents a critical target in cancer neuroscience, offering both mechanistic insights and translational opportunities for the development of next-generation cancer therapeutics, especially P2X7R, CD39/CD73, AR, P2X3R will offer unprecedented opportunities to intervene at the neural-tumor interface for the treatment of cancer in the future.
Hypericin alleviates high glucose-induced ferroptosis in cultured rat satellite glial cells via targeting P2X7R to activate the Akt/GSK3β/Nrf2 axis.
Hu Q, Zhou C, Guo H … +6 more , Zhang Y, Zhou Z, Zhao X, Chen X, Liang S, Li G
Neuropharmacology · 2026 May · PMID 42214457 · Publisher ↗
Hyperglycemia is a major risk factor for diabetic cardiovascular autonomic neuropathy (DCAN), but the underlying cellular mechanisms remain incompletely understood. To address this gap, this in vitro study aimed to deter...
Hyperglycemia is a major risk factor for diabetic cardiovascular autonomic neuropathy (DCAN), but the underlying cellular mechanisms remain incompletely understood. To address this gap, this in vitro study aimed to determine whether high glucose induces ferroptosis in primary satellite glial cells (SGCs) isolated from rat stellate ganglia (SG) and to evaluate the protective mechanism of hypericin. Our results showed that high glucose markedly upregulates P2X7 receptor (P2X7R) expression in SGCs, leading to reduced cell viability and characteristic ferroptotic events, including increased levels of reactive oxygen species (ROS), abnormal iron accumulation, enhanced lipid peroxidation, and a marked decline in both glutathione (GSH) content and the activity of glutathione peroxidase 4 (GPX4). Hypericin at 0.1 μmol/L exhibited strong protective effects against high glucose-induced injury. Mechanistically, hypericin directly binds to the K110 site of P2X7R, inhibiting its function and subsequently activating the Akt/GSK3β pathway. This activation stabilizes Nrf2 by suppressing its ubiquitin-mediated degradation, promotes Nrf2 nuclear translocation, and upregulates the GPX4/SLC7A11 antioxidant axis. Genetic knockdown of P2X7R or Nrf2 confirmed their essential roles in this pathway. These findings reveal a previously unrecognized mechanism by which hypericin alleviates SGCs ferroptosis under high glucose conditions through the P2X7R/Akt/GSK3β/Nrf2 axis, highlighting its potential relevance to DCAN.
Study on the effect and mechanism of sesamin on P2X3-related cheek allergic contact dermatitis in mice induced by SADBE stimulation.
Ma X, Zhang Y, Yang Y … +3 more , Sun Y, Liang S, Li G
Neuropharmacology · 2026 Oct · PMID 42214456 · Publisher ↗
Allergic contact dermatitis (ACD) is a common inflammatory skin condition characterized by cutaneous inflammation and pruritus. Purinergic 2X receptor 3 (P2X3) and transient receptor potential ankyrin 1 (TRPA1) are impli...
Allergic contact dermatitis (ACD) is a common inflammatory skin condition characterized by cutaneous inflammation and pruritus. Purinergic 2X receptor 3 (P2X3) and transient receptor potential ankyrin 1 (TRPA1) are implicated in acute and chronic pruritus, but their interactions remain unclear. Sesamin has anti-inflammatory, antioxidant, and antitumor properties; however, its effectiveness in alleviating ACD and the underlying mechanism remain unknown. In this study, male C57BL/6 mice (20-25 g body weight) were used. Results showed that squaric acid dibutylester (SADBE) increased scratching behavior and upregulated P2X3, TRPA1, IL-1β, and TNF-α expression in the right trigeminal ganglion (TG). Intraperitoneal administration of sesamin attenuated these effects, reducing pruritic behavior and inflammation-related gene expression. Compared to the control group, the ACD model group showed significantly increased co-expression of Mas-related G protein-coupled receptor member A3 (MrgprA3) and P2X3. Transfection experiments in HEK293 cells demonstrated that P2X3 regulated TRPA1 channel activation by modulating intracellular calcium levels. These findings suggest that sesamin alleviates pruritus in ACD mice, likely through downregulation of P2X3 and suppression of P2X3-mediated intracellular calcium elevation. Furthermore, sesamin inhibited TRPA1 expression and reduced calcium levels in cells co-transfected with the TRPA1 plasmid. Thus, sesamin may attenuate activation and expression of the inflammatory receptor TRPA1 by inhibiting P2X3, highlighting its potential as an antipruritic agent for SADBE-induced ACD.
Cerebrospinal fluid-contacting nucleus mediates the balance of depth during general anesthesia in mice.
Zhang YW, Jia WX, Wang YQ … +6 more , Zhou P, Zhang XY, Liu CW, Wang J, Lu XF, Dai CF
Neuropharmacology · 2026 May · PMID 42214455 · Publisher ↗
AIMS: Research on the mechanisms of underlying general anesthesia has traditionally focused on specific neural circuits. In this study, we investigated the role of the cerebrospinal fluid-contacting nucleus (CSF-CN), whi...
AIMS: Research on the mechanisms of underlying general anesthesia has traditionally focused on specific neural circuits. In this study, we investigated the role of the cerebrospinal fluid-contacting nucleus (CSF-CN), which directly interfaces with the CSF, in modulating general anesthesia in mice. METHODS: CSF-CN was labeled by administering the retrograde tracer cholera toxin subunit B-594 into the lateral ventricle, and it was selectively ablated using a conjugate of saporin and cholera toxin subunit B. Anesthesia was induced in mice via propofol injection through the tail vein or isoflurane inhalation. RESULTS: During deep anesthesia with propofol or isoflurane, mice in the CSF-CN lesion group exhibited a significantly higher burst suppression ratio compared to controls, indicating a greater depth of anesthesia. In contrast, during the emergence phase, lesion mice showed a significantly shorter latency to the recovery of the righting, reflecting premature emergence, and exhibited more severe postoperative agitation. The levels of tumor necrosis factor-α and interleukin-10 in the CSF were elevated in deep anesthesia. Behavioral assessments further revealed that mice with CSF-CN lesions displayed anxiety-like behavior after deep anesthesia. CONCLUSION: These findings indicate that the CSF-CN plays a critical homeostatic role in general anesthesia. During deep anesthesia, it may buffer excessive anesthetic inhibition, whereas during emergence, it regulates the recovery process to prevent premature or overly rapid awakening.
Rosiglitazone alleviates Parkinson's disease phenotypes of Drosophila via dCTP-mediated inhibition of AGE-RAGE pathway.
Kang Y, Yang Y, Wang Z … +8 more , Chang Y, Wang N, Yang J, Lim K, Yu F, Wang M, Lu L, Zhang C
Neuropharmacology · 2026 Oct · PMID 42214454 · Publisher ↗
BACKGROUND: Parkinson's disease (PD) is an aging-related neurodegenerative disorder, which threatens the health and life of millions of patients worldwide, but remains incurable. Developing novel interventive strategy is...
BACKGROUND: Parkinson's disease (PD) is an aging-related neurodegenerative disorder, which threatens the health and life of millions of patients worldwide, but remains incurable. Developing novel interventive strategy is urgent yet unmet. In recent years, it was well accepted that pathogenesis of PD closely correlated with aberrant glucolipid metabolism. The antidiabetic drug, Rosiglitazone (Rosi), one typical PPARγ agonist was found to exert neuroprotective effect. However, whether Rosi can rescue the PD-related phenotypes and the underlying mechanisms remain to be elucidated. METHODS: In present study, after Rosi administration, the PD phenotypes were characterized via immunofluorescent staining, climbing ability, lifespan assays, as well as transmission electron microscopy (TEM). Mechanisms were investigated by transcriptomics and MALDI-TOF-MSI analysis. The AGE-RAGE pathway was identified through KEGG screening and validated via qPCR and glyoxal cell experiments. Finally, the screened metabolite dCTP was replenished to PD drosophila to explore its therapeutic effects and mechanism. RESULTS: It showed that Rosi administration substantially ameliorated PD phenotypes, reduced LDs accumulation and restored mitochondrial quality control (MQC) in the PD drosophila brain. MALDI-TOF-MSI analysis demonstrated that Rosi administration elevated content of dCTP, which reduced in PD drosophila brain. Moreover, both Rosi and dCTP inhibited the over-activated AGE-RAGE/EGR1 pathway in PD context. CONCLUSIONS: In summary, present study for the first time revealed that Rosi and its downstream metabolite dCTP could serve as novel therapeutic option for PD by inhibiting AGE-RAGE/EGR1 pathway. It not only provided novel clues for treatment of PD but also highlighted the potential of drug repositioning.
Thyroid hormones are positive allosteric modulators of acid-sensing ion channels ASIC1a and ASIC3.
Qin L, Wiemuth D, Gründer S
Neuropharmacology · 2026 May · PMID 42208759 · Publisher ↗
Acid-sensing ion channels (ASICs) are excitatory ligand-gated ion channels directly gated by extracellular protons. Proton-sensitivity of ASICs is subject to modulation by different compounds, for example neuropeptides a...
Acid-sensing ion channels (ASICs) are excitatory ligand-gated ion channels directly gated by extracellular protons. Proton-sensitivity of ASICs is subject to modulation by different compounds, for example neuropeptides and lipids. In this study, we uncovered that the currents of the two most proton-sensitive ASICs, homomeric ASIC1a and ASIC3, are strongly potentiated by thyroid hormones, particularly triiodothyronine (T3). Potentiation by T3 had micromolar affinities and rapid on- and offset kinetics. Moreover, T3 did not affect gramicidin A-induced currents, suggesting that thyroid hormones had direct action on ASICs, indicating that they are a new class of allosteric ASIC modulators. Interestingly, for ASIC1a, T3 increased the efficacy of protons, whereas for ASIC3, it increased potency of protons. These results suggest that thyroid hormones could modulate ASIC activity in particular brain regions where their concentration is sufficiently high.
Cyclic neuronostatin regulates glucose homeostasis and food intake through GPR107 phosphorylation.
Yang S, Zhang Y, Li M … +4 more , Li Y, Guo Y, Li Y, Shao T
Neuropharmacology · 2026 May · PMID 42208758 · Publisher ↗
Glucose homeostasis is vital for energy metabolism, and its dysregulation is central to metabolic diseases. To enhance the stability of the endogenous peptide neuronostatin (NST), we designed a conformationally stabilize...
Glucose homeostasis is vital for energy metabolism, and its dysregulation is central to metabolic diseases. To enhance the stability of the endogenous peptide neuronostatin (NST), we designed a conformationally stabilized cyclic NST peptide via disulfide-bridge cyclization. This study demonstrates that cyclic NST serves as a potent agonist for the G protein-coupled receptor 107 (GPR107), and promotes protein kinase activation. Intraperitoneal administration of cyclic NST induced sustained hyperglycemia, which was more effectively than linear NST, it also suppressed insulin and modulating leptin levels in zebrafish and mice. It differentially regulated glycolytic enzymes in pancreas and liver, and stimulated pancreatic α-cells to promote hepatic glucose production. Centrally, cyclic NST reduced food intake by activating the arcuate nucleus and the ventromedial hypothalamus. Notably, it upregulates the expression of key neuropeptides and receptors involved in appetite regulation, including the orexigenic peptides agouti-related protein (AgRP) and neuropeptide Y (NPY), as well as the anorexigenic peptide somatostatin, and the receptors gastric inhibitory polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R). Mechanistically, cyclic NST enhanced mitochondrial energy metabolism in a manner associated with phosphorylation-dependent Golgi retention of GPR107, with Tyr315 identified as a critical site for maintaining mitochondrial protein expression and regulating reactive oxygen species. Collectively, these findings establish the cyclic NST-GPR107 axis as a key regulator of glucose homeostasis and appetite, suggesting a novel therapeutic target for metabolic disorders.
Targeting the microbiome-NLRP3-ferroptosis axis in multiple sclerosis: Neuropharmacological implications for microglial dysfunction and demyelination.
Fawzy MN, Abdelaziz AM, Shokr MM … +1 more , Fathy MK
Neuropharmacology · 2026 Oct · PMID 42208757 · Publisher ↗
Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and neurodegeneration. Recent evidence has established a mechanistic connect...
Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and neurodegeneration. Recent evidence has established a mechanistic connection between gut microbial dysbiosis, the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, and ferroptosis, an iron-dependent regulated cell death marked by lipid peroxidation. This review synthesizes current understanding of how alterations in the gut microbiome disrupt the gut-brain axis and compromise the blood-brain barrier (BBB), thereby promoting the activation of the microglial NLRP3 inflammasome in the central nervous system. The resulting neuroinflammatory milieu, marked by oxidative stress and iron dysregulation, renders oligodendrocytes and neurons susceptible to ferroptosis via essential enzymes like ACSL4 and ALOX15. We examine the reciprocal relationship between NLRP3-induced inflammation and ferroptotic cell death, emphasizing microglia as crucial mediators of this detrimental cycle. We explore innovative neuropharmacological strategies targeting the gut microbiota, NLRP3 inhibition, and ferroptosis pathways (e.g., ACSL4/ALOX15 inhibitors) to achieve neuroprotection and reduce disease progression. This extensive perspective enhances understanding of MS pathophysiology and identifies actionable therapeutic targets within the microbiome-inflammasome-ferroptosis axis for the development of mechanism-based therapies.
Retraction notice to "Ginsenoside Re exerts neuroprotective in MPTP mice: potential links to gut microbiota and serum metabolism" [Neuropharmacology 282 (2026) 110596].
Li J, Zhao G, Yu C … +6 more , Qu Y, Shen X, Zhao Y, Zhang J, Lian W, Zhao Y
Neuropharmacology · 2026 Oct · PMID 42191442 · Publisher ↗
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Comprehensive evaluation of neurosteroid monotherapy and neurosteroid-midazolam combination therapy in mitigating the nerve agent soman-induced chronic neuropsychiatric dysfunction, epileptogenesis, neuroinflammation and neurodegeneration in pediatric models.
Reddy SD, Ramakrishnan S, Singh T … +2 more , Wu X, Reddy DS
Neuropharmacology · 2026 May · PMID 42190906 · Publisher ↗
Children are especially vulnerable to the neurotoxic effects of nerve agents, which can cause lasting neuronal dysfunction, including cognitive impairments, epilepsy, and related comorbidities. Current benzodiazepine ant...
Children are especially vulnerable to the neurotoxic effects of nerve agents, which can cause lasting neuronal dysfunction, including cognitive impairments, epilepsy, and related comorbidities. Current benzodiazepine anticonvulsants often fail to prevent long-term neuropathology following neurotoxic chemical exposure, underscoring the urgent need for more effective treatments. This study investigated the therapeutic potential of the synthetic neurosteroid ganaxolone (GX) in a pediatric rat model of the nerve agent soman exposure. Pediatric (postnatal day 21) rats were acutely exposed to soman and received GX alone or in combination with midazolam treatment 40 min later. Continuous video-EEG monitoring, behavioral assessments and MRI imaging were conducted over a 3-month period after the acute challenge. Soman exposure led to persistent epileptic seizures, electrographic ictal biomarkers, cognitive dysfunction, behavioral impairments, hippocampal atrophy, neuroinflammation and neurodegeneration. Midazolam alone had minimal neuroprotective effects. In both monotherapy and combination regimen, GX significantly reduced memory deficits, anxiety, and depressive-like behaviors. GX attenuated spontaneous seizures and suppressed non-convulsive epileptiform discharges, interictal spikes, and high-frequency oscillations, suggesting disease-modifying effects. Mechanistic immunohistology analyses showed that GX preserved parvalbumin-positive inhibitory interneurons and NeuN-positive principal neurons, enhanced doublecortin-positive neurogenesis in the hippocampus, and reduced inflammatory microgliosis as indicated by IBA1 expression. MRI scans confirmed reduced neuropathological changes in GX-treated animals. Collectively, these findings demonstrate that GX alone or in combination with midazolam offers strong neuroprotective, antiepileptogenic, and anti-inflammatory benefits, highlighting its promise as a robust pediatric anticonvulsant for nerve agent-induced seizures and long-term neurologic dysfunction.
Corrigendum to "Antidepressant-like activity of JZ-1201 in male rodents: a novel selective 5-HT/NE reuptake inhibitor and 5-HT receptor partial agonist" [Neuropharmacology (2026) 111009].
Gao H, Wang S, Liu Q … +3 more , Jia J, Yang Y, Jin Z
Neuropharmacology · 2026 Oct · PMID 42185118 · Publisher ↗
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Neuroprotective effects of serum- and glucocorticoid-regulated kinase 1 protein in a Parkinson's disease model.
Seo MH, Kim SH, Kim SH … +1 more , Yeo S
Neuropharmacology · 2026 Oct · PMID 42176731 · Publisher ↗
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with non-motor symptoms including autonomic dysfunction, cognitive decline, depression, and gastrointestinal dysfunction. PD is characterize...
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with non-motor symptoms including autonomic dysfunction, cognitive decline, depression, and gastrointestinal dysfunction. PD is characterized by reductions in the number of dopaminergic neurons and the tyrosine hydroxylase (TH) enzyme level; however, the reasons for these reductions have not been elucidated. The accumulation of α-syneclein (α-syn) is the neuropathological characteristic of PD. In this study, we investigated whether serum- and glucocorticoid-regulated kinase 1 (SGK1) treatment may have a positive effect on neurodegenerative changes in PD. SGK1, a serine/threonine-protein kinase involved in Na/K pump activity, is encoded by sgk1. SGK1-myc, transiently expressed in tobacco leaves, was extracted and used to treat SW480 and SH-SY5Y cells. The changes in the expression levels of the factors related to PD, i.e., TH and α-syn, were investigated in the cells and in the colons of the 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced PD model. The SGK1 expression level was associated with TH and α-syn expression levels, and SGK1 treatment positively affected PD-related pathological symptoms. In addition, SGK1 treatment led to improved TH expression in the substantia nigra and striatum regions. The increase in SGK1 expression following treatment with the recombinant SGK1-myc protein resulted in beneficial alterations in the pathological factors associated with PD. These findings position SGK1 as a potential therapeutic target for early-stage PD therapy, as it is associated with the Na/K pump and gastrointestinal dysfunction, features often disrupted in early PD.
The adenosine A receptor antagonist KW6002 mitigates aldosterone-induced central serous chorioretinopathy in mice.
Liu Q, Yu Z, Tang WH … +6 more , Yang J, Que JN, Li J, Xu K, Qu J, Chen JF
Neuropharmacology · 2026 Oct · PMID 42176730 · Publisher ↗
PURPOSE: Central serous chorioretinopathy (CSC), a prevalent disease characterized by choroidal vascular abnormalities, has extremely limited treatment options. This study investigates the effects of the selective adenos...
PURPOSE: Central serous chorioretinopathy (CSC), a prevalent disease characterized by choroidal vascular abnormalities, has extremely limited treatment options. This study investigates the effects of the selective adenosine A receptor (AR) antagonist KW6002 on choroidal vascular hyperpermeability and the blood-retinal barrier (BRB), and explores its therapeutic potential in experimental CSC. METHODS: We examined AR expression in the retinal pigment epithelium (RPE)-choroid-sclera complex using quantitative real-time PCR (qPCR) and Western blotting (WB) in mice with an established aldosterone-induced acute CSC model. Before modeling and after model establishment, mice were administered 5 mg/kg KW6002 or a vehicle control via intraperitoneal injection. The retinal and choroidal thickness was assessed by optical coherence tomography (OCT) and hematoxylin-eosin (H&E) staining. We observed Müller cells activation, retinal microglia infiltration, and proinflammatory cytokine expression via immunofluorescence and qPCR. Next, we employed the effects of the AR antagonist KW6002 and genetic AR knockout (AR-KO) on BRB integrity using immunofluorescence and WB. Finally, to clarify how AR knockout confers therapeutic benefits in CSC, we assessed activation of the TNF-α/NF-κB-MMP-2/9 signaling pathway. RESULTS: We found that AR signaling was significantly upregulated in the RPE-choroid-sclera complex in CSC models, and both AR antagonist KW6002 and AR-KO significantly inhibited the aldosterone-induced central retinal and choroidal pathologic thickening. Moreover, the KW6002 intervention decreased the activation of Müller cells and the proliferation of microglia, inhibited the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), and ameliorated the retinal damage caused by aldosterone; in contrast, AR-KO resulted in significant upregulation of key tight junction proteins (ZO-1, Claudin-1, and Claudin-5). In summary, these results suggest that the protective effects may be correlated with the suppression of the TNF-α/NF-κB-MMP-2/9 signaling axis. CONCLUSIONS: Our findings show that the AR antagonist KW6002 or AR-KO offers a protective effect in experimental CSC, reduces inflammation, and maintains the integrity of the BRB, which may be associated with the inhibition of the TNF-α/NF-κB-MMP-2/9 pathway. These findings present a new method for preventing and treating CSC, which will guide our future clinical strategy development.
Genetic variation in cerebellar nicotinic acetylcholine receptor (nAChR) function impacts efficacy of nicotine and varenicline treatment of alcohol withdrawal-induced motor impairment.
McLean NA, Greenway AE, Gray TL … +3 more , Stiles SNS, Denton TT, Rossi DJ
Neuropharmacology · 2026 Oct · PMID 42162603 · Publisher ↗
In the U.S., 10% of the population is diagnosed with Alcohol Use Disorder (AUD), and 80% of those individuals also use nicotine, making both substances major public health concerns. AUD is characterized by chronic alcoho...
In the U.S., 10% of the population is diagnosed with Alcohol Use Disorder (AUD), and 80% of those individuals also use nicotine, making both substances major public health concerns. AUD is characterized by chronic alcohol (EtOH) consumption, dependence, and withdrawal, sustained by neurological adaptations, such as occurs in the cerebellum. Specifically, in the cerebellum, acute EtOH increases inhibition, but during prolonged exposure, homeostatic adaptations decrease cerebellar inhibition, which during withdrawal causes the onset of both motoric and emotional withdrawal symptoms. These aversive withdrawal symptoms are ameliorated by renewed EtOH use, thereby generating negative reinforcement for renewed EtOH consumption. Similarly, nicotine alleviates aspects of EtOH withdrawal symptoms, likely contributing to AUD-nicotine comorbidity. Relatedly, clinical trials are using the smoking cessation drug, varenicline, a full nAChRα7 and partial nAChRα4β2 agonist, to treat AUD. However, genetic variation in nAChR expression suggests this approach may not work for everyone. The goal of this study was to determine how genetic differences in nAChR function between C57BL6/N (B6N) and DBA/2J (D2) mice, two strains known for high EtOH withdrawal severity, influence the efficacy of nicotine and varenicline for treating EtOH withdrawal. We found that D2 mice had higher cerebellar nAChR function (manifested as increased synaptic GABA release onto primary cerebellar input granule cells) than B6N mice. Additionally, nicotine and varenicline improved motor impairment during EtOH withdrawal only in D2 mice, showing the necessity of functional cerebellar nAChRs for treatment EtOH withdrawal symptoms. Finally, we found that nicotine's rapid metabolism limits its therapeutic effect in D2 mice, which provides a possible explanation for the urge to chain smoke during withdrawal. These findings highlight the importance of genetic variability in AUD treatment, and support varenicline as a potential nicotine substitute during withdrawal.
Progress in precision drug delivery systems for neurodegenerative diseases with muscle atrophy.
Zhang G, Hu F, Zhang Y … +9 more , Li D, Deng Y, Yang M, Huang T, Deng X, Li Y, Fu C, Zhou L, Dong B
Neuropharmacology · 2026 Oct · PMID 42144072 · Publisher ↗
Neurodegenerative diseases frequently co-occur with skeletal muscle atrophy, creating a complex comorbid condition that significantly accelerates functional decline and increases mortality. This dual pathology is driven...
Neurodegenerative diseases frequently co-occur with skeletal muscle atrophy, creating a complex comorbid condition that significantly accelerates functional decline and increases mortality. This dual pathology is driven by interconnected mechanisms such as protein aggregation, neuroinflammation, and impaired axonal transport, disrupting critical neuromuscular junctions (NMJs). However, a significant research gap exists in the development of therapeutic strategies that can effectively and simultaneously target both the central nervous system (CNS) and peripheral muscle tissues. We systematically summarizes the core pathological targets and critically evaluates recent advances in precision drug delivery systems designed to overcome these challenges. We explore innovative strategies, including engineered viral vectors and receptor-targeted nanoparticles for CNS delivery, as well as smart biomaterials and extracellular vesicles (EVs) for muscle-specific and dual-organ intervention, highlighting the growing role of artificial intelligence (AI) in optimizing their design. Furthermore, this review discusses the construction of multidimensional efficacy evaluation systems that integrate behavioral, molecular, and imaging biomarkers and addresses pivotal clinical translation challenges, from scalable production to species-specific differences. By examining the pathological landscape across the central nervous system and skeletal muscle together, this review connects mechanisms that have more often been considered in isolation and evaluates how their convergence may inform the design of delivery strategies targeting both tissue compartments.
Erythropoietin targets parvalbumin-positive inhibitory neurons and microglia to promote plasticity in the thalamic reticular nucleus.
Gramuntell Y, Klimzack P, Curto Y … +6 more , Alcaide J, Garcia-Verellen E, Perez-Rando M, Nave KA, Ehrenreich H, Nacher J
Neuropharmacology · 2026 Oct · PMID 42142650 · Publisher ↗
Erythropoietin (EPO) and its receptor (EPOR) promote neuroprotection and neural plasticity. The effects of recombinant human (rh)EPO have been extensively studied in the hippocampus, where significant effects on inhibito...
Erythropoietin (EPO) and its receptor (EPOR) promote neuroprotection and neural plasticity. The effects of recombinant human (rh)EPO have been extensively studied in the hippocampus, where significant effects on inhibitory neurons have been recently discovered. However, little is known about the effects of EPO on the thalamus, particularly on the thalamic reticular nucleus (TRN), a GABAergic structure regulating corticothalamic communication, which is altered in different CNS disorders. Here, we investigated EPOR expression and the impact of chronic rhEPO treatment on TRN neurons, their plasticity-related molecules, and glial populations, as well as the projections of these neurons to thalamic excitatory nuclei. EPOR was expressed by all Gad1+/Pvalb + TRN neurons, along with subsets of astrocytes and microglia. Young male mice treated with rhEPO for 3 weeks exhibited increased density of PV + neurons and VGLUT2+ puncta in the TRN, while the density of VGLUT1+ and VGAT + puncta remained unaffected. The activity marker FosB was significantly decreased in PV+, but not PV-cells, of the TRN. No changes were detected in the volume of the TRN, PSA-NCAM expression, the immunofluorescence intensity of Wisteria floribunda-labeled perineuronal nets or the density of PV + puncta in the ventral posterolateral and lateral posterior excitatory nuclei. Interestingly, microglial density was significantly reduced, with no changes in astroglial cells. These findings indicate that rhEPO directly targets TRN PV-expressing neurons, modulating their maturation, physiology and connectivity and has important effects on microglial cells. Altogether, our results suggest that EPO contributes to thalamic circuit plasticity, further supporting its potential therapeutic relevance in neuropsychiatric disorders.
Astrocytic reactivity and amyloid load are reduced in a sex-dependent manner in a mouse model of amyloid pathology following protease-activated receptor 2 activation.
Edwards N, Sakata S, McConnell G … +1 more , Bushell TJ
Neuropharmacology · 2026 Oct · PMID 42140519 · Publisher ↗
Alzheimer's disease is a leading cause of death, but current treatments are limited in their use and primarily offer symptomatic relief. Recent developments targeting amyloid plaques have given some hope, but their true...
Alzheimer's disease is a leading cause of death, but current treatments are limited in their use and primarily offer symptomatic relief. Recent developments targeting amyloid plaques have given some hope, but their true value remains equivocal. Hence, alternative therapeutic targets are required with neuroinflammation, particularly glial cells, been a recent area of interest. Indeed, there has been intense research into the role of reactive astrocytes in neurodegenerative diseases with several studies indicating that reducing their reactivity is beneficial in animal models of disease. Building on our previous work using the blood brain barrier permeable protease-activated receptor 2 (PAR2) activator, AC264613 (AC), we investigate the consequence of AC administration on mouse behaviour, astrocytic reactivity and amyloid plaque load in the 5xFAD mouse model of amyloid pathology. Our data reveal similar behavioural changes in both 5xFAD and 5xFAD mice that are sex-independent. However, AC reduces both GFAP and C3 expression levels, markers for astrocyte reactivity, in female but not male 5xFAD mice. In contrast, AC did not affect Iba1 and CD68 expression levels, markers for microglial activation and function, in mice of either sex. Significantly, AC reduced amyloid plaque load only in female 5xFAD mice similar to that seen with astrocyte reactivity. These data reveal that PAR2 activation can reduce astrocyte reactivity and amyloid plaque load in 5xFAD mice. Our findings add further weight to the proposal that targeting astrocyte reactivity to reduce neuroinflammation in neurodegenerative disorders, in this case using PAR2 activation, may be a viable therapeutic strategy.
Antibiotic-mediated gut microbiota depletion partially attenuates methamphetamine-induced reward and linoleic acid metabolic disturbance.
Liang M, Wang X, Li J … +7 more , Li R, Peng J, Gao B, An R, Chen X, Zhang J, Liu X
Neuropharmacology · 2026 Sep · PMID 42134644 · Publisher ↗
Methamphetamine (METH) is a highly addictive psychostimulant that possesses potent toxicity to multiple organs. Emerging evidence has suggested associations between gut microbiota dysbiosis and METH-induced rewarding eff...
Methamphetamine (METH) is a highly addictive psychostimulant that possesses potent toxicity to multiple organs. Emerging evidence has suggested associations between gut microbiota dysbiosis and METH-induced rewarding effects. However, the role and underlying mechanisms of gut microbiota in METH addiction remain poorly understood. Using a mouse conditioned place preference (CPP) model combined with multi-omics profiling of gut microbiota and metabolites, we first investigated how METH exposure affects gut microbiota composition. Then, antibiotic (ABX)-mediated gut microbiota depletion was conducted to explore the role of gut microbiota in the METH-induced associative memory of context-reward (METH reward) and metabolic dynamics. Furthermore, associations among gut microbiota, metabolites, and behavioral phenotypes were determined to reveal the potential key microbial taxa and metabolites in METH reward. Finally, the key metabolite was intervened to reveal the role of it in the METH reward. Our results demonstrated that repeated METH administration induced significant alterations in gut microbiota profiles. ABX-mediated microbiota depletion attenuated METH-induced rewarding effects and metabolic perturbations, especially in linoleic acid (LA) metabolism. METH exposure led to an increase in, while gut microbiota depletion rescued the activation of LA metabolism. Correlation analyses consistently demonstrated associations among specific bacterial species, LA metabolites, and CPP scores. Supplementation of LA could facilitate, while inhibition of its oxidative metabolism could attenuate the METH-induced CPP. These findings highlight LA metabolism as a potential mechanistic link between gut microbiota dysbiosis and METH reward. Future gut microbiota-targeted therapeutic interventions, particularly those modulating LA metabolism, may improve the treatment of METH use disorder.
PACAP in Parkinson's disease: A multifunctional neuropeptide at the crossroad of autophagy, inflammation, and metabolic repurposing.
Hassan ME, Al-Kuraishy HM, Fawzy MN … +5 more , Hussain NR, Al-Gareeb AI, Rashwan EK, Albuhadily AK, Batiha GE
Neuropharmacology · 2026 Sep · PMID 42107921 · Publisher ↗
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of α-synuclein, mitochondrial dysfunction, and chronic neuroinflammation. In this complex pathology, pituitary adenyl...
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of α-synuclein, mitochondrial dysfunction, and chronic neuroinflammation. In this complex pathology, pituitary adenylate cyclase-activating polypeptide (PACAP) has become a crucial neuroprotective regulator; however, its signaling pathways are markedly impaired in Parkinson's disease (PD). This review consolidates the increasing evidence that PACAP counteracts the pathogenesis of PD through multiple mechanisms: restoring autophagic flux, diminishing oxidative stress, altering the balance from pro-apoptotic to anti-apoptotic pathways, and alleviating microglial-mediated neuroinflammation. Recognizing the difficulties associated with peptide-based therapies, we explore novel strategies to utilize PACAP's protective properties, including the repurposing of FDA-approved medications like linagliptin and metformin, which engage PACAP-dependent pathways. Despite preclinical models consistently demonstrating significant neuroprotective effects, there is a marked absence of clinical validation. This review integrates mechanistic insights, evidence from particular models, and potential biomarkers to establish PACAP as a promising therapeutic target and delineates a strategy for accelerating its transition from laboratory research to clinical application in PD.
RGS6 regulates Kappa opioid receptor-mediated antinociceptive behaviors.
Blount AP, Sutton LP
Neuropharmacology · 2026 Sep · PMID 42107525 · Full text
Targeting the kappa opioid receptor (KOR) system has emerged as a potential alternative to current analgesics, however, advancing the therapeutic development of KOR requires further elucidation of its intracellular signa...
Targeting the kappa opioid receptor (KOR) system has emerged as a potential alternative to current analgesics, however, advancing the therapeutic development of KOR requires further elucidation of its intracellular signaling events and modulators. Among these intracellular modulators, Regulators of G protein Signaling (RGS) proteins act as key modulators of GPCR signaling to shape nociceptive circuits and influence pain processing. Despite this, the molecular diversity of RGS proteins that shape KOR signaling and its behavioral consequences remains largely unexplored. Here we report that RGS6, a member of the R7 RGS family, is highly expressed in nociceptive areas and modulates multiple modalities of KOR-dependent anti-nociception and nocifensive behaviors. Using global single and double knockout mouse models we show that this anti-nociceptive phenotype was highly specific to RGS6 within the R7 RGS family. Further we demonstrate that the R7 RGS family displays a lack of functional redundancy in regulation of KOR signaling and behaviors. Using peripherally restricted KOR agonists, we found that KOR-RGS6 anti-nociceptive signaling displays sex differences in a site-specific manner, as females but not males displayed enhanced anti-nociceptive and blunted nocifensive behaviors. Our findings indicate that RGS6 contributes to KOR-dependent anti-nociceptive signaling and influences nociceptive circuits, raising the possibility that it may represent a relevant target for the development of future analgesic strategies.
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