Delirium is a common complication observed in intensive care units (ICUs). Propofol is one of the most widely used sedatives and is believed to be closely connected with the incidence of delirium. The study was carried out to explore the relationship between delirium and the average rate of propofol infusion.
Methods
Patients who underwent invasive mechanical ventilation (IMV) while receiving propofol from the Medical Information Mart for Intensive Care IV (MIMIC IV) database were included in the study. The primary outcome was to identify the potential risk factors for the incidence of delirium and investigate the relationship between the average rate of propofol infusion and the incidence of delirium. The secondary outcome was to further analyze the relationship by subgroup analysis. Propensity score matching (PSM) was employed to minimize bias.
Results
A total of 16,956 patients (delirium: 5805; control: 11,151) were ultimately included in the study after PSM. The median diagnostic time of delirium was 18 h. An average propofol infusion rate ≥ 20 μg/(kg*h) during the initial 18 h was found to be independently significant [OR = 1.84, 95% CI = (1.72, 1.98), p < 0.001], while an average propofol infusion rate ≤ 40 μg/(kg*h) in the first hour showed no statistically significant difference in the incidence of delirium [OR = 0.95, 95% CI = (0.88, 1.02), p = 0.163]. Besides, an average propofol infusion rate ≥ 20 μg/(kg*h) was also found to be statistically significant in all the subgroup analyses.
Conclusion
An average propofol infusion rate ≥ 20 μg/(kg*h) during the initial 18 h was identified as an independent risk factor for delirium, suggesting that the accumulation of propofol might be associated with an increased incidence of delirium.
{"title":"The Relationship Between the Average Infusion Rate of Propofol and the Incidence of Delirium During Invasive Mechanical Ventilation: A Retrospective Study Based on the MIMIC IV Database","authors":"Qi-Yue Ge, Chao Zheng, Xiao-Bin Song, Zhuang-Zhuang Cong, Jing Luo, Hao-Tian Zheng, Peng-Long Zhao, Yan-Qing Wang, Bing-Wei Chen, Yi Shen","doi":"10.1111/cns.70273","DOIUrl":"https://doi.org/10.1111/cns.70273","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Delirium is a common complication observed in intensive care units (ICUs). Propofol is one of the most widely used sedatives and is believed to be closely connected with the incidence of delirium. The study was carried out to explore the relationship between delirium and the average rate of propofol infusion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients who underwent invasive mechanical ventilation (IMV) while receiving propofol from the Medical Information Mart for Intensive Care IV (MIMIC IV) database were included in the study. The primary outcome was to identify the potential risk factors for the incidence of delirium and investigate the relationship between the average rate of propofol infusion and the incidence of delirium. The secondary outcome was to further analyze the relationship by subgroup analysis. Propensity score matching (PSM) was employed to minimize bias.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 16,956 patients (delirium: 5805; control: 11,151) were ultimately included in the study after PSM. The median diagnostic time of delirium was 18 h. An average propofol infusion rate ≥ 20 μg/(kg*h) during the initial 18 h was found to be independently significant [OR = 1.84, 95% CI = (1.72, 1.98), <i>p</i> < 0.001], while an average propofol infusion rate ≤ 40 μg/(kg*h) in the first hour showed no statistically significant difference in the incidence of delirium [OR = 0.95, 95% CI = (0.88, 1.02), <i>p</i> = 0.163]. Besides, an average propofol infusion rate ≥ 20 μg/(kg*h) was also found to be statistically significant in all the subgroup analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>An average propofol infusion rate ≥ 20 μg/(kg*h) during the initial 18 h was identified as an independent risk factor for delirium, suggesting that the accumulation of propofol might be associated with an increased incidence of delirium.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peter M. Andrew, Jeremy A. MacMahon, Xiuzhen Liu, Naomi H. Saito, Kyle E. Berger, Julia E. Morgan, Ashish Dhir, Danielle J. Harvey, Hilary S. McCarren, Michael A. Rogawski, Pamela J. Lein
Aims
Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP-induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman-induced SE.
Methods
Soman-intoxicated male rats with robust seizure behavior and high-amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses.
Results
Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure activity. The combination therapy also significantly reduced soman-induced neurodegeneration and neuroinflammation compared to 2 doses of midazolam. High but not low dose ALLO was associated with transitory and reversible respiratory compromise during the 1 h period after dosing.
Conclusions
Treatment with midazolam followed by ALLO was more effective than 2 doses of midazolam in suppressing benzodiazepine-refractory, soman-induced SE, and in mitigating its acute neuropathological consequences.
目的 人和动物急性中毒后会出现持续状态癫痫（SE），并迅速对苯二氮卓类药物产生难治性。我们比较了咪达唑仑（目前治疗 OP 诱导的 SE 的标准药物）与咪达唑仑和异丙孕酮（ALO）联合疗法在索曼诱导的 SE 大鼠模型中的抗癫痫疗效。 方法 对具有强烈癫痫发作行为和高振幅脑电图（EEG）活动的索曼中毒雄性大鼠，在癫痫发作开始 20 分钟后给予咪达唑仑（0.65 毫克，静注），10 分钟后再给予第二剂量的咪达唑仑或 ALLO（12 或 24 毫克/千克，静注）。治疗后 4 小时监测癫痫发作行为和脑电图。监测期结束后收集大脑进行组织学分析。 结果 接受 2 次咪达唑仑治疗的动物表现出持续的 SE。连续服用咪达唑仑和 ALLO 可抑制电图癫痫发作活动。与两种剂量的咪达唑仑相比，联合疗法还能明显减少索曼诱导的神经变性和神经炎症。在用药后的 1 小时内，高剂量 ALLO 与短暂的、可逆的呼吸衰竭有关，但与低剂量 ALLO 无关。 结论 在抑制苯二氮卓难治性索曼诱导的SE和减轻其急性神经病理学后果方面，使用咪达唑仑治疗后再使用ALO比使用两种剂量的咪达唑仑更有效。
{"title":"Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman-Induced Status Epilepticus in Male Rats","authors":"Peter M. Andrew, Jeremy A. MacMahon, Xiuzhen Liu, Naomi H. Saito, Kyle E. Berger, Julia E. Morgan, Ashish Dhir, Danielle J. Harvey, Hilary S. McCarren, Michael A. Rogawski, Pamela J. Lein","doi":"10.1111/cns.70215","DOIUrl":"https://doi.org/10.1111/cns.70215","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP-induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman-induced SE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Soman-intoxicated male rats with robust seizure behavior and high-amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure activity. The combination therapy also significantly reduced soman-induced neurodegeneration and neuroinflammation compared to 2 doses of midazolam. High but not low dose ALLO was associated with transitory and reversible respiratory compromise during the 1 h period after dosing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Treatment with midazolam followed by ALLO was more effective than 2 doses of midazolam in suppressing benzodiazepine-refractory, soman-induced SE, and in mitigating its acute neuropathological consequences.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70215","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143521999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acupuncture significantly improves cognitive dysfunction in rats with chronic cerebral ischemia. However, the underlying signaling pathways remain unclear. This study investigates the role of the CKLF1/HIF-1α/VEGF/Notch1 signaling pathway in the acupuncture-mediated improvement of cognitive function in rats with chronic cerebral ischemia.
Methods
Male SD rats were randomly divided into the normal control group, sham-operated group, 2-VO model group, 2-VO + acupuncture group, and 2-VO + Ginaton group (Ginkgo biloba extract 14.4 mg/kg/day), with 10 rats in each group. The 2-VO + acupuncture group received acupuncture at the Shuigou, Baihui, bilateral Fengchi, and bilateral Zusanli points for 14 consecutive sessions over 2 weeks. The rats' memory function was assessed using the Morris water maze and novel object recognition tests. Cerebral blood volume changes were measured using laser speckle imaging. Ultrastructural changes in microvessels were observed via transmission electron microscopy. Neuronal and myelin alterations were evaluated using HE staining, Nissl staining, and LFB myelin staining. The expression levels of CKLF1, CCR5, HIF-1α, VEGF, and Notch1 proteins were measured using Western blot, and multiple immunofluorescence staining was performed to assess the colocalization of CKLF1 and neurons.
Results
Compared with the 2-VO model group, acupuncture treatment reduced the latency period and increased the number of platform crossings in the Morris water maze test, and the 2-VO model group had a higher recognition index in the novel object recognition test. We found that acupuncture improved the condition of endothelial cells, repaired the morphology of the vascular lumen, and alleviated astrocyte edema. We also showed that acupuncture could ameliorate pathological damage in rats with chronic cerebral ischemia. Moreover, acupuncture reduced the expression of CKLF1, CCR5, and HIF-1α proteins in the hippocampus, decreased the fluorescence intensity of CKLF1 expression, and increased the fluorescence intensity of neurons in the hippocampal CA1 region.
Conclusion
Acupuncture may exert neuroprotective effects and improve cognitive dysfunction caused by chronic cerebral ischemia by regulating the CKLF1/HIF-1α/VEGF/Notch1 pathway to inhibit inflammatory factors and increase cerebral blood flow.
{"title":"Acupuncture Improves Chronic Cerebral Ischemia by Inhibiting the CKLF1/HIF-1α/VEGF/Notch1 Signaling Pathway","authors":"Jilong Guo, Guangqi Wang, Tian Liu, Jianjun Zhang, Qinqing Li, Yousong Zhu, Huijuan Luo","doi":"10.1111/cns.70246","DOIUrl":"https://doi.org/10.1111/cns.70246","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Acupuncture significantly improves cognitive dysfunction in rats with chronic cerebral ischemia. However, the underlying signaling pathways remain unclear. This study investigates the role of the CKLF1/HIF-1α/VEGF/Notch1 signaling pathway in the acupuncture-mediated improvement of cognitive function in rats with chronic cerebral ischemia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male SD rats were randomly divided into the normal control group, sham-operated group, 2-VO model group, 2-VO + acupuncture group, and 2-VO + Ginaton group (<i>Ginkgo biloba</i> extract 14.4 mg/kg/day), with 10 rats in each group. The 2-VO + acupuncture group received acupuncture at the Shuigou, Baihui, bilateral Fengchi, and bilateral Zusanli points for 14 consecutive sessions over 2 weeks. The rats' memory function was assessed using the Morris water maze and novel object recognition tests. Cerebral blood volume changes were measured using laser speckle imaging. Ultrastructural changes in microvessels were observed via transmission electron microscopy. Neuronal and myelin alterations were evaluated using HE staining, Nissl staining, and LFB myelin staining. The expression levels of CKLF1, CCR5, HIF-1α, VEGF, and Notch1 proteins were measured using Western blot, and multiple immunofluorescence staining was performed to assess the colocalization of CKLF1 and neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with the 2-VO model group, acupuncture treatment reduced the latency period and increased the number of platform crossings in the Morris water maze test, and the 2-VO model group had a higher recognition index in the novel object recognition test. We found that acupuncture improved the condition of endothelial cells, repaired the morphology of the vascular lumen, and alleviated astrocyte edema. We also showed that acupuncture could ameliorate pathological damage in rats with chronic cerebral ischemia. Moreover, acupuncture reduced the expression of CKLF1, CCR5, and HIF-1α proteins in the hippocampus, decreased the fluorescence intensity of CKLF1 expression, and increased the fluorescence intensity of neurons in the hippocampal CA1 region.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Acupuncture may exert neuroprotective effects and improve cognitive dysfunction caused by chronic cerebral ischemia by regulating the CKLF1/HIF-1α/VEGF/Notch1 pathway to inhibit inflammatory factors and increase cerebral blood flow.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Valproic acid (VPA) exposure during the gestational period has been found to impair the cognition of the offspring. The study aimed to investigate whether VPA leads to offspring cognitive impairment through disturbing interneuron development.
Methods
Pregnant mice were injected with VPA peritoneally to establish the prenatal VPA exposure model. Cortical interneurons were labeled with Rosa26-EYFP/− reporter mice activated by Nkx2.1-Cre. Interneuron subtypes both in the cortex and the hippocampus were detected by immunofluorescence. A battery of behavioral tests was conducted on postnatal Day 28 to assess the cognition and anxiety of the offspring. RNA-Seq analysis was performed to investigate the underlying molecular mechanisms.
Results
We found that after the exposure to VPA, all the groups of the male offspring exerted anxiety. When VPA injection was performed on gestational Day 12.5, the memory of the offspring was impaired. Mechanistically, the distribution of cortical interneurons was disrupted. The distribution of interneuron subtypes was abnormal both in the cortex and hippocampus after the VPA exposure, which affected the somatostatin-positive neurons but not the parvalbumin-positive neurons, indicating the effects of VPA were subtype specific. Biological processes related to ion homeostasis were greatly changed after VPA exposure.
Conclusion
Prenatal VPA exposure during the neurogenic period impaired the cognition of the offspring by disrupting interneuron migration and differentiation. The study provides a novel perspective on the influence of VPA over neurodevelopment.
{"title":"Prenatal Valproic Acid Exposure Impairs Offspring Cognition Through Disturbing Interneuron Development","authors":"Kaiyuan Shen, Yandong Zhang, Yunyun Huang, Yunli Xie, Jing Ding, Xin Wang","doi":"10.1111/cns.70303","DOIUrl":"https://doi.org/10.1111/cns.70303","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Valproic acid (VPA) exposure during the gestational period has been found to impair the cognition of the offspring. The study aimed to investigate whether VPA leads to offspring cognitive impairment through disturbing interneuron development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Pregnant mice were injected with VPA peritoneally to establish the prenatal VPA exposure model. Cortical interneurons were labeled with Rosa26-EYFP/− reporter mice activated by Nkx2.1-Cre. Interneuron subtypes both in the cortex and the hippocampus were detected by immunofluorescence. A battery of behavioral tests was conducted on postnatal Day 28 to assess the cognition and anxiety of the offspring. RNA-Seq analysis was performed to investigate the underlying molecular mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that after the exposure to VPA, all the groups of the male offspring exerted anxiety. When VPA injection was performed on gestational Day 12.5, the memory of the offspring was impaired. Mechanistically, the distribution of cortical interneurons was disrupted. The distribution of interneuron subtypes was abnormal both in the cortex and hippocampus after the VPA exposure, which affected the somatostatin-positive neurons but not the parvalbumin-positive neurons, indicating the effects of VPA were subtype specific. Biological processes related to ion homeostasis were greatly changed after VPA exposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Prenatal VPA exposure during the neurogenic period impaired the cognition of the offspring by disrupting interneuron migration and differentiation. The study provides a novel perspective on the influence of VPA over neurodevelopment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70303","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sepsis-associated encephalopathy (SAE) leads to increased mortality. Hydrogen (H2) has been proven to be effective in protecting against SAE. This study aimed to investigate the protective mechanism of a high concentration of H2 (HCH) (67%) against SAE.
Methods
A mouse sepsis model was established via cecal ligation and puncture (CLP). 67% H2 was inhaled for 1 h at 1 h and 6 h after the operation. First, mice were randomly divided into 5 groups: Sham, CLP, CLP + CQ (a mitophagy inhibitor), CLP + H2, and CLP + H2 + CQ. Seven-day survival, cognitive function, and hippocampal damage were assessed. Then, mice were randomly divided into four groups: Sham, CLP, CLP + UA (a mitophagy agonist), and CLP + H2. Seven-day survival was recorded, cognitive function was assessed via Y-maze and Morris water maze tests, and hippocampal damage was evaluated via Nissl staining. Phosphorylated tau, inflammatory factors, ATP, and antioxidant enzyme levels and mitochondrial membrane potential (MMP) were detected. Mitochondria were observed via transmission electron microscopy. The protein levels of the PINK1/Parkin pathway and STING-TBK-IRF3 pathway were detected via western blotting.
Results
HCH inhalation improves 7-day survival and cognitive function in septic mice and reduces brain tissue damage, proinflammatory cytokine levels, and phosphorylated tau levels. These effects were reversed by a mitophagy inhibitor. HCH significantly improves mitochondrial function, enhances PINK1/Parkin-mediated mitophagy, and reduces the activity of the STING-TBK-IRF3 pathway in brain tissue.
Conclusions
HCH inhalation effectively improved the survival rate of septic mice, alleviated SAE, and reduced tau phosphorylation. The mechanism may involve HCH enhancing PINK1/Parkin-mediated mitophagy, which inhibits the activity of the cGAS-STING-IRF3 pathway, thereby reducing neuroinflammation.
{"title":"High Concentration Hydrogen Protects Sepsis-Associated Encephalopathy by Enhancing Pink1/Parkin-Mediated Mitophagy and Inhibiting cGAS-STING-IRF3 Pathway","authors":"Yan Cui, Jianfeng Liu, Yu Song, Chen Chen, Yuehao Shen, Keliang Xie","doi":"10.1111/cns.70305","DOIUrl":"https://doi.org/10.1111/cns.70305","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sepsis-associated encephalopathy (SAE) leads to increased mortality. Hydrogen (H<sub>2</sub>) has been proven to be effective in protecting against SAE. This study aimed to investigate the protective mechanism of a high concentration of H<sub>2</sub> (HCH) (67%) against SAE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A mouse sepsis model was established via cecal ligation and puncture (CLP). 67% H<sub>2</sub> was inhaled for 1 h at 1 h and 6 h after the operation. First, mice were randomly divided into 5 groups: Sham, CLP, CLP + CQ (a mitophagy inhibitor), CLP + H<sub>2</sub>, and CLP + H<sub>2</sub> + CQ. Seven-day survival, cognitive function, and hippocampal damage were assessed. Then, mice were randomly divided into four groups: Sham, CLP, CLP + UA (a mitophagy agonist), and CLP + H<sub>2</sub>. Seven-day survival was recorded, cognitive function was assessed via Y-maze and Morris water maze tests, and hippocampal damage was evaluated via Nissl staining. Phosphorylated tau, inflammatory factors, ATP, and antioxidant enzyme levels and mitochondrial membrane potential (MMP) were detected. Mitochondria were observed via transmission electron microscopy. The protein levels of the PINK1/Parkin pathway and STING-TBK-IRF3 pathway were detected via western blotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>HCH inhalation improves 7-day survival and cognitive function in septic mice and reduces brain tissue damage, proinflammatory cytokine levels, and phosphorylated tau levels. These effects were reversed by a mitophagy inhibitor. HCH significantly improves mitochondrial function, enhances PINK1/Parkin-mediated mitophagy, and reduces the activity of the STING-TBK-IRF3 pathway in brain tissue.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>HCH inhalation effectively improved the survival rate of septic mice, alleviated SAE, and reduced tau phosphorylation. The mechanism may involve HCH enhancing PINK1/Parkin-mediated mitophagy, which inhibits the activity of the cGAS-STING-IRF3 pathway, thereby reducing neuroinflammation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Di An, Chuling Zhang, Peng Zhou, Yifei Wang, Sining Meng, Yanlong Chen, Weixiao Xu, Jiankang Xuan, Jianping Xiong, Jie Cheng, Rong Gao, Jun Wang, Xufeng Chen
Background
Methamphetamine (Meth) is a potent psychoactive stimulant that triggers complex neurotoxicity characterized by autophagy-associated neuronal death. However, the potential mechanisms remain poorly understood. This study aimed to decipher the Meth-induced neuronal necroptosis involving mitochondrial defect-initiated excessive mitophagy caused by aberrant presenilin-associated rhomboid-like (PARL) cleavage of PTEN-induced kinase 1 (PINK1) and phosphoglycerate mutase family member 5 (PGAM5).
Methods and Results
With the transcriptome analysis, Meth exposure significantly affected autophagy, mitophagy, and necroptosis pathways; meanwhile, the proteomic analysis revealed a marked decline in the level of PARL, which led to an imbalance in intramembrane proteolysis of PINK1 and PGAM5. In behavioral tests, Meth administration elicited pronounced cognitive decline in mice, accompanied by decreased neuronal numbers, massive autophagosomes, and mitochondrial fragmentation, and these processes can be dramatically reversed by knockin of PARL and knockdown of PGAM5 in the mouse hippocampus, molecularly manifesting as decreased necrosome formation and phosphorylated mixed lineage kinase domain-like (p-MLKL) mitochondrial membrane translocation, and improved autophagic flux.
Conclusion
In summary, these findings collectively underscore the key roles of the PARL-PGAM5 axis in Meth-mediated neuronal necroptosis and that targeting this axis may provide promising therapeutic strategies for mitigating Meth-induced neurotoxicity.
{"title":"Cleaving PINK1 or PGAM5? Involvement of PARL in Methamphetamine-Induced Excessive Mitophagy and Neuronal Necroptosis","authors":"Di An, Chuling Zhang, Peng Zhou, Yifei Wang, Sining Meng, Yanlong Chen, Weixiao Xu, Jiankang Xuan, Jianping Xiong, Jie Cheng, Rong Gao, Jun Wang, Xufeng Chen","doi":"10.1111/cns.70293","DOIUrl":"https://doi.org/10.1111/cns.70293","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Methamphetamine (Meth) is a potent psychoactive stimulant that triggers complex neurotoxicity characterized by autophagy-associated neuronal death. However, the potential mechanisms remain poorly understood. This study aimed to decipher the Meth-induced neuronal necroptosis involving mitochondrial defect-initiated excessive mitophagy caused by aberrant presenilin-associated rhomboid-like (PARL) cleavage of PTEN-induced kinase 1 (PINK1) and phosphoglycerate mutase family member 5 (PGAM5).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>With the transcriptome analysis, Meth exposure significantly affected autophagy, mitophagy, and necroptosis pathways; meanwhile, the proteomic analysis revealed a marked decline in the level of PARL, which led to an imbalance in intramembrane proteolysis of PINK1 and PGAM5. In behavioral tests, Meth administration elicited pronounced cognitive decline in mice, accompanied by decreased neuronal numbers, massive autophagosomes, and mitochondrial fragmentation, and these processes can be dramatically reversed by knockin of PARL and knockdown of PGAM5 in the mouse hippocampus, molecularly manifesting as decreased necrosome formation and phosphorylated mixed lineage kinase domain-like (p-MLKL) mitochondrial membrane translocation, and improved autophagic flux.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In summary, these findings collectively underscore the key roles of the PARL-PGAM5 axis in Meth-mediated neuronal necroptosis and that targeting this axis may provide promising therapeutic strategies for mitigating Meth-induced neurotoxicity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parkinson's disease (PD) is characterized by dopaminergic system dysfunction that results from the degeneration of neurons in the substantia nigra. However, studies suggest that other neurotransmitters, especially histamine, may also play a role in the development of PD.
Recent Findings
Numerous studies show that histamine levels in the basal ganglia significantly change in PD pathology, correlating with motor symptoms observed in animal models of PD. Histamine activates H1R or H4R on microglia in the substantia nigra, triggering an inflammatory response and promoting dopaminergic neuron degeneration. Additionally, histamine modulates neuronal excitability and firing activity (firing rate and pattern) by activating H1R, H2R, or H3R on neurons in the basal ganglia nucleus, ultimately impacting normal motor behavior as well as motor symptoms in models of PD.
Summary
This review presents the role of histamine and its receptor ligands in the basal ganglia nuclei, along with downstream ion channels linked to histamine receptors that influence immune response, neuronal excitability, and firing activity in PD. It highlights their effects on neuronal firing and their connection to PD motor symptoms. Investigating new ligands targeting basal ganglia histamine receptors and associated ion channels may facilitate the development of novel treatments for PD.
{"title":"Histamine Modulation of the Basal Ganglia Circuitry in the Motor Symptoms of Parkinson's Disease","authors":"Hui-Xian Zhu, Wei-Wei Lou, Yi-Miao Jiang, Alina Ciobanu, Chen-Xin Fang, Cheng-Ye Liu, Yan-Li Yang, Jing-Yang Cao, Ling Shan, Qian-Xing Zhuang","doi":"10.1111/cns.70308","DOIUrl":"https://doi.org/10.1111/cns.70308","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose of Review</h3>\u0000 \u0000 <p>Parkinson's disease (PD) is characterized by dopaminergic system dysfunction that results from the degeneration of neurons in the substantia nigra. However, studies suggest that other neurotransmitters, especially histamine, may also play a role in the development of PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Recent Findings</h3>\u0000 \u0000 <p>Numerous studies show that histamine levels in the basal ganglia significantly change in PD pathology, correlating with motor symptoms observed in animal models of PD. Histamine activates H1R or H4R on microglia in the substantia nigra, triggering an inflammatory response and promoting dopaminergic neuron degeneration. Additionally, histamine modulates neuronal excitability and firing activity (firing rate and pattern) by activating H1R, H2R, or H3R on neurons in the basal ganglia nucleus, ultimately impacting normal motor behavior as well as motor symptoms in models of PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Summary</h3>\u0000 \u0000 <p>This review presents the role of histamine and its receptor ligands in the basal ganglia nuclei, along with downstream ion channels linked to histamine receptors that influence immune response, neuronal excitability, and firing activity in PD. It highlights their effects on neuronal firing and their connection to PD motor symptoms. Investigating new ligands targeting basal ganglia histamine receptors and associated ion channels may facilitate the development of novel treatments for PD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<div> <section> <h3> Objective</h3> <p>To identify and validate causal protein targets that may serve as potential therapeutic interventions for both the onset and progression of Parkinson's disease (PD) through integrative proteomic and genetic analyses.</p> </section> <section> <h3> Method</h3> <p>We utilized large-scale plasma and brain protein quantitative trait loci (pQTL) datasets from the deCODE Health study and the Religious Orders Study/Rush Memory and Aging Project (ROS/MAP), respectively. Proteome-wide association studies (PWAS) were conducted using the OTTERS framework for plasma proteins and the FUSION tool for brain proteins, examining associations with PD onset and three progression phenotypes: composite, motor, and cognitive. Significant protein associations (FDR-corrected <i>p</i> < 0.05) from PWAS were further validated using summary-based Mendelian randomization (SMR), colocalization analyses, and reverse Mendelian randomization (MR) to establish causality. Phenome-wide Mendelian randomization (PheW-MR) was performed to assess potential side effects across 679 disease traits when targeting these proteins to reduce PD-related phenotype risk by 20%. Additionally, we conducted cellular distribution-based clustering using gene expression data from the Allen Brain Atlas (ABA) to explore the distribution of key proteins across brain regions, constructed protein–protein interaction (PPI) networks via the STRING database to explore interactions among proteins, and evaluated the druggability of identified targets using the DrugBank database to identify opportunities for drug repurposing.</p> </section> <section> <h3> Result</h3> <p>Our analyses identified 25 candidate proteins associated with PD phenotypes, including 16 plasma proteins linked to PD progression (10 cognitive, 4 motor, and 3 composite) and 9 plasma proteins associated with PD onset. Notably, GPNMB was implicated in both plasma and brain tissues for PD onset. PheW-MR revealed predominantly beneficial side effects for the identified targets, with 83.7% of associations indicating positive outcomes and 16.3% indicating adverse effects. Cellular clustering categorized candidate targets into three distinct expression profiles across brain cell types using ABA. PPI network analysis highlighted one key interaction cluster among the proteins for PD cognitive progression and PD onset. Druggability assessment revealed 15 out of 25 proteins had repurposing opportunities for PD treatment.</p> </section> <section> <h3> Conclusion</h3> <p>We have identified 25 causal protein targets as
{"title":"Proteome-Wide Association Study for Finding Druggable Targets in Progression and Onset of Parkinson's Disease","authors":"Chenhao Gao, Haobin Zhou, Weixuan Liang, Zhuofeng Wen, Wanzhe Liao, Zhixin Xie, Cailing Liao, Limin He, Jingzhang Sun, Zhilin Chen, Duopin Li, Naijun Yuan, Chuiguo Huang, Jiewen Zhang","doi":"10.1111/cns.70294","DOIUrl":"https://doi.org/10.1111/cns.70294","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To identify and validate causal protein targets that may serve as potential therapeutic interventions for both the onset and progression of Parkinson's disease (PD) through integrative proteomic and genetic analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>We utilized large-scale plasma and brain protein quantitative trait loci (pQTL) datasets from the deCODE Health study and the Religious Orders Study/Rush Memory and Aging Project (ROS/MAP), respectively. Proteome-wide association studies (PWAS) were conducted using the OTTERS framework for plasma proteins and the FUSION tool for brain proteins, examining associations with PD onset and three progression phenotypes: composite, motor, and cognitive. Significant protein associations (FDR-corrected <i>p</i> < 0.05) from PWAS were further validated using summary-based Mendelian randomization (SMR), colocalization analyses, and reverse Mendelian randomization (MR) to establish causality. Phenome-wide Mendelian randomization (PheW-MR) was performed to assess potential side effects across 679 disease traits when targeting these proteins to reduce PD-related phenotype risk by 20%. Additionally, we conducted cellular distribution-based clustering using gene expression data from the Allen Brain Atlas (ABA) to explore the distribution of key proteins across brain regions, constructed protein–protein interaction (PPI) networks via the STRING database to explore interactions among proteins, and evaluated the druggability of identified targets using the DrugBank database to identify opportunities for drug repurposing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Our analyses identified 25 candidate proteins associated with PD phenotypes, including 16 plasma proteins linked to PD progression (10 cognitive, 4 motor, and 3 composite) and 9 plasma proteins associated with PD onset. Notably, GPNMB was implicated in both plasma and brain tissues for PD onset. PheW-MR revealed predominantly beneficial side effects for the identified targets, with 83.7% of associations indicating positive outcomes and 16.3% indicating adverse effects. Cellular clustering categorized candidate targets into three distinct expression profiles across brain cell types using ABA. PPI network analysis highlighted one key interaction cluster among the proteins for PD cognitive progression and PD onset. Druggability assessment revealed 15 out of 25 proteins had repurposing opportunities for PD treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We have identified 25 causal protein targets as","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70294","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Siyi Lin, Huangjie Fu, Hanxiao Wang, Yingying Xu, Yu Zhao, Shiyu Du, Jiale Wei, Ping Qiu, Senlin Shi, Changyu Li, Thomas Efferth, Chunlan Hong
Purpose
The aim of this study was to investigate the protective effect of Free and Easy Wanderer (FAEW) on the avoidance behavior induced by feeding Heat-Killed Escherichia coli, and to elucidate the underlying mechanisms.
Methods
Initially, the effects of FAEW on avoidance behavior, survival, neuroendocrine signaling gene expression, and intestinal bloating were examined. The impact of FAEW on gut-germline-neural signaling was assessed by monitoring H4K8ac expression and the avoidance behavior of par-5 RNAi animals and glp-1(e2141) mutants. RNA-sequencing was conducted to analyze potential signaling pathways. Finally, avoidance behavior was examined using daf-16(mu86) mutants and the rescued animals.
Results
FAEW delayed avoidance behavior. FAEW significantly downregulated gene expression in the neuroendocrine signaling pathway and alleviated intestinal bloating of C. elegans. The levels of H4K8ac and par-5 in the germline decreased significantly with FAEW's treatment, and FAEW failed to affect the avoidance behavior of par-5 RNAi animals and glp-1(e2141) mutants. FAEW's effect on avoidance behavior diminished in daf-16(mu86) mutants but was restored in daf-16 rescued animals. FAEW has been observed to restore daf-16 levels.
Conclusion
FAEW protects against avoidance behavior of C. elegans through downregulating H4K8ac protein expression and activating DAF-16. This study provides crucial experimental evidence supporting FAEW as a promising candidate for protecting against avoidance behavior associated with PTSD.
{"title":"Free and Easy Wanderer Ameliorates Intestinal Bloating-Dependent Avoidance Behavior of Caenorhabditis elegans Through Gut-Germline-Neural Signaling","authors":"Siyi Lin, Huangjie Fu, Hanxiao Wang, Yingying Xu, Yu Zhao, Shiyu Du, Jiale Wei, Ping Qiu, Senlin Shi, Changyu Li, Thomas Efferth, Chunlan Hong","doi":"10.1111/cns.70291","DOIUrl":"https://doi.org/10.1111/cns.70291","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>The aim of this study was to investigate the protective effect of <i>Free and Easy Wanderer</i> (FAEW) on the avoidance behavior induced by feeding Heat-Killed <i>Escherichia coli</i>, and to elucidate the underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Initially, the effects of FAEW on avoidance behavior, survival, neuroendocrine signaling gene expression, and intestinal bloating were examined. The impact of FAEW on gut-germline-neural signaling was assessed by monitoring H4K8ac expression and the avoidance behavior of <i>par-5</i> RNAi animals and <i>glp-1(e2141)</i> mutants. RNA-sequencing was conducted to analyze potential signaling pathways. Finally, avoidance behavior was examined using <i>daf-16(mu86)</i> mutants and the rescued animals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>FAEW delayed avoidance behavior. FAEW significantly downregulated gene expression in the neuroendocrine signaling pathway and alleviated intestinal bloating of <i>C. elegans</i>. The levels of H4K8ac and <i>par-5</i> in the germline decreased significantly with FAEW's treatment, and FAEW failed to affect the avoidance behavior of <i>par-5</i> RNAi animals and <i>glp-1(e2141)</i> mutants. FAEW's effect on avoidance behavior diminished in <i>daf-16(mu86)</i> mutants but was restored in <i>daf-16</i> rescued animals. FAEW has been observed to restore <i>daf-16</i> levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>FAEW protects against avoidance behavior of <i>C. elegans</i> through downregulating H4K8ac protein expression and activating DAF-16. This study provides crucial experimental evidence supporting FAEW as a promising candidate for protecting against avoidance behavior associated with PTSD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hailiang Tang, Feng Xu, Dan Sun, Lingyang Hua, Ji Xiong, Ming Xu, Jian Xu, Ping Zhong
<div> <section> <h3> Introduction</h3> <p>Neurofibromatosis type 2 (<i>Nf2</i>) gene inactivation is common in sporadic and <i>Nf2</i>-related meningioma. There is currently scant literature describing the development of an intracranial meningioma model in animals. Given the role of <i>Nf2</i> and other gene inactivation in meningeal cells, we used Cas9 mice here as the background host to establish a new animal model of skull base meningioma in this study.</p> </section> <section> <h3> Aims</h3> <p>Cas9 transgenic mice were purchased from Jackson Laboratory and raised in our institution. Subsequently, meningeal cells were obtained from the Cas9 transgenic mice, cultured in medium, and passaged in vitro. We then prepared lentivirus vector pLentiCre/gRNA, which could express the elements blocking the function of four genes: <i>Nf2, P15</i><sup><i>Ink4b</i></sup>, <i>P16</i><sup><i>Ink4a</i></sup><i>,</i> and <i>P19</i><sup><i>Arf</i></sup>. We infected the meningeal cells with the lentivirus vector pLentiCre/gRNA and tested the expression of these four genes in those infected meningeal cells. Next, adeno-associated virus vector pAAVCre/gRNA was injected in vivo into the skull base meningeal cells of the neonate Cas9 transgenic mice. These mice were observed once a week and killed 10 months later for brain inspection and pathological analysis.</p> </section> <section> <h3> Results</h3> <p>Twenty Cas9 transgenic mice were successfully bred. Five mice were killed so that meningeal cells could be extracted, cultured, and infected with the lentivirus vector pLentiCre/gRNA for 72 h in vitro. The gene function test showed that <i>Nf2, P15</i><sup><i>Ink4b</i></sup>, <i>P16</i><sup><i>Ink4a</i></sup><i>,</i> and <i>P19</i><sup><i>Arf</i></sup> were all blocked in the infected meningeal cells, which indicated that the lentivirus vector pLentiCre/gRNA could effectively block the expression of the four genes in targeted cells. Then pAAVCre/gRNA was injected into the skull base meningeal cells of 15 mice in vivo, and nine mice were observed for 10 months so that the intracranial tumor growth could be assessed. Among these nine mice, pathological analysis showed that six mice had benign meningioma subtypes similar to human meningioma, one mouse had atypical meningioma, one mouse had malignant meningioma, and one mouse had sarcoma.</p> </section> <section> <h3> Conclusions</h3> <p>The Cas9 mouse model of skull base meningioma generated with the <i>Nf2</i> genetic defect and the combinational loss of <i>P15</i><sup><i>Ink4b</i></sup>, <i>P16</i><sup><i>Ink4a</i></s
{"title":"Cas9 Mouse Model of Skull Base Meningioma Driven by Combinational Gene Inactivation in Meningeal Cells","authors":"Hailiang Tang, Feng Xu, Dan Sun, Lingyang Hua, Ji Xiong, Ming Xu, Jian Xu, Ping Zhong","doi":"10.1111/cns.70287","DOIUrl":"https://doi.org/10.1111/cns.70287","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Neurofibromatosis type 2 (<i>Nf2</i>) gene inactivation is common in sporadic and <i>Nf2</i>-related meningioma. There is currently scant literature describing the development of an intracranial meningioma model in animals. Given the role of <i>Nf2</i> and other gene inactivation in meningeal cells, we used Cas9 mice here as the background host to establish a new animal model of skull base meningioma in this study.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Cas9 transgenic mice were purchased from Jackson Laboratory and raised in our institution. Subsequently, meningeal cells were obtained from the Cas9 transgenic mice, cultured in medium, and passaged in vitro. We then prepared lentivirus vector pLentiCre/gRNA, which could express the elements blocking the function of four genes: <i>Nf2, P15</i><sup><i>Ink4b</i></sup>, <i>P16</i><sup><i>Ink4a</i></sup><i>,</i> and <i>P19</i><sup><i>Arf</i></sup>. We infected the meningeal cells with the lentivirus vector pLentiCre/gRNA and tested the expression of these four genes in those infected meningeal cells. Next, adeno-associated virus vector pAAVCre/gRNA was injected in vivo into the skull base meningeal cells of the neonate Cas9 transgenic mice. These mice were observed once a week and killed 10 months later for brain inspection and pathological analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Twenty Cas9 transgenic mice were successfully bred. Five mice were killed so that meningeal cells could be extracted, cultured, and infected with the lentivirus vector pLentiCre/gRNA for 72 h in vitro. The gene function test showed that <i>Nf2, P15</i><sup><i>Ink4b</i></sup>, <i>P16</i><sup><i>Ink4a</i></sup><i>,</i> and <i>P19</i><sup><i>Arf</i></sup> were all blocked in the infected meningeal cells, which indicated that the lentivirus vector pLentiCre/gRNA could effectively block the expression of the four genes in targeted cells. Then pAAVCre/gRNA was injected into the skull base meningeal cells of 15 mice in vivo, and nine mice were observed for 10 months so that the intracranial tumor growth could be assessed. Among these nine mice, pathological analysis showed that six mice had benign meningioma subtypes similar to human meningioma, one mouse had atypical meningioma, one mouse had malignant meningioma, and one mouse had sarcoma.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The Cas9 mouse model of skull base meningioma generated with the <i>Nf2</i> genetic defect and the combinational loss of <i>P15</i><sup><i>Ink4b</i></sup>, <i>P16</i><sup><i>Ink4a</i></s","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70287","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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