{"title":"ANA-12 Targets and Inhibits BDNF/TrkB Signaling to Alleviate Pain Behaviors in Rheumatoid Arthritis Mice","authors":"Man Yuan, Long Zhang, Ye Zheng, Min Xie","doi":"10.1007/s11064-025-04487-8","DOIUrl":"10.1007/s11064-025-04487-8","url":null,"abstract":"<div><p>Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease. Sensitization of central pain pathways by pro-inflammatory mediators has been implicated in RA pain. Locus coeruleus (LC) functions in pain pathways. Brain-derived neurotrophic factor (BDNF) participates in the modulation of nociception and pain. A mouse model of RA immunized with collagen-induced arthritis (CIA) was used for investigating the mechanisms of pain relief by administration of the tropomyosin receptor kinase B (TrkB) receptor antagonist ANA-12. We measured the pain behaviors and locomotor activity and found increased pain sensitivity and locomotor deficit in RA mice; ANA-12 treatment reduced pain behaviors and promoted locomotor function recovery. The glial activation and increased activities of BDNF/TrkB and MAPK signal pathways were found in LC of RA mice. The components of NLRP3 inflammasome were all increased and consequently enhanced the production of pro-inflammatory cytokine interleukin (IL)-1β. Upon ANA-12 treatment, glial cell activation was reduced, BDNF/TrkB and MAPK pathways were suppressed, and the expression levels of the above-mentioned proteins were reduced. Finally, U251 cells were conducted to further confirm the regulatory mechanisms of ANA-12 on inflammation. The results showed the colocalization of BDNF/NLRP3/IL-1β and GFAP. ANA-12 treatment decreased the protein levels of BDNF, TrkB, MAPK, NLRP3, and caspase-1 in IL-1β-induced cells. Besides, ANA-12 treatment decreased NLRC4 and AIM2 inflammasomes both in RA mice and IL-1β-induced cells. These results suggested that ANA-12 alleviates hyperalgesia in RA mice by inhibiting BDNF/TrkB signaling in LC, thereby reducing glial cell activation and inflammatory cytokine release.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mariana Neuparth-Sottomayor, Tatiana P. Morais, Mark Good, Ana Maria Sebastião, Giuseppe Di Giovanni, Vincenzo Crunelli, Sandra H. Vaz
{"title":"Impairment of Spatial Working Memory but Preservation of Recognition Memory in Female Rats with Spontaneous Absence Seizures","authors":"Mariana Neuparth-Sottomayor, Tatiana P. Morais, Mark Good, Ana Maria Sebastião, Giuseppe Di Giovanni, Vincenzo Crunelli, Sandra H. Vaz","doi":"10.1007/s11064-025-04485-w","DOIUrl":"10.1007/s11064-025-04485-w","url":null,"abstract":"<div><p>Epidemiological studies reveal gender-specific differences in epilepsy. Childhood absence epilepsy (CAE), which is more prevalent in females, is characterized by typical absence seizures (ASs) consisting of brief periods of unconsciousness, associated with 2.5–4 Hz spike-wave discharges (SWDs) in the electroencephalogram (EEG). Children with CAE often present neuropsychological comorbidities, including deficits in attention and executive function. In this study, we investigated anxiety-like behaviour and memory in female Genetic Absence Epilepsy Rat from Strasbourg (GAERS), a validated model of ASs, compared to Non-Epileptic Control (NEC) and Wistar rats. We found that female GAERS generally showed normal anxiety-like behaviour relative to both control strains, although some tests suggested a reduction in anxiety. Importantly, female GAERS showed impaired spatial working memory, while recognition memory was preserved. These findings when compared with previous data in males indicate that while anxiety levels in female GAERS are preserved as those of male GAERS, memory performance differs, with males showing impairments in both spatial working memory and recognition memory. These findings emphasize the importance of considering gender differences in both clinical and preclinical epilepsy research to better understand the neuropsychological comorbidities associates with ASs. This knowledge is crucial for the identification of gender-specific mechanism, as well as the development of gender-sensitive, personalized therapies targeting both seizures and associated cognitive impairments.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weiqing Huang, Xionghui Wu, Shuting Chang, Xiaoming Peng, Xiao Li
{"title":"Novel GLP-1/GIP Dual Receptor Agonist Alleviates Neonatal Hypoxic-Ischemic Encephalopathy by Inhibiting TLR2/NF-κB/NLRP3 Mediated-Neuroinflammation","authors":"Weiqing Huang, Xionghui Wu, Shuting Chang, Xiaoming Peng, Xiao Li","doi":"10.1007/s11064-025-04475-y","DOIUrl":"10.1007/s11064-025-04475-y","url":null,"abstract":"<div><p>Hypoxic-ischemic encephalopathy (HIE) is an irreversible brain injury attributable to impaired blood oxygen delivery in the brain after perinatal asphyxia. The pathogeny of HIE is very complex, and there is still shortage of effective treatment. DA5-CH is a novel dual receptor agonist of glucose dependent insulin stimulating polypeptide (GIP) and glucagon like peptide-1 (GLP-1). However, the function and mechanism of DA5-CH in HIE remain unclear. In this paper, cultured cortical neurons were exposed to oxygen-glucose deprivation (OGD) and neonatal rats were subjected to hypoxic-ischemic damage to explore the protective effects of DA5-CH. Our work revealed that DA5-CH markedly increased cell viability, reduced intracellular ROS levels and DNA damage, and decreased cell apoptosis in OGD-treated cultured cortical neurons. In vivo, DA5-CH treatment significantly improved cognitive dysfunction and neuronal damage, decreased the infarct volume and neuronal death of hypoxic-ischemic (HI) neonatal rats. In addition, DA5-CH decreased TNFα, IL-1β and IL-6 levels in cortical tissue of HI neonatal rats and in microglia cells subjected to OGD. Moreover, DA5-CH treated microglia medium increased the cell viability, but decreased apoptosis of cortical neurons. DA5-CH suppressed NLRP3 inflammasome activation through inactivation of the TLR2/NF-κB signalling pathway. Furthermore, the protective effects of DA5-CH on the hypoxic-ischemic brain injury were antagonized by nigericin (an NLRP3 agonist). Taken together, our findings revealed that DA5-CH alleviates neonatal hypoxic-ischemic encephalopathy by inhibiting TLR2/NF-κB/NLRP3 mediated-neuroinflammation.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sanghoon Kim, Edward Pajarillo, Alexis Digman, Itunu Ajayi, Deok-Soo Son, Michael Aschner, Eunsook Lee
{"title":"CAD (Cath. a-Differentiated) Cells Produce Dopamine along with Dopamine-Synthesizing Enzymes","authors":"Sanghoon Kim, Edward Pajarillo, Alexis Digman, Itunu Ajayi, Deok-Soo Son, Michael Aschner, Eunsook Lee","doi":"10.1007/s11064-025-04474-z","DOIUrl":"10.1007/s11064-025-04474-z","url":null,"abstract":"<div><p>Brain dopaminergic (DAergic) neurons play a critical role in mediating motor, reward, and cognitive processes, but are particularly vulnerable to toxic insults associated with Parkinson’s disease and manganism. Several cell lines have been used to study DAergic function and toxicity, and each has distinct advantages and limitations. Here, we investigated whether cath. a-differentiated (CAD) cells, a mouse-derived catecholaminergic cell line, are suitable for DAergic neurotoxicity research as an in vitro model, focusing on their ability to synthesize dopamine (DA) and the expression of key associated proteins. Manganese (Mn) was also tested to determine its DAergic toxicity potential. CAD cells were differentiated with serum deprivation. High-performance liquid chromatography, western blotting, and RT-qPCR were used to assess DA levels, and the expressions of DAergic proteins such as tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AAAD), vesicular monoamine transporter-2 (VMAT-2), and DA transporter (DAT). The results showed that differentiated CAD cells had higher DA levels compared to undifferentiated cells. L-3,4-dihydroxyphenylalanine (L-DOPA), the DA precursor, increased DA production, while carbidopa, an AAAD inhibitor, decreased its production. CAD cells also expressed AAAD protein, indicating that the latter participates in DA synthesis in this cell line. Moreover, Mn decreased DA as well as mRNA and protein levels of DA synthesizing enzymes, such as TH and AAAD, and VMAT-2, thus impairing the DAergic system. Taken together, differentiated CAD cells possess the capability to synthesize DA and express DA-synthesizing enzymes. In addition, Mn caused DAergic toxicity in CAD cells, suggesting that CAD cells are suitable for studying DAergic neurotoxicity.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhijie Yin, Zhiyong Zhang, Haiming Li, Xingping Zhang, Baozhe Jin
{"title":"Effect of Dynamin-2 Gene Modified OECs on Functional and Molecular Neuroprotection After Spinal Cord Injury in Rats","authors":"Zhijie Yin, Zhiyong Zhang, Haiming Li, Xingping Zhang, Baozhe Jin","doi":"10.1007/s11064-025-04491-y","DOIUrl":"10.1007/s11064-025-04491-y","url":null,"abstract":"<div><p>Spinal cord injury (SCI) imposes a significant economic burden on individuals and society, with limited options for repairing the central nervous system after injury. Cell transplantation therapy, particularly using olfactory ensheathing cells (OECs), has shown promise. However, the neuroprotective mechanisms underlying genetically modified OECs remain unclear. This study aimed to investigate the effects of Dynamin-2 (Dnm2) gene-modified OECs (Dnm2-OECs) on SCI repair in a rat model. OECs were harvested from three-day-old rats. Adult rats were divided into sham, SCI, SCI-OEC, and SCI-Dnm2-OECs groups. Dnm2-OECs were transplanted one day post-SCI model, and recovery was assessed through BBB scores, histological analyses, and molecular markers of inflammation. Results showed that the purity and infection efficiency of OECs were 87.28 ± 7.65% and 89.04 ± 5.56%, respectively. Dnm2-OECs survived for at least 28 days post-transplantation and significantly improved BBB scores by day 21. Additionally, neuronal counts increased, syringomyelia decreased, demyelination lessened, and mitochondrial structure improved. Dnm2 levels rose in spinal tissue, while NF-κB pathway proteins and pro-inflammatory cytokines (TRAF6, IL-17, IL-1β and TNF-α) were reduced. Microglial cells (Iba1) decreased correspondingly. These results indicate that Dnm2-OECs transplantation enhances neurological recovery after by inhibiting the NF-κB signaling pathway, offering a potential therapeutic strategy for SCI repair.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"When the Stars Misfire: Astrocytic Dysfunctions in Major Depressive Disorder","authors":"Candela González-Arias, Gertrudis Perea","doi":"10.1007/s11064-025-04483-y","DOIUrl":"10.1007/s11064-025-04483-y","url":null,"abstract":"<div><p>Major depressive disorder (MDD) is a global public health concern and the leading cause of disability worldwide. It severely impairs cognitive, emotional, and social functioning, and is associated with attention, memory, and executive function deficits. MDD was traditionally considered as a neuropsychiatric disorder focused on neuronal dysfunction; however, growing evidence recognizes glial cells, particularly astrocytes, as crucial cells for the pathophysiology and pathogenesis of MDD. Astrocytes play essential roles in the central nervous system, including neurotransmitter uptake, metabolic support, neurotrophic factor production, and synaptic regulation. Evidence from MDD human patients, as well as studies involving animal models have revealed the astrocytic dysfunction as a critical factor in the pathophysiology of MDD, pointing to widespread alterations in astrocyte density, morphology, and function. This review summarizes current knowledge regarding astrocytes and MDD and discuss the potential of targeting astrocytes as a novel avenue for antidepressant development.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
George Lagamjis, Huy Lu, Nicole M Roeder, Brittany J Richardson, Matthew Marion, Teresa Quattrin, Lucy D. Mastrandrea, Michael Hadjiargyrou, David E. Komatsu, Panayotis K. Thanos
{"title":"Combined Chronic Oral Methylphenidate and Fluoxetine Decreases D2R Levels in the Caudate Putamen and Nucleus Accumbens","authors":"George Lagamjis, Huy Lu, Nicole M Roeder, Brittany J Richardson, Matthew Marion, Teresa Quattrin, Lucy D. Mastrandrea, Michael Hadjiargyrou, David E. Komatsu, Panayotis K. Thanos","doi":"10.1007/s11064-025-04481-0","DOIUrl":"10.1007/s11064-025-04481-0","url":null,"abstract":"<div><p>Methylphenidate (MP) is a commonly prescribed psychostimulant for treating Attention-Deficit/Hyperactive Disorder (ADHD). Many patients with ADHD also experience anxiety and depression, often leading to co-dosing with selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (FLX), commonly used for ADHD-related and adolescent depression. Our laboratory and others have shown that MP increases striatal dopamine (DA) transporters and DA type 1 receptor binding (D1R) in rats, and FLX has been shown to affect the DA reward pathway through the effect DA receptors play on increased cellular serotonin (5-HT). However, the effects of combined MP and FLX on DA receptor binding remain unclear. This study investigated how MP, FLX, and their combination affect D1R and DA type 2 (D2R) binding. At three weeks of age, adolescent rats received four weeks of oral drug treatments via a previously established dosing paradigm that replicates human pharmacokinetics. Rats were separated into four groups, receiving water, MP, FLX, or MP + FLX. Following treatment, autoradiography binding was conducted on coronal brain sections and showed chronic combined treatment with MP + FLX resulted in significant decreases in D2R levels relative to controls in the: Dorsal Caudate Putamen (DCPU) (51.5%), Dorsolateral Caudate Putamen (DLCPU) (50.4%), Nucleus Accumbens Core (Nac Core) (44.8%), Ventral Caudate Putamen (VCPU) (47.7%), and Ventromedial Caudate Putamen (VMCPU) (49.1%). No significant effects were reported for D1R binding. Thus, the combined treatment of MP + FLX in attenuating D2R levels may be involved in the mechanism that prior literature has described an increased risk for substance use disorder, cognitive deficits and motor dysregulation.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chan Shen, Yanghongyun Guo, Jun Zheng, Jiayu Wang, Liangcheng Zhang
{"title":"Correction: Mechanisms of Fat Mass and Obesity-Associated Protein in Regulating Cognitive Impairment Induced by Sevoflurane Anesthesia in Neonatal Rats","authors":"Chan Shen, Yanghongyun Guo, Jun Zheng, Jiayu Wang, Liangcheng Zhang","doi":"10.1007/s11064-025-04482-z","DOIUrl":"10.1007/s11064-025-04482-z","url":null,"abstract":"","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}