Pub Date : 2024-07-01Epub Date: 2024-05-16DOI: 10.1097/WNR.0000000000002049
Shahd Qutifan, Tareq Saleh, Nisreen Abu Shahin, Maha ELBeltagy, Fatimah Obeidat, Duaa Qattan, Heba Kalbouneh, Noor A Barakat, Mohammad Alsalem
Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.
{"title":"Melatonin mitigates cisplatin-induced cognitive impairment in rats and improves hippocampal dendritic spine density.","authors":"Shahd Qutifan, Tareq Saleh, Nisreen Abu Shahin, Maha ELBeltagy, Fatimah Obeidat, Duaa Qattan, Heba Kalbouneh, Noor A Barakat, Mohammad Alsalem","doi":"10.1097/WNR.0000000000002049","DOIUrl":"10.1097/WNR.0000000000002049","url":null,"abstract":"<p><p>Cisplatin-induced cognitive impairment (chemobrain) affects a considerable percentage of cancer patients and has no established pharmacological treatment. Chemobrain can be associated with neuroinflammation and oxidative stress. Melatonin, a pineal hormone, is known to have antioxidant, anti-inflammatory and neuroprotective potential. In this study, we investigated cisplatin-induced cognitive impairment in rats and whether melatonin can improve or reverse this impairment. Behavioral testing involved measuring working memory using the novel location recognition test (NLRT) under conditions of cisplatin or cisplatin + melatonin treatment, followed by the collection of rats' brains. The brains were subsequently stained with Golgi-Cox stain and then the hippocampus area CA3 of each one was examined, and dendritic spine density was calculated. Treatment with cisplatin resulted in deficits in the rats' performance in the NLRT (P < 0.05). These deficits were prevented by the coadministration of melatonin (P < 0.05). Cisplatin also reduced the density of dendritic spines in the hippocampus (P < 0.0001), specifically CA3 area, while the coadministration of melatonin significantly reversed this reduction (P < 0.001). This study showed that melatonin can ameliorate cisplatin-induced spatial memory deficits and dendritic spines density abnormalities in rats. Given that melatonin is a safe and wildly used supplement, it is feasible to explore its use as a palliative intervention in cancer treatment.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Epilepsy is a common neurologic disorder. While a good clinical solution is still missing, studies have confirmed that exosomes (Exos) derived from adipose-derived stem cells (ADSCs) had a therapeutic effect on various diseases, including neurological diseases. Therefore, this study aimed to reveal whether ADSC-Exo treatment could improve kainic acid (KA)-induced seizures in epileptic mice. ADSCs and Exos were isolated. Mice were generated with KA-induced epileptic seizures. ELISA was used to detect inflammatory factor expression. Luciferase reporter analysis detection showed a relationship among miR-23b-3p, STAT1, and glyoxylate reductase 1 (GlyR1). ADSC-Exos had a protective effect on KA-induced seizures by inhibiting inflammatory factor expression and the M1 microglia phenotype. The result showed that miR-23b-3p played an important role in the Exo-mediated protective effect in KA-induced seizures in epileptic mice by regulating STAT1 and GlyR1. Luciferase reporter analysis confirmed that miR-23b-3p interacted with the 3'-UTR of STAT1 and GlyR1. The miR-23b-3p inhibited M1 microglia-mediated inflammatory factor expression in microglial cells by regulating STAT1 and GlyR1. The downregulation of miR-23b-3p decreased the protective effect of ADSC-Exos on KA-induced seizures in epileptic mice. The miR-23b-3p from ADSC-Exos alleviated inflammation in mice with KA-induced epileptic seizures.
{"title":"The miR-23b-3p from adipose-derived stem cell exosomes alleviate inflammation in mice experiencing kainic acid-induced epileptic seizures.","authors":"Xue Yang, Xiaxin Yang, Anqi Sun, Si Chen, Xiaotang Wang, Xiuhe Zhao","doi":"10.1097/WNR.0000000000002044","DOIUrl":"10.1097/WNR.0000000000002044","url":null,"abstract":"<p><p>Epilepsy is a common neurologic disorder. While a good clinical solution is still missing, studies have confirmed that exosomes (Exos) derived from adipose-derived stem cells (ADSCs) had a therapeutic effect on various diseases, including neurological diseases. Therefore, this study aimed to reveal whether ADSC-Exo treatment could improve kainic acid (KA)-induced seizures in epileptic mice. ADSCs and Exos were isolated. Mice were generated with KA-induced epileptic seizures. ELISA was used to detect inflammatory factor expression. Luciferase reporter analysis detection showed a relationship among miR-23b-3p, STAT1, and glyoxylate reductase 1 (GlyR1). ADSC-Exos had a protective effect on KA-induced seizures by inhibiting inflammatory factor expression and the M1 microglia phenotype. The result showed that miR-23b-3p played an important role in the Exo-mediated protective effect in KA-induced seizures in epileptic mice by regulating STAT1 and GlyR1. Luciferase reporter analysis confirmed that miR-23b-3p interacted with the 3'-UTR of STAT1 and GlyR1. The miR-23b-3p inhibited M1 microglia-mediated inflammatory factor expression in microglial cells by regulating STAT1 and GlyR1. The downregulation of miR-23b-3p decreased the protective effect of ADSC-Exos on KA-induced seizures in epileptic mice. The miR-23b-3p from ADSC-Exos alleviated inflammation in mice with KA-induced epileptic seizures.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-05-20DOI: 10.1097/WNR.0000000000002043
Gao Chen, Zhan Jin, Xi Wang, Qi-Hui Yu, Gao-Bo Hu
Danshen injection (DI) is effective in treating cardiovascular and cerebrovascular diseases, including ischemic stroke (IS), including IS, but its mechanism is unclear. A middle cerebral artery occlusion model was used to simulate ischemia/reperfusion (I/R) injury in SD rats. Overexpression of hypoxia-inducible factor 1α (HIF-1α) was achieved by AAV-HIF-1α. Rats were treated with DI or saline. Neurological scores and infarction rates were assessed. I/R damage was examined by HE, 2,3,5-triphenyltetrazolium and Nissl stainings. Expression levels of relative proteins [TNF-α, IL-6, IL-1β, SOD, MDA, ROS, HIF-1α, CXC chemokine receptor 4 (CXCR4) and NF-κB] were measured. DI treatment improved neurological scores and reduced infarction rates, suggesting that it inhibits inflammation and oxidative stress. The expression levels of HIF-1α, CXCR4 and NF-κB were decreased. However, the effectiveness of DI on inflammation inhibition was lost after HIF-1α overexpression. DI may directly target HIF-1α to suppress neuroinflammation and reduce I/R injury by suppressing the HIF-1α/CXCR4/NF-κB signaling pathway.
{"title":"Danshen injection mitigated the cerebral ischemia/reperfusion injury by suppressing neuroinflammation via the HIF-1α/CXCR4/NF-κB signaling pathway.","authors":"Gao Chen, Zhan Jin, Xi Wang, Qi-Hui Yu, Gao-Bo Hu","doi":"10.1097/WNR.0000000000002043","DOIUrl":"10.1097/WNR.0000000000002043","url":null,"abstract":"<p><p>Danshen injection (DI) is effective in treating cardiovascular and cerebrovascular diseases, including ischemic stroke (IS), including IS, but its mechanism is unclear. A middle cerebral artery occlusion model was used to simulate ischemia/reperfusion (I/R) injury in SD rats. Overexpression of hypoxia-inducible factor 1α (HIF-1α) was achieved by AAV-HIF-1α. Rats were treated with DI or saline. Neurological scores and infarction rates were assessed. I/R damage was examined by HE, 2,3,5-triphenyltetrazolium and Nissl stainings. Expression levels of relative proteins [TNF-α, IL-6, IL-1β, SOD, MDA, ROS, HIF-1α, CXC chemokine receptor 4 (CXCR4) and NF-κB] were measured. DI treatment improved neurological scores and reduced infarction rates, suggesting that it inhibits inflammation and oxidative stress. The expression levels of HIF-1α, CXCR4 and NF-κB were decreased. However, the effectiveness of DI on inflammation inhibition was lost after HIF-1α overexpression. DI may directly target HIF-1α to suppress neuroinflammation and reduce I/R injury by suppressing the HIF-1α/CXCR4/NF-κB signaling pathway.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traditional Chinese medicine (TCM) has long been used to treat various diseases, including cerebral ischemia. The specific molecular mechanism of TCM in the treatment of cerebral ischemia, however, is still unclear. This study investigated the effects of gastrodin, electroacupuncture and their combination on cerebral ischemic rats. We used Nissl staining, immunohistochemical staining and immunoblotting to detect the expression changes of brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) in the frontal cortex. The results showed that the combination therapy of gastrodin and electroacupuncture significantly increased the number of Nissl-positive neurons and improved cell morphology compared with other groups. Mechanistically, we found that the combination of gastrodin and electroacupuncture treatment group can restore the abnormal morphology of neuronal cells caused by cerebral ischemia by rebalancing the expression levels of BDNF and IL-6. Our research indicates that gastrodin combined with electroacupuncture has a significant protective effect on cerebral ischemic injury in rats, possibly by regulating the expression of BDNF and IL-6. This combination therapy is superior to single-drug or electroacupuncture therapy.
{"title":"Gastrodin combined with electroacupuncture prevents the development of cerebral ischemia via rebalance of brain-derived neurotrophic factor and interleukin-6 in stroke model rats.","authors":"Min Liu, Rujie Gong, Lina Ding, Yingdi Zhao, Xili Yan, Liangbin Shi, Yegui Zhang, Zhiliang Xu","doi":"10.1097/WNR.0000000000002050","DOIUrl":"10.1097/WNR.0000000000002050","url":null,"abstract":"<p><p>Traditional Chinese medicine (TCM) has long been used to treat various diseases, including cerebral ischemia. The specific molecular mechanism of TCM in the treatment of cerebral ischemia, however, is still unclear. This study investigated the effects of gastrodin, electroacupuncture and their combination on cerebral ischemic rats. We used Nissl staining, immunohistochemical staining and immunoblotting to detect the expression changes of brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) in the frontal cortex. The results showed that the combination therapy of gastrodin and electroacupuncture significantly increased the number of Nissl-positive neurons and improved cell morphology compared with other groups. Mechanistically, we found that the combination of gastrodin and electroacupuncture treatment group can restore the abnormal morphology of neuronal cells caused by cerebral ischemia by rebalancing the expression levels of BDNF and IL-6. Our research indicates that gastrodin combined with electroacupuncture has a significant protective effect on cerebral ischemic injury in rats, possibly by regulating the expression of BDNF and IL-6. This combination therapy is superior to single-drug or electroacupuncture therapy.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-05-15DOI: 10.1097/WNR.0000000000002045
Yi-Jing Jiang, Ping-Hong Lai, Xin Huang
Age-related macular degeneration (AMD) is a prevalent disease leading to severe visual impairment in the elderly population. Despite this, the pathogenesis of AMD remains largely unexplored. The application of resting-state functional MRI (rs-fMRI) allows for the detection of coherent intrinsic brain activities along with the interactions taking place between the two hemispheres. In the frame of our study, we utilize voxel-mirrored homotopic connectivity (VMHC) as an rs-fMRI method to carry out a comparative analysis of functional homotopy between the two hemispheres with the aim of further understanding the pathogenesis of AMD patients. In our study, we utilized the VMHC method to explore levels of brain activity in individuals diagnosed with AMD, planning to investigate potential links with their clinical characteristics. We extended our invitation to 20 AMD patients and 20 healthy controls from Jiangxi Provincial People's Hospital to participate in this research. rs-fMRIs were captured for each participant, and associated neural activity levels were examined using the VMHC method. Remarkably, our comparative examination with the healthy control group revealed significantly reduced VMHC in the cuneus, superior occipital lobe, precentral gyrus, and superior parietal lobule in the patient cohort. Utilizing the VMHC method allows us to identify discrepancies in the visual pathways of AMD patients compared with standard controls, potentially explaining the common challenges among AMD patients with object recognition, face recognition, and reading.
{"title":"Interhemispheric functional in age-related macular degeneration patient: a resting-state functional MRI study.","authors":"Yi-Jing Jiang, Ping-Hong Lai, Xin Huang","doi":"10.1097/WNR.0000000000002045","DOIUrl":"10.1097/WNR.0000000000002045","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is a prevalent disease leading to severe visual impairment in the elderly population. Despite this, the pathogenesis of AMD remains largely unexplored. The application of resting-state functional MRI (rs-fMRI) allows for the detection of coherent intrinsic brain activities along with the interactions taking place between the two hemispheres. In the frame of our study, we utilize voxel-mirrored homotopic connectivity (VMHC) as an rs-fMRI method to carry out a comparative analysis of functional homotopy between the two hemispheres with the aim of further understanding the pathogenesis of AMD patients. In our study, we utilized the VMHC method to explore levels of brain activity in individuals diagnosed with AMD, planning to investigate potential links with their clinical characteristics. We extended our invitation to 20 AMD patients and 20 healthy controls from Jiangxi Provincial People's Hospital to participate in this research. rs-fMRIs were captured for each participant, and associated neural activity levels were examined using the VMHC method. Remarkably, our comparative examination with the healthy control group revealed significantly reduced VMHC in the cuneus, superior occipital lobe, precentral gyrus, and superior parietal lobule in the patient cohort. Utilizing the VMHC method allows us to identify discrepancies in the visual pathways of AMD patients compared with standard controls, potentially explaining the common challenges among AMD patients with object recognition, face recognition, and reading.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-05-17DOI: 10.1097/WNR.0000000000002051
Blaine E Weiss, Susan D Kraner, Irina A Artiushin, Christopher M Norris
Hyperactivation of the Ca2+/calmodulin-dependent phosphatase calcineurin (CN) is observed in reactive astrocytes associated with neuroinflammation and progressive degenerative diseases, like Alzheimer's disease. Apart from key transcription factors (e.g. nuclear factor of activated t cells and nuclear factor-κB) very few other CN-dependent pathways have been studied in astrocytes. The hemichannel protein, connexin 43 (Cx43) is found at high levels in astrocytes and contains a CN-sensitive Ser residue near its carboxy terminus. CN-dependent dephosphorylation of Cx43 has been reported in primary astrocytes treated with injurious stimuli, but much remains unknown about CN/Cx43 interactions in the context of neuroinflammation and disease. Western blots were used to assess total Cx43 and dephosphorylated Cx43 subtypes in rat embryonic primary astrocytes treated with a hyperactive CN fragment (ΔCN, via adenovirus), or with a proinflammatory cytokine cocktail. Under similar treatment conditions, an ethidium bromide (EtBr) uptake assay was used to assess membrane permeability. Effects of ΔCN and cytokines were tested in the presence or absence of the CN inhibitor, cyclosporin A. A connexin inhibitor, carbenoxolone was also used in EtBr assays to assess the involvement of connexins in membrane permeability. Treatment with ΔCN or cytokines increased dephosphorylated Cx43 levels in conjunction with increased membrane permeability (elevated EtBr uptake). Effects of ΔCN or cytokine treatment were blocked by cyclosporine A. Treatment-induced changes in EtBr uptake were also inhibited by carbenoxolone. The results suggest that Cx43 hemichannels could be an important mechanism through which astrocytic CN disrupts neurologic function associated with neurodegenerative disease.
在与神经炎症和渐进性退行性疾病(如阿尔茨海默病)相关的反应性星形胶质细胞中,可以观察到 Ca2+/calmodulin 依赖性磷酸酶钙调磷酸酶(CN)的过度激活。除了关键的转录因子(如活化 t 细胞核因子和核因子-κB)外,很少有人研究过星形胶质细胞中其他依赖 CN 的途径。在星形胶质细胞中发现了高水平的半通道蛋白--连接蛋白 43(Cx43),其羧基末端附近含有对 CN 敏感的 Ser 残基。据报道,在受到损伤性刺激的原代星形胶质细胞中,Cx43会发生CN依赖性去磷酸化,但在神经炎症和疾病的背景下,CN/Cx43之间的相互作用仍有很多未知之处。研究人员使用 Western 印迹来评估用高活性 CN 片段(ΔCN,通过腺病毒)或促炎细胞因子鸡尾酒处理的大鼠胚胎原代星形胶质细胞中的总 Cx43 和去磷酸化 Cx43 亚型。在类似的处理条件下,使用溴化乙锭(EtBr)摄取试验来评估膜通透性。在有或没有氯化萘抑制剂环孢素 A 的情况下,测试了ΔCN 和细胞因子的影响。用ΔCN或细胞因子处理会增加去磷酸化的Cx43水平,同时增加膜通透性(EtBr摄取量增加)。环孢素 A 可阻断ΔCN 或细胞因子处理的影响。这些结果表明,Cx43 半通道可能是星形胶质细胞 CN 干扰与神经退行性疾病相关的神经功能的重要机制。
{"title":"Elevated calcineurin activity in primary astrocytes leads to the dephosphorylation of connexin 43 in conjunction with increased membrane permeability.","authors":"Blaine E Weiss, Susan D Kraner, Irina A Artiushin, Christopher M Norris","doi":"10.1097/WNR.0000000000002051","DOIUrl":"10.1097/WNR.0000000000002051","url":null,"abstract":"<p><p>Hyperactivation of the Ca2+/calmodulin-dependent phosphatase calcineurin (CN) is observed in reactive astrocytes associated with neuroinflammation and progressive degenerative diseases, like Alzheimer's disease. Apart from key transcription factors (e.g. nuclear factor of activated t cells and nuclear factor-κB) very few other CN-dependent pathways have been studied in astrocytes. The hemichannel protein, connexin 43 (Cx43) is found at high levels in astrocytes and contains a CN-sensitive Ser residue near its carboxy terminus. CN-dependent dephosphorylation of Cx43 has been reported in primary astrocytes treated with injurious stimuli, but much remains unknown about CN/Cx43 interactions in the context of neuroinflammation and disease. Western blots were used to assess total Cx43 and dephosphorylated Cx43 subtypes in rat embryonic primary astrocytes treated with a hyperactive CN fragment (ΔCN, via adenovirus), or with a proinflammatory cytokine cocktail. Under similar treatment conditions, an ethidium bromide (EtBr) uptake assay was used to assess membrane permeability. Effects of ΔCN and cytokines were tested in the presence or absence of the CN inhibitor, cyclosporin A. A connexin inhibitor, carbenoxolone was also used in EtBr assays to assess the involvement of connexins in membrane permeability. Treatment with ΔCN or cytokines increased dephosphorylated Cx43 levels in conjunction with increased membrane permeability (elevated EtBr uptake). Effects of ΔCN or cytokine treatment were blocked by cyclosporine A. Treatment-induced changes in EtBr uptake were also inhibited by carbenoxolone. The results suggest that Cx43 hemichannels could be an important mechanism through which astrocytic CN disrupts neurologic function associated with neurodegenerative disease.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11279532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danshensu, also known as salvianic acid A, is a primary active compound extracted from a traditional Chinese herb Danshen (Salvia miltiorrhiza). While its antioxidative and neuroprotective effects are well-documented, the underlying mechanisms are poorly understood. In this study, we sought out to investigate if and how Danshensu modulates neuronal excitability and voltage-gated ionic currents in the central nervous system. We prepared brain slices of the mouse brainstem and performed patch-clamp recording in bushy cells in the anteroventral cochlear nucleus, with or without Danshensu incubation for 1 h. QX-314 was used internally to block Na+ current, while tetraethylammonium and 4-aminopyridine were used to isolate different subtypes of K+ current. We found that Danshensu of 100 μm decreased the input resistance of bushy cells by approximately 60% and shifted the voltage threshold of spiking positively by approximately 7 mV, resulting in significantly reduced excitability. Furthermore, we found this reduced excitability by Danshensu was caused by enhanced voltage-gated K+ currents in these neurons, including both low voltage-activated IK,A, by approximately 100%, and high voltage-activated IK,dr, by approximately 30%. Lastly, we found that the effect of Danshensu on K+ currents was dose-dependent in that no enhancement was found for Danshensu of 50 μm and Danshensu of 200 μm failed to cause significantly more enhancement on K+ currents when compared to that of 100 μm. We found that Danshensu reduced neuronal excitability in the central nervous system by enhancing voltage-gated K+ currents, providing mechanistic support for its neuroprotective effect widely seen in vivo.
{"title":"Danshensu reduces neuronal excitability by enhancing potassium currents in bushy cells in the mouse cochlear nucleus.","authors":"Mengfan Xu, Liqin Wang, Geng-Lin Li, Zheng-Quan Tang","doi":"10.1097/WNR.0000000000002047","DOIUrl":"10.1097/WNR.0000000000002047","url":null,"abstract":"<p><p>Danshensu, also known as salvianic acid A, is a primary active compound extracted from a traditional Chinese herb Danshen (Salvia miltiorrhiza). While its antioxidative and neuroprotective effects are well-documented, the underlying mechanisms are poorly understood. In this study, we sought out to investigate if and how Danshensu modulates neuronal excitability and voltage-gated ionic currents in the central nervous system. We prepared brain slices of the mouse brainstem and performed patch-clamp recording in bushy cells in the anteroventral cochlear nucleus, with or without Danshensu incubation for 1 h. QX-314 was used internally to block Na+ current, while tetraethylammonium and 4-aminopyridine were used to isolate different subtypes of K+ current. We found that Danshensu of 100 μm decreased the input resistance of bushy cells by approximately 60% and shifted the voltage threshold of spiking positively by approximately 7 mV, resulting in significantly reduced excitability. Furthermore, we found this reduced excitability by Danshensu was caused by enhanced voltage-gated K+ currents in these neurons, including both low voltage-activated IK,A, by approximately 100%, and high voltage-activated IK,dr, by approximately 30%. Lastly, we found that the effect of Danshensu on K+ currents was dose-dependent in that no enhancement was found for Danshensu of 50 μm and Danshensu of 200 μm failed to cause significantly more enhancement on K+ currents when compared to that of 100 μm. We found that Danshensu reduced neuronal excitability in the central nervous system by enhancing voltage-gated K+ currents, providing mechanistic support for its neuroprotective effect widely seen in vivo.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mitochondria play a crucial role in maintaining cellular energy supply and serve as a source of energy for repairing nerve damage following a stroke. Given that exercise has the potential to enhance energy metabolism, investigating the impact of exercise on mitochondrial function provides a plausible mechanism for stroke treatment. In our study, we established the middle cerebral artery occlusion (MCAO) model in Sprague-Dawley rats and implemented early exercise intervention. Neurological severity scores, beam-walking test score, and weight were used to evaluate neurological function. The volume of cerebral infarction was measured by MRI. Nerve cell apoptosis was detected by TUNEL staining. Mitochondrial morphology and structure were detected by mitochondrial electron microscopy. Mitochondrial function was assessed using membrane potential and ATP measurements. Western blotting was used to detect the protein expression of AMPK/PGC-1α/GLUT4. Through the above experiments, we found that early exercise improved neurological function in rats after MCAO, reduced cerebral infarction volume and neuronal apoptosis, promoted the recovery of mitochondrial morphology and function. We further examined the protein expression of AMPK/PGC-1α/GLUT4 signaling pathway and confirmed that early exercise was able to increase its expression. Therefore, we suggest that early exercise initiated the AMPK/PGC-1α/GLUT4 signaling pathway, restoring mitochondrial function and augmenting energy supply. This, in turn, effectively improved both nerve and body function in rats following ischemic stroke.
线粒体在维持细胞能量供应方面起着至关重要的作用,是中风后修复神经损伤的能量来源。鉴于运动具有增强能量代谢的潜力,研究运动对线粒体功能的影响为中风治疗提供了一种可信的机制。在我们的研究中,我们在 Sprague-Dawley 大鼠中建立了大脑中动脉闭塞(MCAO)模型,并实施了早期运动干预。神经严重程度评分、横梁行走测试评分和体重用于评估神经功能。核磁共振成像测量了脑梗塞的体积。通过 TUNEL 染色检测神经细胞凋亡。线粒体电子显微镜检测线粒体形态和结构。线粒体功能通过膜电位和 ATP 测量进行评估。用 Western 印迹法检测 AMPK/PGC-1α/GLUT4 的蛋白表达。通过以上实验,我们发现早期运动能改善 MCAO 后大鼠的神经功能,减少脑梗死体积和神经元凋亡,促进线粒体形态和功能的恢复。我们进一步检测了AMPK/PGC-1α/GLUT4信号通路的蛋白表达,证实早期运动能够增加其表达。因此,我们认为早期运动启动了AMPK/PGC-1α/GLUT4信号通路,恢复了线粒体功能并增加了能量供应。这反过来又有效改善了缺血性中风后大鼠的神经和身体功能。
{"title":"The activation of AMPK/PGC-1α/GLUT4 signaling pathway through early exercise improves mitochondrial function and mitigates ischemic brain damage.","authors":"Xinyue Wu, Chen Li, Changkai Ke, Chuan Huang, Bingchen Pan, Chunxiao Wan","doi":"10.1097/WNR.0000000000002048","DOIUrl":"10.1097/WNR.0000000000002048","url":null,"abstract":"<p><p>Mitochondria play a crucial role in maintaining cellular energy supply and serve as a source of energy for repairing nerve damage following a stroke. Given that exercise has the potential to enhance energy metabolism, investigating the impact of exercise on mitochondrial function provides a plausible mechanism for stroke treatment. In our study, we established the middle cerebral artery occlusion (MCAO) model in Sprague-Dawley rats and implemented early exercise intervention. Neurological severity scores, beam-walking test score, and weight were used to evaluate neurological function. The volume of cerebral infarction was measured by MRI. Nerve cell apoptosis was detected by TUNEL staining. Mitochondrial morphology and structure were detected by mitochondrial electron microscopy. Mitochondrial function was assessed using membrane potential and ATP measurements. Western blotting was used to detect the protein expression of AMPK/PGC-1α/GLUT4. Through the above experiments, we found that early exercise improved neurological function in rats after MCAO, reduced cerebral infarction volume and neuronal apoptosis, promoted the recovery of mitochondrial morphology and function. We further examined the protein expression of AMPK/PGC-1α/GLUT4 signaling pathway and confirmed that early exercise was able to increase its expression. Therefore, we suggest that early exercise initiated the AMPK/PGC-1α/GLUT4 signaling pathway, restoring mitochondrial function and augmenting energy supply. This, in turn, effectively improved both nerve and body function in rats following ischemic stroke.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05Epub Date: 2024-04-29DOI: 10.1097/WNR.0000000000002042
Guoqiang Du, Zixi Yang, Yin Wen, Xusheng Li, Wenhong Zhong, Zhuo Li, Shiying Zhang, Ensi Luo, Hongguang Ding, Weifeng Li
Heat stroke induced cerebral damage via neuroinflammation. This study aimed to approach whether heat stress would promote NOD-like receptor protein 3 (NLRP3) inflammasome via reactive oxygen species (ROS). The mice were randomly divided into the sham group, the heat stress group, and the heat stress + TEMPOL (ROS scavenger) group. And the NLRP3 -/- mice were applied and divided into the NLRP3 -/- + sham group and the NLRP3 -/- + heat stress group. Furthermore, the BV2 cells were divided into four groups following the intervention measures: the heat stress + TEMPOL group, the heat stress + Z-VAD-FMK (caspase-1 inhibitor) group, the heat stress group, and the control group. ROS levels were examined. The expression levels of NLRP3, caspase-1, IL-1β, and IL-18 were detected by western blotting and double immunofluorescence. We found that heat stress attack induced excessive ROS in microglia and subsequently activated NLRP3 inflammasome in both mice and BV2 cells. When ROS scavenged, the expression level of NLRP3 was downregulated. Furthermore, with NLRP3 inflammasome activation, the expression levels of caspase-1, IL-1β, and IL-18 were increased. In NLRP3 -/- mice, however, the caspase-1, IL-1β, and IL-18 were significantly declined. Further experiments showed that pretreatment of caspase-1 inhibitor decreased the expression levels of IL-1β and IL-18. These results suggest that heat stress attack caused neuroinflammation via excessive ROS activating the NLRP3 inflammasome in microglia cells.
{"title":"Heat stress induces IL-1β and IL-18 overproduction via ROS-activated NLRP3 inflammasome: implication in neuroinflammation in mice with heat stroke.","authors":"Guoqiang Du, Zixi Yang, Yin Wen, Xusheng Li, Wenhong Zhong, Zhuo Li, Shiying Zhang, Ensi Luo, Hongguang Ding, Weifeng Li","doi":"10.1097/WNR.0000000000002042","DOIUrl":"10.1097/WNR.0000000000002042","url":null,"abstract":"<p><p>Heat stroke induced cerebral damage via neuroinflammation. This study aimed to approach whether heat stress would promote NOD-like receptor protein 3 (NLRP3) inflammasome via reactive oxygen species (ROS). The mice were randomly divided into the sham group, the heat stress group, and the heat stress + TEMPOL (ROS scavenger) group. And the NLRP3 -/- mice were applied and divided into the NLRP3 -/- + sham group and the NLRP3 -/- + heat stress group. Furthermore, the BV2 cells were divided into four groups following the intervention measures: the heat stress + TEMPOL group, the heat stress + Z-VAD-FMK (caspase-1 inhibitor) group, the heat stress group, and the control group. ROS levels were examined. The expression levels of NLRP3, caspase-1, IL-1β, and IL-18 were detected by western blotting and double immunofluorescence. We found that heat stress attack induced excessive ROS in microglia and subsequently activated NLRP3 inflammasome in both mice and BV2 cells. When ROS scavenged, the expression level of NLRP3 was downregulated. Furthermore, with NLRP3 inflammasome activation, the expression levels of caspase-1, IL-1β, and IL-18 were increased. In NLRP3 -/- mice, however, the caspase-1, IL-1β, and IL-18 were significantly declined. Further experiments showed that pretreatment of caspase-1 inhibitor decreased the expression levels of IL-1β and IL-18. These results suggest that heat stress attack caused neuroinflammation via excessive ROS activating the NLRP3 inflammasome in microglia cells.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05Epub Date: 2024-04-29DOI: 10.1097/WNR.0000000000002041
Qing-Na Hao, Xiao-Bo Xue, Heng Zhou, Zhao-Li Hu
Pyroptosis, a form of programmed cell death, drives inflammation in the context of cerebral ischemia/reperfusion. The molecular mechanism of pyroptosis underlying ischemia/reperfusion, however, is not fully understood. The transient middle cerebral artery occlusion was applied to wild-type and caspase-1 knockout mice. 2,3,5-Triphenyltetrazolium chloride-staining and immunohistochemistry were used to identify the ischemic region, and western blot and immunofluorescence for the examination of neuronal pyroptosis. The expression of inflammatory factors and the behavioral function assessments were further conducted to examine the effects of caspase-1 knockout on protection against ischemia/reperfusion injury. Ischemia/reperfusion injury increased pyroptosis-related signals represented by the overexpression of pyroptosis-related proteins including caspase-1 and gasdermin D (GSDMD). Meanwhile, the number of GSDMD positive neurons increased in penumbra by immunofluorescence staining. Compared with wild-type mice, those with caspase-1 knockout exhibited decreased levels of pyroptosis-related proteins following ischemia/reperfusion. Furthermore, ischemia/reperfusion attack-induced brain infarction, cerebral edema, inflammatory factors, and neurological outcomes were partially improved in caspase-1 knockout mice. The data indicate that pyroptosis participates in ischemia/reperfusion induced-damage, and the caspase-1 might be involved, it provides some new insights into the molecular mechanism of ischemia.
在脑缺血/再灌注的情况下,嗜热细胞增多症(一种程序性细胞死亡)会引发炎症。然而,缺血/再灌注所引发的裂解热的分子机制尚未完全明了。对野生型小鼠和 caspase-1 基因敲除小鼠进行瞬时大脑中动脉闭塞实验。采用 2,3,5-三苯基氯化四氮唑染色法和免疫组化法确定缺血区域,并用 Western 印迹法和免疫荧光法检测神经元热解。为了研究caspase-1基因敲除对缺血再灌注损伤的保护作用,还进一步进行了炎症因子表达和行为功能评估。缺血/再灌注损伤增加了热蛋白沉积相关信号,表现为包括caspase-1和gasdermin D(GSDMD)在内的热蛋白沉积相关蛋白的过度表达。同时,通过免疫荧光染色,半影中 GSDMD 阳性神经元的数量增加。与野生型小鼠相比,caspase-1基因敲除的小鼠在缺血/再灌注后表现出热休克相关蛋白水平的下降。此外,缺血再灌注诱发的脑梗塞、脑水肿、炎症因子和神经系统结果在caspase-1基因敲除小鼠中得到了部分改善。这些数据表明,热蛋白沉积参与了缺血/再灌注诱导的损伤,而caspase-1可能参与其中,这为缺血的分子机制提供了一些新的见解。
{"title":"Caspase-1 deletion reveals pyroptosis participates in neural damage induced by cerebral ischemia/reperfusion in tMCAO model mice.","authors":"Qing-Na Hao, Xiao-Bo Xue, Heng Zhou, Zhao-Li Hu","doi":"10.1097/WNR.0000000000002041","DOIUrl":"10.1097/WNR.0000000000002041","url":null,"abstract":"<p><p>Pyroptosis, a form of programmed cell death, drives inflammation in the context of cerebral ischemia/reperfusion. The molecular mechanism of pyroptosis underlying ischemia/reperfusion, however, is not fully understood. The transient middle cerebral artery occlusion was applied to wild-type and caspase-1 knockout mice. 2,3,5-Triphenyltetrazolium chloride-staining and immunohistochemistry were used to identify the ischemic region, and western blot and immunofluorescence for the examination of neuronal pyroptosis. The expression of inflammatory factors and the behavioral function assessments were further conducted to examine the effects of caspase-1 knockout on protection against ischemia/reperfusion injury. Ischemia/reperfusion injury increased pyroptosis-related signals represented by the overexpression of pyroptosis-related proteins including caspase-1 and gasdermin D (GSDMD). Meanwhile, the number of GSDMD positive neurons increased in penumbra by immunofluorescence staining. Compared with wild-type mice, those with caspase-1 knockout exhibited decreased levels of pyroptosis-related proteins following ischemia/reperfusion. Furthermore, ischemia/reperfusion attack-induced brain infarction, cerebral edema, inflammatory factors, and neurological outcomes were partially improved in caspase-1 knockout mice. The data indicate that pyroptosis participates in ischemia/reperfusion induced-damage, and the caspase-1 might be involved, it provides some new insights into the molecular mechanism of ischemia.</p>","PeriodicalId":19213,"journal":{"name":"Neuroreport","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}