Experimental Neurology最新文献

{"title":"Cellular expression of low-density lipoprotein receptor-related protein 1 and amyloid beta deposition in human and rat epileptogenic brain","authors":"Annemieke Rozeboom ,&nbsp;Diede W.M. Broekaart ,&nbsp;Jasper J. Anink ,&nbsp;Lynn Boonkamp ,&nbsp;Sander Idema ,&nbsp;Charlotte E. Teunissen ,&nbsp;Eleonora Aronica ,&nbsp;Jan A. Gorter ,&nbsp;Erwin A. van Vliet","doi":"10.1016/j.expneurol.2025.115149","DOIUrl":"10.1016/j.expneurol.2025.115149","url":null,"abstract":"<div><div>Decreased capillary expression of low-density lipoprotein receptor-related protein 1 (LRP1) has been linked to increased brain amyloid beta (Aβ) accumulation in Alzheimer's disease (AD). Aβ accumulation has also been observed in (a subset of) temporal lobe epilepsy (TLE) patients, suggesting a potential link between epilepsy and AD. This study examines cellular LRP1 expression in human and rat epileptogenic brain tissue to explore LRP1's role in epilepsy.</div><div>LRP1 expression and localization were analyzed in hippocampal sections from patients with status epilepticus (SE, <em>n</em> = 12), TLE (n = 12), autopsy controls (<em>n</em> = 20), and AD (<em>n</em> = 10) using immunohistochemistry. Soluble Aβ levels and deposits were compared across TLE, AD, and control tissues. LRP1 expression was also studied in an electrical post-SE rat model of TLE.</div><div>Decreased capillary LRP1 expression was found in both human and rat brain tissue (SE and TLE). Higher LRP1 expression was detected in CA1 neurons (only in human TLE) and glial cells (SE and TLE). Aβ deposits were observed in only one out of 12 TLE patients, and soluble Aβ levels were not significantly elevated. In contrast, AD patients showed decreased capillary LRP1 expression accompanied by Aβ plaques and increased soluble Aβ40/42 levels.</div><div>The significant reduction in LRP1 expression in brain capillaries in both adult human and rat TLE was not clearly associated with notable Aβ accumulation implying that alternative amyloid clearance mechanisms beyond LRP1 in blood vessels might be at play. It also supports previous findings indicating that Aβ pathology may be less prominent in adult TLE than some studies suggest.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115149"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A post-injury immune challenge with lipopolysaccharide following adult traumatic brain injury alters neuroinflammation and the gut microbiome acutely, but has little effect on chronic outcomes","authors":"Sarah S.J. Rewell ,&nbsp;Ali Shad ,&nbsp;Lingjun Chen ,&nbsp;Matthew Macowan ,&nbsp;Erskine Chu ,&nbsp;Natasha Gandasasmita ,&nbsp;Pablo M. Casillas-Espinosa ,&nbsp;Jian Li ,&nbsp;Terence J. O'Brien ,&nbsp;Bridgette D. Semple","doi":"10.1016/j.expneurol.2025.115150","DOIUrl":"10.1016/j.expneurol.2025.115150","url":null,"abstract":"<div><div>Patients with a traumatic brain injury (TBI) are susceptible to hospital-acquired infections, presenting a significant challenge to an already-compromised immune system. The consequences and mechanisms by which this dual insult worsens outcomes are poorly understood. This study aimed to explore how a systemic immune stimulus (lipopolysaccharide, LPS) influences outcomes following experimental TBI in young adult mice. Male and female C57Bl/6J mice underwent controlled cortical impact or sham surgery, followed by 1 mg/kg i.p. LPS or saline-vehicle at 4 days post-TBI, before behavioral assessment and tissue collection at 6 h, 24 h, 7 days or 6 months. LPS induced acute sickness behaviors including weight loss, transient hypoactivity, and increased anxiety-like behavior. Early systemic immune activation by LPS was confirmed by increased spleen weight and serum cytokines. In brain tissue, gene expression analysis revealed a time course of inflammatory immune activation in TBI or LPS-treated mice (e.g., IL-1β, IL-6, CCL2, TNFα), which was exacerbated in TBI + LPS mice. This group also presented with fecal microbiome dysbiosis at 24 h post-LPS, with reduced bacterial diversity and changes in the relative abundance of key bacterial genera associated with sub-acute neurobehavioral and immune changes. Chronically, TBI induced hyperactivity and cognitive deficits, brain atrophy, and increased seizure susceptibility, similarly in vehicle and LPS-treated groups. Together, findings suggest that an immune challenge with LPS early after TBI, akin to a hospital-acquired infection, alters the acute neuroinflammatory response to injury, but has no lasting effects. Future studies could consider more clinically-relevant models of infection to build upon these findings.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115150"},"PeriodicalIF":4.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel peptidomimetic compounds attenuate hypoxic-ischemic brain injury in neonatal rats","authors":"Xiaodi F. Chen ,&nbsp;Brynn Kroke ,&nbsp;Jun Ni ,&nbsp;Christian Munoz ,&nbsp;Mark Appleman ,&nbsp;Bryce Jacobs ,&nbsp;Tuong Tran ,&nbsp;Kevin V. Nguyen ,&nbsp;Chenxi Qiu ,&nbsp;Barbara S. Stonestreet ,&nbsp;John Marshall","doi":"10.1016/j.expneurol.2025.115151","DOIUrl":"10.1016/j.expneurol.2025.115151","url":null,"abstract":"<div><div>Hypoxic-ischemic (HI) brain injury is a common neurological problem in neonates. The postsynaptic density protein-95 (PSD-95) is an excitatory synaptic scaffolding protein that regulates synaptic function, and represents a potential therapeutic target to attenuate HI brain injury. Syn3 and d-Syn3 are novel high affinity cyclic peptides that bind the PDZ3 domain of PSD-95. We investigated the neuroprotective efficacy of Syn3 and d-Syn3 after exposure to HI in neonatal rodents. Postnatal (P) day-7 rats were treated with Syn3 and d-Syn3 at zero, 24, and 48-h after carotid artery ligation and 90-min of 8 % oxygen. Hemispheric volume atrophy and Iba-1 positive microglia were quantified by cresyl violet and immunohistochemical staining. Treatment with Syn3 and d-Syn3 reduced tissue volume loss by 47.0 % and 41.0 % in the male plus female, and by 42.1 % and 65.0 % in the male groups, respectively. Syn3 reduced tissue loss by 52.3 % in females. D-Syn3 reduced Iba-1 positive microglia/DAPI ratios in the pooled group, males, and females. Syn3 effects were observed in the pooled group and females. Changes in Iba-1 positive microglia/DAPI cellular ratios correlated directly with reduced hemispheric volume loss, suggesting that Syn3 and d-Syn3 provide neuroprotection in part by their effects on Iba-1 positive microglia. The pathogenic cis phosphorylated Thr231 in Tau (cis P-tau) is a marker of neuronal injury. Cis P-tau was induced in cortical cells of the placebo-treated pooled group, males and females after HI, and reduced by treatment with d-Syn3. Therefore, treatment with these peptidomimetic agents exert neuroprotective effects after exposure of neonatal subjects to HI related brain injury.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115151"},"PeriodicalIF":4.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Albumin antagonizes Alzheimer’s disease-related Tau pathology and enhances cognitive performance by inhibiting aberrant Tau aggregation","authors":"Ming-Xuan Yang ,&nbsp;Zhuo-Ran Wang ,&nbsp;Yan-Li Zhang ,&nbsp;Zhi-Na Zhang ,&nbsp;Yan-Li Li ,&nbsp;Rui Wang ,&nbsp;Qiang Su ,&nbsp;Jun-Hong Guo","doi":"10.1016/j.expneurol.2025.115155","DOIUrl":"10.1016/j.expneurol.2025.115155","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive impairment, for which effective treatments remain lacking. Albumin (ALB) is an essential carrier protein found in various body fluids, playing crucial roles in anti-inflammatory processes, antioxidation, and signal transduction. Recent research indicates that ALB may play a significant role in the development and progression of AD, though its specific function is not yet fully understood. In this study, we observed a link between serum ALB levels and cognitive performance in the elderly. Administration of ALB intranasally was shown to enhance learning and memory in MAPT/P301S transgenic mice, markedly decreasing hyperphosphorylation of Tau protein and reducing neuronal apoptosis. In a neuronal cell model overexpressing Tau, ALB administration in vitro attenuated Tau-induced toxicity and reduced the production of phosphorylated Tau. Additionally, co-incubation of Tau with ALB significantly reduced the formation of neurofibrillary tangles. These results suggest that ALB improves AD-related cognitive function by preventing the pathological aggregation of Tau and reducing its abnormal phosphorylation. Furthermore, ALB's neuroprotective effect helps prevent neuronal apoptosis in the cortex and hippocampus, providing potential targets for AD prevention and treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115155"},"PeriodicalIF":4.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sleep fragmentation impairs cognitive function and exacerbates Alzheimer's disease-related pathology in a mouse model by disrupting mitochondrial biogenesis","authors":"Shunjie Liu,&nbsp;Xingyi Liu,&nbsp;Man Ke,&nbsp;Jinliang Wang","doi":"10.1016/j.expneurol.2025.115153","DOIUrl":"10.1016/j.expneurol.2025.115153","url":null,"abstract":"<div><div>A large proportion of Alzheimer's disease (AD) patients suffer from various types of chronic sleep disturbances, including sleep fragmentation (SF). In addition, impaired mitochondrial biogenesis is an important feature of AD, but whether it is altered in sleep disorders has not been fully elucidated. Hence, we aimed to investigate the relationship between SF and mitochondrial biogenesis and the possible impact of SF on AD-related pathology. In this study, thirty-six 9-month-old 3xTgAD model mice and thirty-six 9-month-old wild-type (WT) C57BL/6 J mice were divided into a control group (6 weeks of normal sleep), a SF group (6 weeks of SF) and a SF + recovery sleep group (6 weeks of SF followed by 2 weeks of recovery sleep). Cognitive functions were assessed by behavioural experiments. Mitochondrial structure and function and the activity of a classic mitochondrial biogenesis signalling pathway were investigated using transmission electron microscopy (TEM), reverse transcription quantitative polymerase chain reaction (RT–qPCR), immunofluorescence and Western blotting. Markers of AD-related pathology, including the levels of amyloid β (Aβ) and tau proteins, were assessed by immunofluorescence and Western blotting. The expression of insulin-degrading enzyme (IDE) was assessed by Western blotting. We found that long-term SF impaired the cognitive functions of the mice. In addition, chronic SF reduced the expression of mitochondrial respiratory chain components, the number of mitochondria, the fluorescence intensity of COX-IV, the level of mitochondrial DNA (mtDNA) and the expression of crucial regulators of the AMPK/SIRT-1/PGC-1α signalling pathway in the mouse prefrontal cortex and hippocampus, while recovery sleep could partly abrogate these effects. Moreover, SF reduced the protein level of IDE and increased the Aβ burden and tau hyperphosphorylation. This study demonstrates that chronic SF can negatively regulate the AMPK/SIRT-1/PGC-1α signalling pathway to disrupt mitochondrial biogenesis in the brains of mice, which may subsequently exacerbate AD-related pathology by decreasing the expression of IDE.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115153"},"PeriodicalIF":4.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overexpressed CD73 attenuates GSDMD-mediated astrocyte pyroptosis induced by cerebral ischemia-reperfusion injury through the A2B/NF-κB pathway","authors":"Hao Zhuang ,&nbsp;Wen Lei ,&nbsp;Qiang Wu ,&nbsp;Songyun Zhao ,&nbsp;Yunxuan Zhao ,&nbsp;Shizhe Zhang ,&nbsp;Ning Zhao ,&nbsp;Jun Sun ,&nbsp;Yuankun Liu","doi":"10.1016/j.expneurol.2025.115152","DOIUrl":"10.1016/j.expneurol.2025.115152","url":null,"abstract":"<div><div>Ischemic stroke, resulting from the blockage or narrowing of cerebral vessels, causes brain tissue damage due to ischemia and hypoxia. Although reperfusion therapy is essential to restore blood flow, it may also result in reperfusion injury, causing secondary damage through mechanisms like oxidative stress, inflammation, and excitotoxicity. These effects significantly impact astrocytes, neurons, and endothelial cells, aggravating brain injury and disrupting the blood-brain barrier. CD73, an ectoenzyme that regulates adenosine production through ATP hydrolysis, plays a critical role in purinergic signaling and neuroprotection. During ischemic stroke, CD73 expression is dynamically regulated in response to ischemia and inflammation. It catalyzes the conversion of AMP to adenosine, which activates adenosine receptors to exert neuroprotective effects. Targeting the CD73-adenosine pathway presents a potential therapeutic strategy for mitigating ischemic stroke damage. Pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasomes like NLRP3 and caspases, plays a significant role in cerebral ischemia-reperfusion injury. Astrocytes, the most abundant CNS cells, contribute to both neuroprotection and injury, with pyroptosis exacerbating inflammation and brain damage. Regulating astrocyte pyroptosis is a promising therapeutic target. Our study investigates CD73's role in regulating astrocyte pyroptosis during ischemia-reperfusion injury. Using CD73 knockout mice and overexpression models, along with in vitro oxygen-glucose deprivation/reperfusion experiments, we found that CD73 overexpression reduces GSDMD-mediated astrocyte pyroptosis via the A2B/NF-κB pathway. These findings offer a novel approach to reducing neuroinflammation, protecting astrocytes, and improving outcomes in ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115152"},"PeriodicalIF":4.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic proteomic and phosphoproteomic analysis reveals key pathways and targets in the early stages of high-altitude traumatic brain injury","authors":"Wenbing Zhao ,&nbsp;Xiyan Zhu ,&nbsp;Xiang Chu ,&nbsp;Hao Wang ,&nbsp;Diyou Chen ,&nbsp;Yibo Zhao ,&nbsp;Yishan Yao ,&nbsp;Zhikang Liao ,&nbsp;Hongyi Xiang ,&nbsp;Wei Dai ,&nbsp;Jingru Xie ,&nbsp;Xing Chen ,&nbsp;Sen Li ,&nbsp;Pengfei Wu ,&nbsp;Hui Zhao","doi":"10.1016/j.expneurol.2025.115147","DOIUrl":"10.1016/j.expneurol.2025.115147","url":null,"abstract":"<div><div>Traumatic brain injury (TBI), particularly at high altitudes (HA-TBI), is a leading cause of mortality and disability, yet clear diagnostic and treatment protocols are lacking. This study explores the early pathophysiological changes occurring within 24 h following HA-TBI, with a focus on differentially expressed proteins (DEPs) and phosphorylated proteins (DEPPs). Using a low-pressure hypoxic chamber to simulate high-altitude conditions combined with a controllable cortical impact (CCI) model, we established a rat model of HA-TBI. Neurological function was evaluated using the modified Neurologic Severity Score (mNSS), while neuropathological and inflammatory responses following HA-TBI were evaluated through hematoxylin and eosin (HE) staining, immunofluorescence, Western blot (WB), and Enzyme-Linked Immunosorbent Assay (ELISA). In-depth proteomic and phosphoproteomic analyses were performed on the cerebral cortex at 6, 12, and 24 h post-injury. Bioinformatic analysis identified time-dependent DEPs, revealing dynamic changes in mRNA metabolism, ATP metabolism, and MAPK signaling during the early stages of HA-TBI. Common DEPs at 6, 12, and 24 h post-injury were linked to complement and coagulation cascades. Time-dependent DEPPs influenced synaptic structure and neurotransmission, with early changes in glutamatergic synapses being especially pronounced. Key pathways, including the complement and coagulation cascades and dopaminergic synapses, emerged as central to the injury response. Furthermore, proteins such as AHSG, APOA1, GRIN2B, phospho-GSK3β-S9, and CAMK2G were identified as critical regulators in these pathways. WB validated these findings, offering new insights into the mechanisms underlying HA-TBI and highlighting potential therapeutic targets for early intervention in high-altitude trauma.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115147"},"PeriodicalIF":4.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) with voluntary and forced exercise in a rat model of ischemic stroke","authors":"Takayuki Nagase,&nbsp;Takao Yasuhara,&nbsp;Kyohei Kin,&nbsp;Susumu Sasada,&nbsp;Satoshi Kawauchi,&nbsp;Satoru Yabuno,&nbsp;Chiaki Sugahara,&nbsp;Yuichi Hirata,&nbsp;Hayato Miyake,&nbsp;Tatsuya Sasaki,&nbsp;Koji Kawai,&nbsp;Shun Tanimoto,&nbsp;Tomoya Saijo,&nbsp;Shota Tanaka","doi":"10.1016/j.expneurol.2025.115145","DOIUrl":"10.1016/j.expneurol.2025.115145","url":null,"abstract":"<div><div>Ischemic stroke results in significant long-term disability and mortality worldwide. Although existing therapies, such as recombinant tissue plasminogen activator and mechanical thrombectomy, have shown promise, their application is limited by stringent conditions. Mesenchymal stem cell (MSC) transplantation, especially using SB623 cells (modified human bone marrow-derived MSCs), has emerged as a promising alternative, promoting neurogenesis and recovery. This study evaluated the effects of voluntary and forced exercise, alone and in combination with SB623 cell transplantation, on neurological and psychological outcomes in a rat model of ischemic stroke. Male Wistar rats that had undergone middle cerebral artery occlusion (MCAO) were divided into six groups: control, voluntary exercise (V-Ex), forced exercise (F-Ex), SB623 transplantation, SB623 + V-Ex, and SB623 + F-Ex. Voluntary exercise was facilitated using running wheels, while forced exercise was conducted on treadmills. Neurological recovery was assessed using the modified neurological severity score (mNSS). Psychological symptoms were evaluated through the open field test (OFT) and forced swim test (FST), and neurogenesis was assessed via BrdU labeling. Both exercise groups exhibited significant changes in body weight post-MCAO. Both exercises enhanced the treatment effect of SB623 transplantation. The forced exercise showed a stronger treatment effect on ischemic stroke than voluntary exercise alone, and the sole voluntary exercise improved depression-like behavior. The SB623 + F-Ex group demonstrated the greatest improvements in motor function, infarct area reduction, and neurogenesis. The SB623 + V-Ex group was most effective in alleviating depression-like behavior. Future research should optimize these exercise protocols and elucidate the underlying mechanisms to develop tailored rehabilitation strategies for stroke patients.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115145"},"PeriodicalIF":4.6,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The immune-inflammatory responses on the hypothalamic-pituitary-adrenal axis and the neurovascular unit in perioperative neurocognitive disorder","authors":"So Yeong Cheon ,&nbsp;Matthew R. Cho ,&nbsp;So Yeon Kim ,&nbsp;Bon-Nyeo Koo","doi":"10.1016/j.expneurol.2025.115146","DOIUrl":"10.1016/j.expneurol.2025.115146","url":null,"abstract":"<div><div>Perioperative neurocognitive disorders (PNDs) refer to a wide spectrum of cognitive impairment persisting days to even after a year postoperative with significant morbidity and mortality. However, despite much efforts involving perioperative managements, PNDs are still prevalent with no standard preventative and therapeutic strategy. To overcome PNDs, a better understanding of pathophysiology of PNDs is crucial and a large number of studies have proven that immune-inflammatory responses from surgical stress are involved in the abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis and destabilization of neurovascular unit (NVU) that lead to PNDs. The HPA axis is one of the key components to maintaining physiological homeostasis in response to stress. Under normal conditions, the HPA axis is involved in multiple roles from memory consolidation to regulating the circadian rhythm by activating adrenal cortex to secret cortisol. However, when overwhelmed with inflammatory response from surgical stress, HPA axis may be abnormally activated to release excessive glucocorticoids to cause PNDs. In addition, NVU, the functional unit of the brain essential for maintaining blood brain barrier and cerebral blood flow, is another possible factor that may lead to PNDs as compromised NVU from inflammatory response can result in disrupted blood brain barrier and impaired brain homeostasis. Therefore, the interaction of immune-inflammatory response with the HPA axis and the NVU seems to play a significant role and therapeutic and/or preventive strategies focused on these interactions may be promising direction for future managements of PNDs.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115146"},"PeriodicalIF":4.6,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal administration of stem cell-derived exosome alleviates cognitive impairment against subarachnoid hemorrhage","authors":"Shuho Gotoh ,&nbsp;Masahito Kawabori ,&nbsp;Sho Yamaguchi ,&nbsp;Yo Nakahara ,&nbsp;Erika Yoshie ,&nbsp;Kohtarou Konno ,&nbsp;Yuki Mizuno ,&nbsp;Yoichiro Fujioka ,&nbsp;Yusuke Ohba ,&nbsp;Yuji Kuge ,&nbsp;Masahiko Watanabe ,&nbsp;Miki Fujimura","doi":"10.1016/j.expneurol.2025.115143","DOIUrl":"10.1016/j.expneurol.2025.115143","url":null,"abstract":"<div><h3>Introduction</h3><div>Brain damage caused by subarachnoid hemorrhage (SAH) currently lacks effective treatment, leading to stagnation in the improvement of functional outcomes for decades. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells (MSC), which effectively attenuate neuronal apoptosis and inflammation in neurological diseases. Due to the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a novel approach for targeting the brain. In this study, we investigate the effects of intranasally administered MSC-derived exosomes in a SAH animal model and elucidate their mode of action.</div></div><div><h3>Methods</h3><div>Exosomes were isolated from the cell supernatants of amnion-derived MSC. SAH was induced in 8-week-old Sprague-Dawley rats using an autologous blood prechiasmatic cistern injection model. A total of 1.2 × 10¹⁰ particles of exosomes in 200 μL of PBS or PBS alone were intranasally administered immediately and 24 h post-injury. Neurological function was assessed up to 7 days after injury, and histological analysis was performed to evaluate their anti-apoptotic and anti-inflammatory effects. The biodistribution of exosomes was assessed using PET/CT imaging of ⁶⁴Cu labeled exosome. In vitro analyses were performed using primary glial cells and cell lines to evaluate the anti-inflammatory effects of the exosomes.</div></div><div><h3>Results</h3><div>Animals treated with exosomes exhibited significant improvement in cognitive function compared with PBS treated animal. Apoptotic cells and inflammation were reduced for the exosome group in the hippocampal CA1 area and in cortex, resulting in better neuronal cell survival. Blood brain barrier permeability was also preserved in the exosome group. Nuclear imaging revealed that exosomes were primarily transferred to the olfactory nerve and cerebrum; furthermore, exosomes were also observed in the trigeminal nerve and brainstem, where exosomes were co-localized with microglia and with endothelial cells. In vitro assessment showed that exosome administration ameliorated inflammation and prevented the death of glial cells.</div></div><div><h3>Conclusions</h3><div>MSC-derived exosomes were successfully transferred into the brain through intranasal administration and alleviated brain damage following SAH.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"386 ","pages":"Article 115143"},"PeriodicalIF":4.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}