Hao Xu, Jiawei He, Hua Du, Xiaolei Jing, Xinfeng Liu
Background
Hydrocephalus is characterized by secretion, circulation, and absorption disorder of cerebrospinal fluid (CSF) with high morbidity and complication rate. The relationship between inflammation and abnormal secretion of CSF by choroid plexus epithelium (CPE) had received more attention. In this study, we aim to detect the role of Toll-like receptor 4/nuclear factor-kappa B/Na+/K+/2Cl-cotransporter 1(TLR4/NF-κB/NKCC1) signal pathway in the development of hydrocephalus.
Method
Hydrocephalus was induced in adult rats (8 weeks) by intracisternal kaolin injection, then pyrrolidinedithiocarbamate (PDTC) and bumetanide were administrated to the rats mode. Then the rat model was evaluated, and ventricular volume was calculated at different time points. Then CPE, cortex, preventricular tissue, and CSF were obtained. Protein expressions of TLR-4, NKCC/serine–threonine STE20/SPS1-related, proline-alanine-rich kinase (SPAK), pNKCC1, pSPAK, GFAP, AQP1, and AQP4 were measured by RT-PCR, western blot, and immunofluorescence (IF) stains in CPE, respectively.
Result
Our data showed that inflammation factors tumor necrosis factor-(TNF-α), interleukin 18(IL-18), and glial fibrillary acidic protein (GFAP) concentrations were significantly higher in the model group than in controls. The TLR4/NF-κB/NKCC1 signal pathway were actived by NF-κB-p65, NKCC1, pNKCC1- pSPAK complex, and Aquaporin1 (AQP1) high expression. PDTC and bumetanide use can help regular TLR4/NF-κB/NKCC1 expression and reduced AQP1 expression by down-regulate NF-B-p65 and inhibiting NKCC1, respectively. As a result, the treatment groups alleviated CPE abnormal secretion and ventricle enlargement.
Conclusion
These results confirmed that the inflammatory reaction contributes TLR4/NF-κB/NKCC1 mediated CPE abnormal secretion and consequent hydrocephalus. Regulation of TLR4/NF-κB/NKCC1 and AQP1 can prevent this process. Our study provides a strong rationale for further exploring alleviating CPE abnormal secretion as a therapeutic perspective of hydrocephalus.
{"title":"Evaluation of the Choroid Plexus Epithelium Inflammation TLR4/NF-κB/NKCC1 Signal Pathway Activation in the Development of Hydrocephalus","authors":"Hao Xu, Jiawei He, Hua Du, Xiaolei Jing, Xinfeng Liu","doi":"10.1111/cns.70085","DOIUrl":"10.1111/cns.70085","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hydrocephalus is characterized by secretion, circulation, and absorption disorder of cerebrospinal fluid (CSF) with high morbidity and complication rate. The relationship between inflammation and abnormal secretion of CSF by choroid plexus epithelium (CPE) had received more attention. In this study, we aim to detect the role of Toll-like receptor 4/nuclear factor-kappa B/Na+/K+/2Cl-cotransporter 1(TLR4/NF-κB/NKCC1) signal pathway in the development of hydrocephalus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Hydrocephalus was induced in adult rats (8 weeks) by intracisternal kaolin injection, then pyrrolidinedithiocarbamate (PDTC) and bumetanide were administrated to the rats mode. Then the rat model was evaluated, and ventricular volume was calculated at different time points. Then CPE, cortex, preventricular tissue, and CSF were obtained. Protein expressions of TLR-4, NKCC/serine–threonine STE20/SPS1-related, proline-alanine-rich kinase (SPAK), pNKCC1, pSPAK, GFAP, AQP1, and AQP4 were measured by RT-PCR, western blot, and immunofluorescence (IF) stains in CPE, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>Our data showed that inflammation factors tumor necrosis factor-(TNF-α), interleukin 18(IL-18), and glial fibrillary acidic protein (GFAP) concentrations were significantly higher in the model group than in controls. The TLR4/NF-κB/NKCC1 signal pathway were actived by NF-κB-p65, NKCC1, pNKCC1- pSPAK complex, and Aquaporin1 (AQP1) high expression. PDTC and bumetanide use can help regular TLR4/NF-κB/NKCC1 expression and reduced AQP1 expression by down-regulate NF-B-p65 and inhibiting NKCC1, respectively. As a result, the treatment groups alleviated CPE abnormal secretion and ventricle enlargement.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These results confirmed that the inflammatory reaction contributes TLR4/NF-κB/NKCC1 mediated CPE abnormal secretion and consequent hydrocephalus. Regulation of TLR4/NF-κB/NKCC1 and AQP1 can prevent this process. Our study provides a strong rationale for further exploring alleviating CPE abnormal secretion as a therapeutic perspective of hydrocephalus.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11503839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491615","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}
Temporal lobe epilepsy (TLE), a prevalent chronic neurological disorder, affects millions of individuals and is often resistant to anti-epileptic drugs. Increasing evidence has shown that acetylcholine (ACh) and cholinergic neurotransmission play a role in the pathophysiology of epilepsy. Tropisetron, an antiemetic drug used for chemotherapy in clinic, has displayed potential in the treatment of Alzheimer's disease, depression, and schizophrenia in animal models. However, as a partial agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), whether tropisetron possesses the therapeutic potential for TLE has not yet been determined.
Methods
In this study, tropisetron was intraperitoneally injected into pilocarpine-induced epileptic rats for 3 weeks. Alpha-bungarotoxin (α-bgt), a specific α7nAChR antagonist, was applied to investigate the mechanism of tropisetron. Rats were assessed for spontaneous recurrent seizures (SRS) and cognitive function using video surveillance and Morris's water maze testing. Hippocampal impairment and synaptic structure were evaluated by Nissl staining, immunohistochemistry, and Golgi staining. Additionally, the levels of glutamate, γ-aminobutyric acid (GABA), ACh, α7nAChRs, neuroinflammatory cytokines, glucocorticoids and their receptors, as well as synapse-associated protein (F-actin, cofilin-1) were quantified.
Results
The results showed that tropisetron significantly reduced SRS, improved cognitive function, alleviated hippocampal sclerosis, and concurrently suppressed synaptic remodeling and the m6A modification of cofilin-1 in TLE rats. Furthermore, tropisetron lowered glutamate levels without affecting GABA levels, reduced neuroinflammation, and increased ACh levels and α7nAChR expression in the hippocampi of TLE rats. The effects of tropisetron treatment were counteracted by α-bgt.
Conclusion
In summary, these findings indicate that tropisetron exhibits an anti-epileptic effect and provides neuroprotection in TLE rats through the activation of α7nAChRs. The potential mechanism may involve the reduction of glutamate levels, enhancement of cholinergic transmission, and suppression of synaptic remodeling. Consequently, the present study not only highlights the potential of tropisetron as an anti-epileptic drug but also identifies α7nAChRs as a promising therapeutic target for the treatment of TLE.
{"title":"Tropisetron, an Antiemetic Drug, Exerts an Anti-Epileptic Effect Through the Activation of α7nAChRs in a Rat Model of Temporal Lobe Epilepsy","authors":"Xu Qian, Xinwen Sheng, Jiqiang Ding, Zulipiya Yiming, Jingjun Zheng, Jiagui Zhong, Tengyue Zhang, Xuemei Li, Shuqiao He, Wei Li, Mei Zhang","doi":"10.1111/cns.70086","DOIUrl":"10.1111/cns.70086","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Temporal lobe epilepsy (TLE), a prevalent chronic neurological disorder, affects millions of individuals and is often resistant to anti-epileptic drugs. Increasing evidence has shown that acetylcholine (ACh) and cholinergic neurotransmission play a role in the pathophysiology of epilepsy. Tropisetron, an antiemetic drug used for chemotherapy in clinic, has displayed potential in the treatment of Alzheimer's disease, depression, and schizophrenia in animal models. However, as a partial agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), whether tropisetron possesses the therapeutic potential for TLE has not yet been determined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, tropisetron was intraperitoneally injected into pilocarpine-induced epileptic rats for 3 weeks. Alpha-bungarotoxin (α-bgt), a specific α7nAChR antagonist, was applied to investigate the mechanism of tropisetron. Rats were assessed for spontaneous recurrent seizures (SRS) and cognitive function using video surveillance and Morris's water maze testing. Hippocampal impairment and synaptic structure were evaluated by Nissl staining, immunohistochemistry, and Golgi staining. Additionally, the levels of glutamate, γ-aminobutyric acid (GABA), ACh, α7nAChRs, neuroinflammatory cytokines, glucocorticoids and their receptors, as well as synapse-associated protein (F-actin, cofilin-1) were quantified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results showed that tropisetron significantly reduced SRS, improved cognitive function, alleviated hippocampal sclerosis, and concurrently suppressed synaptic remodeling and the m<sup>6</sup>A modification of cofilin-1 in TLE rats. Furthermore, tropisetron lowered glutamate levels without affecting GABA levels, reduced neuroinflammation, and increased ACh levels and α7nAChR expression in the hippocampi of TLE rats. The effects of tropisetron treatment were counteracted by α-bgt.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In summary, these findings indicate that tropisetron exhibits an anti-epileptic effect and provides neuroprotection in TLE rats through the activation of α7nAChRs. The potential mechanism may involve the reduction of glutamate levels, enhancement of cholinergic transmission, and suppression of synaptic remodeling. Consequently, the present study not only highlights the potential of tropisetron as an anti-epileptic drug but also identifies α7nAChRs as a promising therapeutic target for the treatment of TLE.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491618","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 the formation of Lewy bodies (LBs), primarily constituted of α-synuclein (α-Syn). Microglial cells exhibit specific reactivity toward misfolded proteins such as α-Syn. However, the exact clearance mechanism and related molecular targets remain elusive.
Methods
BV2 cells, primary microglia from wild-type and MT1 knockout mice, and primary cortical neurons were utilized as experimental models. The study investigated relevant mechanisms by modulating microglial MT1 expression through small RNA interference (RNAi) and lentiviral overexpression techniques. Furthermore, pathological aggregation of α-Syn was induced using pre-formed fibrils (PFF) α-Syn. Co-immunoprecipitation, immunofluorescence, Western blot (WB), and quantitative real-time PCR were used to elucidate the mechanisms of molecular regulation.
Results
In this study, we elucidated the regulatory role of the melatonin receptor 1 (MT1) in the microglial phagocytic process. Following MT1 knockout, the ability of microglial cells to engulf latex beads and zymosan particles decreased, subsequently affecting the phagocytic degradation of fibrillar α-Syn by microglial cells. Furthermore, the loss of MT1 receptors in microglial cells exacerbates the aggregation of α-Syn in neurons induced by pre-formed fibrils (PFF) α-Syn. Mechanistically, MT1 influences the phagocytic function of microglial cells by regulating the Rubicon-dependent LC3-associated phagocytosis (LAP) pathway.
Conclusion
Taken together, the results suggest the neuroprotective function of microglial cells in clearing α-Syn through MT1-mediated LAP, highlighting the potential key role of MT1 in pathogenic mechanisms associated with α-Syn.
{"title":"Microglial Melatonin Receptor 1 Degrades Pathological Alpha-Synuclein Through Activating LC3-Associated Phagocytosis In Vitro","authors":"Xiao-Yu Yao, Bing-Er Cao, Jun-Yi Liu, Qian-Kun Lv, Jia-Rui Zhang, Xiao-Yu Cheng, Cheng-Jie Mao, Quan-Hong Ma, Fen Wang, Chun-Feng Liu","doi":"10.1111/cns.70088","DOIUrl":"10.1111/cns.70088","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), primarily constituted of α-synuclein (α-Syn). Microglial cells exhibit specific reactivity toward misfolded proteins such as α-Syn. However, the exact clearance mechanism and related molecular targets remain elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>BV2 cells, primary microglia from wild-type and MT1 knockout mice, and primary cortical neurons were utilized as experimental models. The study investigated relevant mechanisms by modulating microglial MT1 expression through small RNA interference (RNAi) and lentiviral overexpression techniques. Furthermore, pathological aggregation of α-Syn was induced using pre-formed fibrils (PFF) α-Syn. Co-immunoprecipitation, immunofluorescence, Western blot (WB), and quantitative real-time PCR were used to elucidate the mechanisms of molecular regulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In this study, we elucidated the regulatory role of the melatonin receptor 1 (MT1) in the microglial phagocytic process. Following MT1 knockout, the ability of microglial cells to engulf latex beads and zymosan particles decreased, subsequently affecting the phagocytic degradation of fibrillar α-Syn by microglial cells. Furthermore, the loss of MT1 receptors in microglial cells exacerbates the aggregation of α-Syn in neurons induced by pre-formed fibrils (PFF) α-Syn. Mechanistically, MT1 influences the phagocytic function of microglial cells by regulating the Rubicon-dependent LC3-associated phagocytosis (LAP) pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Taken together, the results suggest the neuroprotective function of microglial cells in clearing α-Syn through MT1-mediated LAP, highlighting the potential key role of MT1 in pathogenic mechanisms associated with α-Syn.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491616","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}
Weikang Zhang, Zhenlei Liu, Kai Wang, Lei Zhang, Shaocheng Liu, Xiangyu Zhang, Yutian Wang, Kun He, Hao Wu
<div> <section> <h3> Background</h3> <p>Spinal adhesive arachnoidopathy (SAA) is a chronic pathology associated with persistent inflammatory responses in the arachnoid. Adhesive arachnoiditis (AA) is one of the major forms of SAA, with accompanying secondary complications. Therefore, we aimed to systematically review both clinical and animal model studies related to SAA to gain a deeper understanding of this unique pathology.</p> </section> <section> <h3> Methods</h3> <p>A literature search was conducted in PubMed, EMBASE, and Cochrane Library databases to retrieve relevant publications up to October 2022. Clinical manifestations, etiologies, imaging modalities, treatments, and prognosis in patients with SAA were collected. Data from animal experiments related to SAA were also extracted.</p> </section> <section> <h3> Results</h3> <p>A total of 176 studies, including 147 clinical and 29 animal model studies, with a total of 510 patients were enrolled in this study. Pain (37.5%), abnormal nerve sensations (39.58%), and abnormal motor function (78.75%) were the top three common symptoms of SAA. Major etiologies included trauma (22.7%), infection (17.73%), surgery (15.37%), and hemorrhage (13.48%). MRI was widely used to confirm the diagnosis. AA could be involved in cervical (96/606, 15.84%), thoracic (297/606, 49.01%), lumbar (174/606, 28.71%), and sacrococcygeal (39/606, 6.44%) vertebral segments. Patients with AA in cervical segments had a higher post-surgery recovery rate (<i>p</i> = 0.016) compared to that of other segments. The common pathological diagnoses of SAA were AA (80.82%), AA combined with arachnoid cyst (12.79%), arachnoid calcification/scars (3.43%), and arachnoid web/fibrosis (2.97%). Patients with AA were more likely to develop syringomyelia, compared with patients with other forms of SAA (<i>p</i> < 0.001). Animal studies mainly focused on new AA therapeutic agents (<i>n</i> = 14), the pathomechanism of AA (<i>n</i> = 14), and the development of new MRI sequences for improved diagnosis (<i>n</i> = 1).</p> </section> <section> <h3> Conclusions</h3> <p>The pathological consequences of SAA are more complex than AA and manifest in different forms, such as AA combined with arachnoid cyst, arachnoid calcification/scars, and arachnoid web/fibrosis. In many instances, AA was associated with secondary syringomyelia. Unspecific clinical manifestations of SAA may easily lead to misdiagnosis and missed diagnosis. Although SAA may result from multiple etiologies, including spinal trauma, meningitis, spinal surgery, and hemorrhage, the pathog
背景：脊髓粘连性蛛网膜病（SAA）是一种与蛛网膜持续炎症反应有关的慢性病变。粘连性蛛网膜炎（AA）是 SAA 的主要形式之一，并伴有继发性并发症。因此，我们旨在系统回顾与 SAA 相关的临床和动物模型研究，以深入了解这种独特的病理现象：方法：在 PubMed、EMBASE 和 Cochrane Library 数据库中进行文献检索，检索截至 2022 年 10 月的相关出版物。收集了 SAA 患者的临床表现、病因、影像学模式、治疗方法和预后。此外，还提取了与SAA相关的动物实验数据：本研究共纳入了 176 项研究，包括 147 项临床研究和 29 项动物模型研究，共计 510 名患者。疼痛（37.5%）、神经感觉异常（39.58%）和运动功能异常（78.75%）是 SAA 常见的三大症状。主要病因包括外伤（22.7%）、感染（17.73%）、手术（15.37%）和出血（13.48%）。核磁共振成像被广泛用于确诊。AA可累及颈椎（96/606，15.84%）、胸椎（297/606，49.01%）、腰椎（174/606，28.71%）和骶尾椎（39/606，6.44%）。与其他节段相比，颈椎节段 AA 患者的术后恢复率更高（P = 0.016）。SAA 常见的病理诊断为 AA（80.82%）、AA 合并蛛网膜囊肿（12.79%）、蛛网膜钙化/疤痕（3.43%）和蛛网膜网/纤维化（2.97%）。与其他形式的 SAA 患者相比，AA 患者更有可能患上鞘膜积液（P 结论）：SAA的病理后果比AA更复杂，表现形式也不同，如AA合并蛛网膜囊肿、蛛网膜钙化/疤痕和蛛网膜网/纤维化。在许多情况下，AA 与继发性鞘膜积液有关。SAA 的临床表现不明确，很容易导致误诊和漏诊。尽管 SAA 可能由多种病因引起，包括脊柱创伤、脑膜炎、脊柱手术和出血，但 SAA 的发病机制和治疗方法仍未统一。
{"title":"Spinal Adhesive Arachnoidopathy, the Disorder More Than Simply Adhesive Arachnoiditis: A Comprehensive Systematic Review of 510 Cases","authors":"Weikang Zhang, Zhenlei Liu, Kai Wang, Lei Zhang, Shaocheng Liu, Xiangyu Zhang, Yutian Wang, Kun He, Hao Wu","doi":"10.1111/cns.70084","DOIUrl":"10.1111/cns.70084","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Spinal adhesive arachnoidopathy (SAA) is a chronic pathology associated with persistent inflammatory responses in the arachnoid. Adhesive arachnoiditis (AA) is one of the major forms of SAA, with accompanying secondary complications. Therefore, we aimed to systematically review both clinical and animal model studies related to SAA to gain a deeper understanding of this unique pathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A literature search was conducted in PubMed, EMBASE, and Cochrane Library databases to retrieve relevant publications up to October 2022. Clinical manifestations, etiologies, imaging modalities, treatments, and prognosis in patients with SAA were collected. Data from animal experiments related to SAA were also extracted.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 176 studies, including 147 clinical and 29 animal model studies, with a total of 510 patients were enrolled in this study. Pain (37.5%), abnormal nerve sensations (39.58%), and abnormal motor function (78.75%) were the top three common symptoms of SAA. Major etiologies included trauma (22.7%), infection (17.73%), surgery (15.37%), and hemorrhage (13.48%). MRI was widely used to confirm the diagnosis. AA could be involved in cervical (96/606, 15.84%), thoracic (297/606, 49.01%), lumbar (174/606, 28.71%), and sacrococcygeal (39/606, 6.44%) vertebral segments. Patients with AA in cervical segments had a higher post-surgery recovery rate (<i>p</i> = 0.016) compared to that of other segments. The common pathological diagnoses of SAA were AA (80.82%), AA combined with arachnoid cyst (12.79%), arachnoid calcification/scars (3.43%), and arachnoid web/fibrosis (2.97%). Patients with AA were more likely to develop syringomyelia, compared with patients with other forms of SAA (<i>p</i> < 0.001). Animal studies mainly focused on new AA therapeutic agents (<i>n</i> = 14), the pathomechanism of AA (<i>n</i> = 14), and the development of new MRI sequences for improved diagnosis (<i>n</i> = 1).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The pathological consequences of SAA are more complex than AA and manifest in different forms, such as AA combined with arachnoid cyst, arachnoid calcification/scars, and arachnoid web/fibrosis. In many instances, AA was associated with secondary syringomyelia. Unspecific clinical manifestations of SAA may easily lead to misdiagnosis and missed diagnosis. Although SAA may result from multiple etiologies, including spinal trauma, meningitis, spinal surgery, and hemorrhage, the pathog","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454188","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}
The aim of this study is to explore the key mechanisms of perioperative neurocognitive dysfunction (PND) after anesthesia/surgery (A/S) by screening hub genes.
Methods
Transcriptome sequencing was conducted on hippocampal samples obtained from 18-month-old C57BL/6 mice assigned to control (Ctrl) and A/S groups. The functionality of differentially expressed genes (DEGs) was investigated using Metascape. Hub genes associated with changes between the two groups were screened by combining weighted gene coexpression network analysis within CytoHubba. Reverse transcription PCR and western blotting were used to validate changes in mRNA and protein expression, respectively. NLRP3 inflammasome activation was detected by western blotting and ELISA. Tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum (ER) stress, was administrated preoperatively to explore its effects on the occurrence of PND. Immunofluorescence analysis was performed to evaluate the activation of astrocytes and microglia in the hippocampus, and hippocampus-dependent learning and memory were assessed using behavioral experiments.
Results
In total, 521 DEGs were detected between the control and A/S groups. These DEGs were significantly enriched in biological processes related to metabolic processes and their regulation. Four hub genes (Hspa5, Igf1r, Sfpq, and Xbp1) were identified. Animal experiments have shown that mice in the A/S group exhibited cognitive impairments accompanied by increased Hspa5 and Xbp1 expression, ER stress, and activation of NLRP3 inflammasome.
Conclusions
Inhibiting ER stress alleviated cognitive impairment in A/S mice; particularly, ER stress induced by A/S results in NLRP3 inflammasome activation and neuroinflammation. Moreover, the preoperative administration of TUDCA inhibited ER stress, NLRP3 inflammasome activation, and neuroinflammation.
{"title":"Inhibiting endoplasmic reticulum stress alleviates perioperative neurocognitive disorders by reducing neuroinflammation mediated by NLRP3 inflammasome activation","authors":"Fanbing Meng, Jian Song, Xinwei Huang, Meixian Zhang, Xiaoxiao Sun, Qi Jing, Silu Cao, Zheng Xie, Qiong Liu, Hui Zhang, Cheng Li","doi":"10.1111/cns.70049","DOIUrl":"10.1111/cns.70049","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The aim of this study is to explore the key mechanisms of perioperative neurocognitive dysfunction (PND) after anesthesia/surgery (A/S) by screening hub genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Transcriptome sequencing was conducted on hippocampal samples obtained from 18-month-old C57BL/6 mice assigned to control (Ctrl) and A/S groups. The functionality of differentially expressed genes (DEGs) was investigated using Metascape. Hub genes associated with changes between the two groups were screened by combining weighted gene coexpression network analysis within CytoHubba. Reverse transcription PCR and western blotting were used to validate changes in mRNA and protein expression, respectively. NLRP3 inflammasome activation was detected by western blotting and ELISA. Tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum (ER) stress, was administrated preoperatively to explore its effects on the occurrence of PND. Immunofluorescence analysis was performed to evaluate the activation of astrocytes and microglia in the hippocampus, and hippocampus-dependent learning and memory were assessed using behavioral experiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In total, 521 DEGs were detected between the control and A/S groups. These DEGs were significantly enriched in biological processes related to metabolic processes and their regulation. Four hub genes (<i>Hspa5</i>, <i>Igf1r</i>, <i>Sfpq</i>, and <i>Xbp1</i>) were identified. Animal experiments have shown that mice in the A/S group exhibited cognitive impairments accompanied by increased <i>Hspa5</i> and <i>Xbp1</i> expression, ER stress, and activation of NLRP3 inflammasome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Inhibiting ER stress alleviated cognitive impairment in A/S mice; particularly, ER stress induced by A/S results in NLRP3 inflammasome activation and neuroinflammation. Moreover, the preoperative administration of TUDCA inhibited ER stress, NLRP3 inflammasome activation, and neuroinflammation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454186","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}
Yicong Wang, Hang Li, Yuesong Pan, Mengxing Wang, Xiaoling Liao, Yingying Yang, Weiqi Chen, Xia Meng, Yongjun Wang, Yilong Wang
Background
The purpose of this study was to explore the relationship between atrial fibrillation (AF), cerebral small vessel disease (CSVD), and ischemic stroke.
Methods
Data were extracted from China's Third National Stroke Registry (CNSR-III), which registered 15,166 patients in China. A total of 12,180 ischemic stroke patients were included excluding those diagnosed with TIA or without MRI. Logistic regression was to explore the relationship between AF, CSVD, and poor functional outcomes at 12-month follow-up. Cox regression is to explore AF, CSVD, and stroke recurrence as well as all-cause mortality at 12-month follow-up.
Results
The average age was 62.40 ± 11.22 years old, and 8362 (68.65%) were men at baseline. Patients with AF had an increased risk of stroke recurrence and all-cause mortality at 12-month follow-up. Those with AF and CSVD imaging such as lacunes, white matter hyperintensity (WMH), and the presence of cerebral microbleeds (CMBs) had an increased risk of poor prognosis. And those with both AF and CSVD burden had an increased risk of worse prognosis at 12-month follow-up.
Conclusion
Among Chinese patients with acute ischemic stroke, those with AF were associated with a higher risk of 12-month mortality and stroke recurrence. When AF was combined with some CSVD imaging features such as lacunes, WMH, presence of CMBs or burdens, the 12-month poor prognosis worsened.
{"title":"Cerebral small vessel disease was associated with the prognosis in ischemic stroke with atrial fibrillation","authors":"Yicong Wang, Hang Li, Yuesong Pan, Mengxing Wang, Xiaoling Liao, Yingying Yang, Weiqi Chen, Xia Meng, Yongjun Wang, Yilong Wang","doi":"10.1111/cns.70052","DOIUrl":"10.1111/cns.70052","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The purpose of this study was to explore the relationship between atrial fibrillation (AF), cerebral small vessel disease (CSVD), and ischemic stroke.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data were extracted from China's Third National Stroke Registry (CNSR-III), which registered 15,166 patients in China. A total of 12,180 ischemic stroke patients were included excluding those diagnosed with TIA or without MRI. Logistic regression was to explore the relationship between AF, CSVD, and poor functional outcomes at 12-month follow-up. Cox regression is to explore AF, CSVD, and stroke recurrence as well as all-cause mortality at 12-month follow-up.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The average age was 62.40 ± 11.22 years old, and 8362 (68.65%) were men at baseline. Patients with AF had an increased risk of stroke recurrence and all-cause mortality at 12-month follow-up. Those with AF and CSVD imaging such as lacunes, white matter hyperintensity (WMH), and the presence of cerebral microbleeds (CMBs) had an increased risk of poor prognosis. And those with both AF and CSVD burden had an increased risk of worse prognosis at 12-month follow-up.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Among Chinese patients with acute ischemic stroke, those with AF were associated with a higher risk of 12-month mortality and stroke recurrence. When AF was combined with some CSVD imaging features such as lacunes, WMH, presence of CMBs or burdens, the 12-month poor prognosis worsened.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454184","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}
Prior research has underscored the importance of sphingolipid metabolism in Parkinson's disease (PD) pathogenesis. Our objective was to explore the associations between plasma ceramide levels and PD patients with cognitive dysfunction (PD-CD).
Methods
We enrolled two study populations from Eastern China and the Parkinson's Progression Markers Initiative (PPMI), comprising 290 (100 HCs, 160 PDs, and 30 MSAs) and 429 (125 HCs and 304 PDs) participants, respectively. The plasma levels of ceramides (Cer 16:0, Cer 18:0, Cer 24:0, and Cer 24:1) were tested via HPLC–MS/MS analysis.
Results
Compared with those in the HC group, the plasma levels of Cer 18:0, Cer 24:1, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were higher in both the PD and MSA groups. Significant differences in the plasma levels of Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were observed among the PD-NC (PD with normal cognition), PD-MCI (PD with mild cognitive impairment), and PDD (PD dementia) groups, with the PDD group exhibiting the highest levels. PD patients with higher baseline levels of plasma ceramides (specifically, Cer 18:0, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0) demonstrated accelerated cognitive decline compared with individuals who had lower baseline plasma ceramide levels during the 5-year follow-up period. A biomarker panel including Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 could effectively differentiate PD-CD from PD-NC with notable diagnostic accuracy.
Conclusions
Our results indicate that plasma ceramide levels could potentially be used as diagnostic biomarkers for PD-CD.
{"title":"Exploratory Analysis of the Association Between Plasma Ceramide Alterations and Cognitive Dysfunction in Parkinson's Disease","authors":"Xu Liu, Xuanjing Liu, Yuning Liu, Bo Yang, Yangdanyu Li, Fujia Li, Kun Qian, Xuesong Liu, Lishun Xiao, Guiyun Cui, Chuanying Xu","doi":"10.1111/cns.70082","DOIUrl":"10.1111/cns.70082","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Prior research has underscored the importance of sphingolipid metabolism in Parkinson's disease (PD) pathogenesis. Our objective was to explore the associations between plasma ceramide levels and PD patients with cognitive dysfunction (PD-CD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We enrolled two study populations from Eastern China and the Parkinson's Progression Markers Initiative (PPMI), comprising 290 (100 HCs, 160 PDs, and 30 MSAs) and 429 (125 HCs and 304 PDs) participants, respectively. The plasma levels of ceramides (Cer 16:0, Cer 18:0, Cer 24:0, and Cer 24:1) were tested via HPLC–MS/MS analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with those in the HC group, the plasma levels of Cer 18:0, Cer 24:1, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were higher in both the PD and MSA groups. Significant differences in the plasma levels of Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were observed among the PD-NC (PD with normal cognition), PD-MCI (PD with mild cognitive impairment), and PDD (PD dementia) groups, with the PDD group exhibiting the highest levels. PD patients with higher baseline levels of plasma ceramides (specifically, Cer 18:0, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0) demonstrated accelerated cognitive decline compared with individuals who had lower baseline plasma ceramide levels during the 5-year follow-up period. A biomarker panel including Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 could effectively differentiate PD-CD from PD-NC with notable diagnostic accuracy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results indicate that plasma ceramide levels could potentially be used as diagnostic biomarkers for PD-CD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454185","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}
Alzheimer's disease (AD) is a complex neurodegenerative disorder, with recent research emphasizing the roles of microglia and their secreted extracellular vesicles in AD pathology. However, the involvement of specific molecular pathways contributing to neuronal death in the context of copper toxicity remains largely unexplored.
Objective
This study investigates the interaction between pyruvate kinase M2 (PKM2) and dihydrolipoamide S-acetyltransferase (DLAT), particularly focusing on copper-induced neuronal death in Alzheimer's disease.
Methods
Gene expression datasets were analyzed to identify key factors involved in AD-related copper toxicity. The role of DLAT was validated using 5xFAD transgenic mice, while in vitro experiments were conducted to assess the impact of microglial exosomes on neuronal PKM2 transfer and DLAT expression. The effects of inhibiting the PKM2 transfer via microglial exosomes on DLAT expression and copper-induced neuronal death were also evaluated.
Results
DLAT was identified as a critical factor in the pathology of AD, particularly in copper toxicity. In 5xFAD mice, increased DLAT expression was linked to hippocampal damage and cognitive decline. In vitro, microglial exosomes were shown to facilitate the transfer of PKM2 to neurons, leading to upregulation of DLAT expression and increased copper-induced neuronal death. Inhibition of PKM2 transfer via exosomes resulted in a significant reduction in DLAT expression, mitigating neuronal death and slowing AD progression.
Conclusion
This study uncovers a novel pathway involving microglial exosomes and the PKM2-DLAT interaction in copper-induced neuronal death, providing potential therapeutic targets for Alzheimer's disease. Blocking PKM2 transfer could offer new strategies for reducing neuronal damage and slowing disease progression in AD.
{"title":"Novel Insights Into DLAT's Role in Alzheimer's Disease-Related Copper Toxicity Through Microglial Exosome Dynamics","authors":"Xiang Ma, Yusheng Sun, Changchun Li, Man Wang, Qijiao Zang, Xuxia Zhang, Feng Wang, Yulan Niu, Jiai Hua","doi":"10.1111/cns.70064","DOIUrl":"10.1111/cns.70064","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is a complex neurodegenerative disorder, with recent research emphasizing the roles of microglia and their secreted extracellular vesicles in AD pathology. However, the involvement of specific molecular pathways contributing to neuronal death in the context of copper toxicity remains largely unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study investigates the interaction between pyruvate kinase M2 (PKM2) and dihydrolipoamide S-acetyltransferase (DLAT), particularly focusing on copper-induced neuronal death in Alzheimer's disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Gene expression datasets were analyzed to identify key factors involved in AD-related copper toxicity. The role of DLAT was validated using 5xFAD transgenic mice, while in vitro experiments were conducted to assess the impact of microglial exosomes on neuronal PKM2 transfer and DLAT expression. The effects of inhibiting the PKM2 transfer via microglial exosomes on DLAT expression and copper-induced neuronal death were also evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>DLAT was identified as a critical factor in the pathology of AD, particularly in copper toxicity. In 5xFAD mice, increased DLAT expression was linked to hippocampal damage and cognitive decline. In vitro, microglial exosomes were shown to facilitate the transfer of PKM2 to neurons, leading to upregulation of DLAT expression and increased copper-induced neuronal death. Inhibition of PKM2 transfer via exosomes resulted in a significant reduction in DLAT expression, mitigating neuronal death and slowing AD progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study uncovers a novel pathway involving microglial exosomes and the PKM2-DLAT interaction in copper-induced neuronal death, providing potential therapeutic targets for Alzheimer's disease. Blocking PKM2 transfer could offer new strategies for reducing neuronal damage and slowing disease progression in AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454187","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}
Asif Ahmad Bhat, Ehssan Moglad, Muhammad Afzal, Riya Thapa, Waleed Hassan Almalki, Imran Kazmi, Sami I. Alzarea, Haider Ali, Kumud Pant, Thakur Gurjeet Singh, Harish Dureja, Sachin Kumar Singh, Kamal Dua, Gaurav Gupta, Vetriselvan Subramaniyan
Huntington's disease (HD) is a devastating neurodegenerative disease that is manifested by a gradual loss of physical, cognitive, and mental abilities. As the disease advances, age has a major impact on the pathogenic signature of mutant huntingtin (mHTT) protein aggregation. This review aims to explore the intricate relationship between aging, mHTT toxicity, and cellular senescence in HD. Scientific data on the interplay between aging, mHTT, and cellular senescence in HD were collected from several academic databases, including PubMed, Google Scholar, Google, and ScienceDirect. The search terms employed were “AGING,” “HUNTINGTON'S DISEASE,” “MUTANT HUNTINGTIN,” and “CELLULAR SENESCENCE.” Additionally, to gather information on the molecular mechanisms and potential therapeutic targets, the search was extended to include relevant terms such as “DNA DAMAGE,” “OXIDATIVE STRESS,” and “AUTOPHAGY.” According to research, aging leads to worsening HD pathophysiology through some processes. As a result of the mHTT accumulation, cellular senescence is promoted, which causes DNA damage, oxidative stress, decreased autophagy, and increased inflammatory responses. Pro-inflammatory cytokines and other substances are released by senescent cells, which may worsen the neuronal damage and the course of the disease. It has been shown that treatments directed at these pathways reduce some of the HD symptoms and enhance longevity in experimental animals, pointing to a new possibility of treating the condition. Through their amplification of the harmful effects of mHTT, aging and cellular senescence play crucial roles in the development of HD. Comprehending these interplays creates novel opportunities for therapeutic measures targeted at alleviating cellular aging and enhancing HD patients’ quality of life.
亨廷顿氏病（Huntington's disease，HD）是一种破坏性神经退行性疾病，表现为身体、认知和智力能力的逐渐丧失。随着疾病的发展，年龄对突变亨廷顿蛋白（mHTT）聚集的致病特征有重大影响。本综述旨在探讨 HD 中衰老、mHTT 毒性和细胞衰老之间错综复杂的关系。有关 HD 中衰老、mHTT 和细胞衰老之间相互作用的科学数据来自多个学术数据库，包括 PubMed、Google Scholar、Google 和 ScienceDirect。搜索关键词为 "衰老"、"亨廷顿氏病"、"突变亨廷顿蛋白 "和 "细胞衰老"。此外，为了收集有关分子机制和潜在治疗目标的信息，搜索范围还扩大到了 "DNA 损伤"、"氧化应激 "和 "自闭症 "等相关术语。根据研究，衰老会通过一些过程导致 HD 病理生理学恶化。由于 mHTT 的积累，促进了细胞衰老，从而造成 DNA 损伤、氧化应激、自噬能力下降和炎症反应增加。衰老细胞会释放促炎细胞因子和其他物质，这可能会加重神经元损伤和病程。实验表明，针对这些途径的治疗可减轻一些 HD 症状，并延长实验动物的寿命，这为治疗这种疾病提供了一种新的可能性。通过放大 mHTT 的有害影响，衰老和细胞衰老在 HD 的发展过程中起着至关重要的作用。了解这些相互作用为采取旨在缓解细胞衰老和提高 HD 患者生活质量的治疗措施创造了新的机会。
{"title":"Therapeutic approaches targeting aging and cellular senescence in Huntington's disease","authors":"Asif Ahmad Bhat, Ehssan Moglad, Muhammad Afzal, Riya Thapa, Waleed Hassan Almalki, Imran Kazmi, Sami I. Alzarea, Haider Ali, Kumud Pant, Thakur Gurjeet Singh, Harish Dureja, Sachin Kumar Singh, Kamal Dua, Gaurav Gupta, Vetriselvan Subramaniyan","doi":"10.1111/cns.70053","DOIUrl":"10.1111/cns.70053","url":null,"abstract":"<p>Huntington's disease (HD) is a devastating neurodegenerative disease that is manifested by a gradual loss of physical, cognitive, and mental abilities. As the disease advances, age has a major impact on the pathogenic signature of mutant huntingtin (mHTT) protein aggregation. This review aims to explore the intricate relationship between aging, mHTT toxicity, and cellular senescence in HD. Scientific data on the interplay between aging, mHTT, and cellular senescence in HD were collected from several academic databases, including PubMed, Google Scholar, Google, and ScienceDirect. The search terms employed were “AGING,” “HUNTINGTON'S DISEASE,” “MUTANT HUNTINGTIN,” and “CELLULAR SENESCENCE.” Additionally, to gather information on the molecular mechanisms and potential therapeutic targets, the search was extended to include relevant terms such as “DNA DAMAGE,” “OXIDATIVE STRESS,” and “AUTOPHAGY.” According to research, aging leads to worsening HD pathophysiology through some processes. As a result of the mHTT accumulation, cellular senescence is promoted, which causes DNA damage, oxidative stress, decreased autophagy, and increased inflammatory responses. Pro-inflammatory cytokines and other substances are released by senescent cells, which may worsen the neuronal damage and the course of the disease. It has been shown that treatments directed at these pathways reduce some of the HD symptoms and enhance longevity in experimental animals, pointing to a new possibility of treating the condition. Through their amplification of the harmful effects of mHTT, aging and cellular senescence play crucial roles in the development of HD. Comprehending these interplays creates novel opportunities for therapeutic measures targeted at alleviating cellular aging and enhancing HD patients’ quality of life.</p>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454189","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}
Jing An, Lulu Wen, Haiyang Yu, Zhongqi Bu, Juan Feng
Aims
Insulin-like growth factor binding protein 2 (IGFBP2) is implicated in various neurodegenerative diseases. However, its role in Parkinson's disease (PD) is unclear.
Methods
PD rat model was established by 6-OHDA injection. After 3 weeks, mRNA-seq was conducted. Rats received rIGFBP2 via intra-MFB injection 6 h prior to 6-OHDA infusion, and the effect of IGFBP2 in PD rats was investigated by western blotting, IHC, specific kits, JC-1 staining, and TUNEL analysis. In vitro, PC12 cells were treated with 6-OHDA, and CCK-8, specific kits, Hoechst 33258 staining, Western blotting, and JC-1 staining were performed to assess the IGFBP2's role.
Results
mRNA-seq revealed DEGs in PD, with attention to downregulated IGFBP2. rIGFBP2 treatment aggravated neurobehavioral deficits, decreased TH expression, Ψm, ATP level and SOD, GSH-Px activities but increased α-synuclein, ROS, MDA, mitochondrial cytochrome c contents, cell apoptosis in 6-OHDA-lesioned rats, which might be mediated through inactivating IGF-1R/AKT pathway. In 6-OHDA-treated PC12 cells, rIGFBP2 aggravated cell injury, demonstrated by decreased cell viability and increased apoptosis, oxidative stress, and mitochondrial dysfunction. Co-treatment with rIGFBP2 and rIGF-1 partially reversed the effect of rIGFBP2 on cell damage.
Conclusion
IGFBP2 exacerbates neurodegeneration in PD through increasing oxidative stress, mitochondrial dysfunction, and apoptosis via inhibiting IGF-1R/AKT pathway.
{"title":"Insulin-Like Growth Factor Binding Protein 2 Drives Neurodegeneration in Parkinson's Disease: Insights From In Vivo and In Vitro Studies","authors":"Jing An, Lulu Wen, Haiyang Yu, Zhongqi Bu, Juan Feng","doi":"10.1111/cns.70076","DOIUrl":"https://doi.org/10.1111/cns.70076","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Insulin-like growth factor binding protein 2 (IGFBP2) is implicated in various neurodegenerative diseases. However, its role in Parkinson's disease (PD) is unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>PD rat model was established by 6-OHDA injection. After 3 weeks, mRNA-seq was conducted. Rats received rIGFBP2 via intra-MFB injection 6 h prior to 6-OHDA infusion, and the effect of IGFBP2 in PD rats was investigated by western blotting, IHC, specific kits, JC-1 staining, and TUNEL analysis. In vitro, PC12 cells were treated with 6-OHDA, and CCK-8, specific kits, Hoechst 33258 staining, Western blotting, and JC-1 staining were performed to assess the IGFBP2's role.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>mRNA-seq revealed DEGs in PD, with attention to downregulated IGFBP2. rIGFBP2 treatment aggravated neurobehavioral deficits, decreased TH expression, Ψm, ATP level and SOD, GSH-Px activities but increased α-synuclein, ROS, MDA, mitochondrial cytochrome <i>c</i> contents, cell apoptosis in 6-OHDA-lesioned rats, which might be mediated through inactivating IGF-1R/AKT pathway. In 6-OHDA-treated PC12 cells, rIGFBP2 aggravated cell injury, demonstrated by decreased cell viability and increased apoptosis, oxidative stress, and mitochondrial dysfunction. Co-treatment with rIGFBP2 and rIGF-1 partially reversed the effect of rIGFBP2 on cell damage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>IGFBP2 exacerbates neurodegeneration in PD through increasing oxidative stress, mitochondrial dysfunction, and apoptosis via inhibiting IGF-1R/AKT pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 10","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443392","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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