Experimental Neurology最新文献

{"title":"Inhibition of PAD4-mediated neutrophil extracellular traps formation attenuates hypoxic-ischemic brain injury in neonatal mice.","authors":"Xiaoping Yu, Zhaoyan Chen, Fei Ruan, Yaqing Jiang, Wei Bao, Di Wu, Lishuo Chao, Rui Wu, Kai Le","doi":"10.1016/j.expneurol.2024.115065","DOIUrl":"https://doi.org/10.1016/j.expneurol.2024.115065","url":null,"abstract":"<p><p>Neonatal hypoxic-ischemic encephalopathy (HIE) is the primary cause of neonatal mortality and severe neurological sequelae. The interaction of neuroinflammation with the immune system represents a significant pathological mechanism underlying the development of HIE. Neutrophil extracellular traps (NETs) are a recently identified antimicrobial mechanism utilized by neutrophils. NETs can act as damage-associated molecular patterns, thereby amplifying the immune response and exerting proinflammatory effects. However, further research is needed to elucidate their role in the pathogenesis of HIE. In this study, we investigated the role of NETs in a hypoxic-ischemic brain injury (HIBI) model. We first reported that a pharmacological intervention to inhibit peptidylarginine deiminase type IV (PAD4) may constitute an effective strategy for reducing HI insult-induced neuroinflammation, neuronal apoptosis, and brain tissue destruction while also enhancing long-term neurobehavioral function in mice. These results support a pathological role for NETs in HIBI, and targeting PAD4 is a potential direction for the treatment of HIE.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115065"},"PeriodicalIF":4.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diminished lactate utilization in LDHB-deficient neurons leads to impaired long-term memory retention.","authors":"Jin Soo Lee, Bok Seon Yoon, Songmi Han, Yihyang Kim, Chan Bae Park","doi":"10.1016/j.expneurol.2024.115064","DOIUrl":"https://doi.org/10.1016/j.expneurol.2024.115064","url":null,"abstract":"<p><p>Neurons' high energy demands for processing, transmitting, and storing information in the brain necessitate efficient energy metabolism to maintain normal neuronal function. The astrocyte-neuron lactate shuttle (ANLS) hypothesis suggests neurons preferentially use lactate from astrocytes over glucose for energy. This study investigated lactate dehydrogenase B (LDHB), which preferentially converts lactate to pyruvate, in neuronal energy metabolism and cognitive function. LDHB-deficient neurons showed reduced lactate-driven energy metabolism in culture, while LDHB-deficient brains accumulated lactate, both indicating decreased lactate utilization. This reduced lactate utilization was correlated with impaired long-term memory in LDHB-deficient mice, while short-term memory remained unaffected and overall neuropathology was only mildly disturbed. Unexpectedly, LDHB-deficient neurons maintain stable energy metabolism under physiological glucose conditions, indicating the presence of lactate dehydrogenase (LDH) activity in LDHB-deficient neurons. The observation of lactate dehydrogenase A (LDHA), which preferentially converts pyruvate to lactate but can also catalyze the reverse reaction less efficiently, in LDHB-deficient neurons may explain their stable energy metabolism and reduced lactate utilization. This study challenges the established concept of strict LDH isoform compartmentalization in brain cells, questioning the exclusive presence of LDHB in neurons and suggesting a more flexible neuronal metabolic profile than previously assumed by the ANSL hypothesis.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115064"},"PeriodicalIF":4.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time of day dependent reduction in stroke infarct volume by the Reverb agonist SR9009 in mice.","authors":"Pradip K Kamat, Mohammad Badruzzaman Khan, Shahneela Siddiqui, Tyler Grace Hattaway, Affan Anas, R Daniel Rudic, Babak Baban, Krishnan M Dhandapani, David C Hess","doi":"10.1016/j.expneurol.2024.115067","DOIUrl":"10.1016/j.expneurol.2024.115067","url":null,"abstract":"<p><p>Ischemic stroke leads to disability and death worldwide and evidence suggests that stroke severity is affected by the time dimension of the stroke. Rev-Erbα regulates the core circadian clock through repression of the positive clock element Bmal1. However, it remains unclear if a Rev-Erbα agonist (SR9009) alleviates stroke pathology in mice. We found that stroke reduces the level of Rev-Erbα and elevates neuroinflammation and stroke severity at zeitgeber time (ZT) ZT06. Therefore, we hypothesized that SR9009 treatment may reduce neuroinflammation and stroke severity in a mouse suture occlusion model. At 12 to 14 weeks, C57BL/6 J (Wild Type, n = 5-10 mice/group) mice were randomly assigned to undergo MCAO stroke for 60 min at either zeitgeber time ZT06 (MCAO-ZT06-sleep phase) or ZT18 (MCAO-ZT18-awake phase). Stroked mice were treated with SR9009 (100 mg/kg) or vehicle at 1 h and 24 h after MCAO. After forty-eight hours of stroke, TTC staining, Western blot, and qRT-PCR were performed. We found that SR9009 treatment alleviates neuroinflammation and infarct volume by Rev-Erb remodeling in ZT06 stroke mice but not in ZT18 stroke mice. Additionally, monocytic and neutrophilic NLRP3 as well as brain NLRP3 levels were reduced by SR9009 treatment in ZT06 stroke though no effects were observed at ZT18 stroke. SR9009 also reduced TNFα expression and increased IL-10 expression in blood and brain in ZT06 stroke mice and no differences were observed at ZT18. There were no significant effects of SR9009 on neurological deficit score and sensorimotor function at ZT06 or ZT18 at 48 h. Our study demonstrates that SR9009 treatment reduces stroke volume, circulating immune response, circadian expression, and that the protection was circadian- and treatment time-dependent.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115067"},"PeriodicalIF":4.6,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial stress and inflammation in neurological disorders.","authors":"Qing Wang, John H Zhang","doi":"10.1016/j.expneurol.2024.115063","DOIUrl":"https://doi.org/10.1016/j.expneurol.2024.115063","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115063"},"PeriodicalIF":4.6,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological inhibition of P2RX4 receptor as a potential therapeutic strategy to prevent intracranial aneurysm formation.","authors":"Isao Ono, Masahiko Itani, Akihiro Okada, Kimiko Yamamoto, Akitsugu Kawashima, Yoshiki Arakawa, Tomohiro Aoki","doi":"10.1016/j.expneurol.2024.115061","DOIUrl":"https://doi.org/10.1016/j.expneurol.2024.115061","url":null,"abstract":"<p><p>Intracranial aneurysms (IA) affect 1-5 % of the population and are a major cause of subarachnoid hemorrhage. Thus, preventing IA development and progression is crucial for public health. IA has been considered a non-physiological, high shear stress-induced chronic inflammatory disease affecting the bifurcation site of the intracranial arteries. Therefore, factors that sense high shear stress and induce IAs by triggering inflammation could potentially act as therapeutic targets. P2RX4 is a member of the purinoreceptor family that converts the strength of shear stress into intracellular signals. To verify its therapeutic potential, we investigated the effects of P2RX4 and a selective antagonist on the formation of IAs. Results showed that P2RX4 deficiency significantly suppressed the formation of IAs. Consistently, the selective P2RX4 antagonist NC-2600, which potently inhibited Ca²⁺ influx in response to shear-stress loading in endothelial cells in vitro, significantly suppressed the formation of IAs. The results of the present study contribute to our understanding of the pathogenesis of IAs and may provide benefits to society through the future development of medical therapies targeting P2RX4.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115061"},"PeriodicalIF":4.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein arginine methyltransferases as regulators of cellular stress.","authors":"Julia Zaccarelli-Magalhães, Cristiane Teresinha Citadin, Julia Langman, Drew James Smith, Luiz Henrique Matuguma, Hung Wen Lin, Mariana Sayuri Berto Udo","doi":"10.1016/j.expneurol.2024.115060","DOIUrl":"https://doi.org/10.1016/j.expneurol.2024.115060","url":null,"abstract":"<p><p>Arginine modification can be a \"switch\" to regulate DNA transcription and a post-translational modification via methylation of a variety of cellular targets involved in signal transduction, gene transcription, DNA repair, and mRNA alterations. This consequently can turn downstream biological effectors \"on\" and \"off\". Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs 1-9) in both the nucleus and cytoplasm, and is thought to be involved in many disease processes. However, PRMTs have not been well-documented in the brain and their function as it relates to metabolism, circulation, functional learning and memory are understudied. In this review, we provide a comprehensive overview of PRMTs relevant to cellular stress, and future directions into PRMTs as therapeutic regulators in brain pathologies.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115060"},"PeriodicalIF":4.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota-derived 3-indoleacetic acid confers a protection against sepsis-associated encephalopathy through microglial aryl hydrocarbon receptors.","authors":"Zhi-Bin Huang, Guo-Pan Zhang, Chen-Xin Lu, Cansheng Gong, Xiaotan Gao, Yanqi Lin, Ping Su, Wenyan Xu, Yongbao Lin, Na Lin, Xuyang Wu, Xiaohui Chen, Ting Zheng, Xiaochun Zheng","doi":"10.1016/j.expneurol.2024.115055","DOIUrl":"10.1016/j.expneurol.2024.115055","url":null,"abstract":"<p><strong>Background: </strong>The gut microbiota significantly contributes to the pathogenesis of central nervous system disorders. Among the bioactive molecules produced by the gut microbiota, 3-indoleacetic acid (IAA) has been shown to attenuate oxidative stress and inflammatory responses. This experiment aimed to determine the impacts of IAA on sepsis-associated encephalopathy (SAE) and the underlying mechanisms.</p><p><strong>Methods: </strong>A total of 34 septic patients and 24 healthy controls were included in the analysis of the clinical correlation between fecal IAA and septic encephalopathy. Fecal microbiota transplantation was used to verify the role of the gut microbiota and its metabolites in SAE. Male C57BL/6 mice aged six to eight weeks, pre-treated with IAA via oral gavage, were subjected to the cecal ligation and puncture (CLP) procedures. This treatment was administered either in combination with an aryl hydrocarbon receptor (AhR) antagonist, CH223191, or a CSF1R inhibitor, PLX3397, to eliminate microglia. Both immunofluorescence staining and enzyme-linked immunosorbent assays were used to evaluate microglia activation and inflammatory cytokine secretion. Behavioral assessments were conducted to quantify neurological deficits.</p><p><strong>Results: </strong>A decreased fecal level of IAA was observed in the patients with sepsis-associated delirium (SAD), a manifestation of SAE. A reduced IAA level was significantly associated with worsen clinical outcomes. Fecal microbiota transplantation from the SAD patients induced an SAE-like phenotype in mice, but supplementing exogenous IAA improved the SAE-like phenotype, mediated by microglia. IAA effectively binded with the aryl hydrocarbon receptor (AhR). Furthermore, IAA increased the nuclear activity of AhR in the lipopolysaccharide (LPS)-treated microglial cells, leading to reduced secretion of inflammatory cytokines. The AhR inhibitor CH223191 counteracted the protective effect of IAA against SAE in mice.</p><p><strong>Conclusions: </strong>Gut microbiota-derived IAA confers a protection against SAE by activating AhR in microglia, improving neuronal and cognitive impairments. Thus, IAA holds the promise as a potential therapeutic agent for managing SAE.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115055"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute intermittent hypoxia elicits sympathetic neuroplasticity independent of peripheral chemoreflex activation and spinal cord tissue hypoxia in a rodent model of high-thoracic spinal cord injury.","authors":"Mehdi Ahmadian, Erin Erskine, Liisa Wainman, Oliver H Wearing, Jennifer S Duffy, Liam C Stewart, Ryan L Hoiland, Alissa Taki, Raphael R Perim, Gordon S Mitchell, Jonathan P Little, Patrick J Mueller, Glen E Foster, Christopher R West","doi":"10.1016/j.expneurol.2024.115054","DOIUrl":"10.1016/j.expneurol.2024.115054","url":null,"abstract":"<p><p>The loss of medullary control of spinal circuits controlling the heart and blood vessels is a unifying mechanism linking both hemodynamic instability and the risk for cardiovascular diseases (CVD) following spinal cord injury (SCI). As such, new avenues to regulate sympathetic activity are essential to mitigate CVD in this population. Acute intermittent hypoxia (AIH) induces a type of neuroplasticity known as long-term facilitation (LTF), a persistent increase in nerve activity post-AIH in spinal motor circuits. Whether LTF occurs within the sympathetic circuit following SCI is largely unknown. We aimed to test whether AIH elicits sympathetic LTF (i.e., sLTF) and attenuates hypoactivity in sub-lesional splanchnic sympathetic circuits in a male rat model of SCI. In 3 experimental series, we tested whether 1) high-thoracic contusion SCI induces hypoactivity in splanchnic sympathetic nerve activity, 2) AIH elicits sLTF following SCI, and 3) sLTF requires carotid chemoreflex activation or spinal cord tissue hypoxia. Our results indicate that a single-session of AIH therapy (10 × 1 min of F_iO₂ = 0.1, interspersed with 2 min of F_iO₂ = 1.0) delivered at 2 weeks following SCI attenuates SCI-induced sympathetic hypoactivity by eliciting sLTF 90 min post-treatment that is independent of peripheral chemoreflex activation and/or spinal cord hypoxia. These findings advance our mechanistic understanding of AIH in the field and yield new insights into factors underpinning AIH-induced sLTF following SCI in a rat model. Our findings also set the stage for the chronic application of AIH to alleviate secondary complications resulting from sympathetic hypoactivity following SCI.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115054"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease","authors":"Sara El-desouky ,&nbsp;Mohammad Abdel-Halim ,&nbsp;Reem K. Fathalla ,&nbsp;Ashraf H. Abadi ,&nbsp;Gary A. Piazza ,&nbsp;Mohamed Salama ,&nbsp;Sabry Ahmed El-khodery ,&nbsp;Mohamed A. Youssef ,&nbsp;Sara Elfarrash","doi":"10.1016/j.expneurol.2024.115058","DOIUrl":"10.1016/j.expneurol.2024.115058","url":null,"abstract":"<div><div>Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, <em>RF26,</em> using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. <em>RF26</em> successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, <em>RF26</em> -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of <em>RF26</em> as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"384 ","pages":"Article 115058"},"PeriodicalIF":4.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of PAR1 contributes to ferroptosis of Schwann cells and inhibits regeneration of myelin sheath after sciatic nerve crush injury in rats via Hippo-YAP/ACSL4 pathway.","authors":"Wu Zhimin, Sun Jun, Liao Zhi, Sun Tao, Huang Lixin, Jia Qiao, Cong Ling, Chuan Chen, Zhang Baoyu, Wang Hui","doi":"10.1016/j.expneurol.2024.115053","DOIUrl":"10.1016/j.expneurol.2024.115053","url":null,"abstract":"<p><strong>Objective: </strong>Peripheral nerve injury (PNI) is characterized by high incidence and sequela rate. Recently, there was increasing evidence that has shown ferroptosis may impede functional recovery. Our objective is to explore the novel mechanism that regulates ferroptosis after PNI.</p><p><strong>Methods: </strong>LC-MS/MS proteomics was used to explore the possible differential signals, while PCR array was performed to investigate the differential factors. Besides, we also tried to activate or inhibit the key factors and then observe the level of ferroptosis. Regeneration of myelin sheath was finally examined in vivo via transmission electron microscopy.</p><p><strong>Results: </strong>Proteomics analysis suggested coagulation signal was activated after sciatic nerve crush injury, in which high expression of F2 (encoding thrombin) and F2r (encoding PAR1) were observed. Both thrombin and PAR1-targeted activator TRAP6 can induce ferroptosis in RSC96 cells, which can be rescued by Vorapaxar (PAR1 targeted inhibitor) in vitro. Further PCR array revealed that activation of PAR1 induced ferroptosis in RSC96 cells by increasing expression of YAP and ACSL4. Immunofluorescence of sciatic nerve confirmed that the expression of YAP and ACSL4 were simultaneously reduced after PAR1 inhibition, which may contribute to myelin regeneration after injury in SD rats.</p><p><strong>Conclusion: </strong>Inhibition of PAR1 can relieve ferroptosis after sciatic nerve crush injury in SD rats through Hippo-YAP/ACSL4 pathway, thereby regulating myelin regeneration after injury. In summary, PAR1/Hippo-YAP/ACSL4 pathway may be a promising therapeutic target for promoting functional recovery post-sciatic crush injury.</p>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":" ","pages":"115053"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}