Neurochemistry international最新文献

{"title":"Oral administration of osthole mitigates maladaptive behaviors through PPARα activation in mice subjected to repeated social defeat stress","authors":"Chao-Wei Chen ,&nbsp;Wei-Lan Yeh ,&nbsp;Vichuda Charoensaensuk ,&nbsp;Chingju Lin ,&nbsp;Liang-Yo Yang ,&nbsp;Mao-Kai Chen ,&nbsp;Tong Yeh ,&nbsp;Cheng-Fang Tsai ,&nbsp;Dah-Yuu Lu","doi":"10.1016/j.neuint.2024.105811","DOIUrl":"10.1016/j.neuint.2024.105811","url":null,"abstract":"<div><p>Psychological stress induces neuroinflammatory responses, which are associated with the pathogenesis of various psychiatric disorders, such as posttraumatic stress disorder and anxiety. Osthole—a natural coumarin isolated from the seeds of the Chinese herb <em>Cnidium monnieri</em>—exerts anti-inflammatory and antioxidative effects on the central nervous system. However, the therapeutic benefits of osthole against psychiatric disorders remain largely unknown. We previously demonstrated that mice subjected to repeated social defeat stress (RSDS) in the presence of aggressor mice exhibited symptoms of posttraumatic stress disorder, such as social avoidance and anxiety-like behaviors. In this study, we investigated the therapeutic effects of osthole and the underlying molecular mechanisms. Osthole exerted therapeutic effects on cognitive behaviors, mitigating anxiety-like behaviors and social avoidance in a mouse model of RSDS. The anti-inflammatory response induced by the oral administration of osthole was strengthened through the upregulation of heme oxygenase-1 expression. The expression of PPARα was inhibited in mice subjected to RSDS. Nonetheless, osthole treatment reversed the inhibition of PPARα expression. We identified a positive correlation between heme oxygenase-1 expression and PPARα expression in osthole-treated mice. In conclusion, osthole has potential as a Chinese herbal medicine for anxiety disorders. When designing novel drugs for psychiatric disorders, researchers should consider targeting the activation of PPARα.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"179 ","pages":"Article 105811"},"PeriodicalIF":4.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caspase-1 inhibitor CZL80 protects against acute seizures via amplifying the inhibitory neural transmission","authors":"Yingying Tang ,&nbsp;Yao Liu ,&nbsp;Yiwei Gong ,&nbsp;Shuo Zhang ,&nbsp;Sunliang Cui ,&nbsp;Yi Wang ,&nbsp;Zhong Chen ,&nbsp;Cenglin Xu","doi":"10.1016/j.neuint.2024.105809","DOIUrl":"10.1016/j.neuint.2024.105809","url":null,"abstract":"<div><p>Current anti-seizure medications (ASDs) primarily target ion channels or neurotransmissions; however, their practicability is limited by unwanted side-effects and pharmacoresistance. Cumulative evidence has proposed pro-inflammatory caspase-1 as a potential target for developing ASDs. In this study, we showed that the small-molecular caspase-1 inhibitor CZL80 can prevent seizures in various models including the maximal electroshock (MES), the pentylenetetrazol (PTZ), and the amygdaloid kindled models. Specifically, we discovered that CZL80 prevented death, reduced the duration of generalized seizures, and increased the threshold of generalized seizures in a dose-dependent manner in the MES model. In the PTZ model, CZL80 decreased the seizure stages, prolonged the latency to stage 4 seizures, and decreased the death rate. And in amygdaloid kindled rats, CZL80 inhibited the seizure stages, shortened the durations of both generalized seizures and after-discharges. And the anti-seizure efficacy of CZL80 was diminished in caspase-1 knockout mice. <em>In vitro</em> electrophysiology recordings revealed that CZL80 was able to decreased the excitability of glutamatergic pyramidal neurons, as denoted by reducing the spontaneous neuronal firings and increasing the rheobase injected currents to elicit action potentials. Furthermore, CZL80 was able to increase the amplitudes of inhibitory post-synaptic currents (IPSC), while the excitatory post-synaptic currents (EPSC) were not influenced. Lastly, daily administration of CZL80 for 3 weeks did not influence the normal locomotor functions in mice. In sum, our results highlighted CZL80 as a potential anti-seizure therapy with therapeutic significance.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"179 ","pages":"Article 105809"},"PeriodicalIF":4.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parkin, a Parkinson's disease-associated protein, mediates the mitophagy that plays a vital role in the pathophysiology of major depressive disorder","authors":"Yi Zhang","doi":"10.1016/j.neuint.2024.105808","DOIUrl":"10.1016/j.neuint.2024.105808","url":null,"abstract":"<div><p>Depression is a complex mood disorder with multifactorial etiology and is also the most frequent non-motor symptom of Parkinson's disease. Emerging research suggests a potential link between mitochondrial dysfunction and the pathophysiology of major depressive disorder. By synthesizing current knowledge and research findings, this review sheds light on the intricate relationship between Parkin, a protein classically associated with Parkinson's disease, and mitochondrial quality control mechanisms (e.g., mitophagy, mitochondrial biogenesis, and mitochondrial dynamic), specifically focusing on their relevance in the context of depression. Additionally, the present review discusses therapeutic strategies targeting Parkin-medicated mitophagy and calls for further research in this field. These findings suggest promise for the development of novel depression treatments through modulating Parkin-mediated mitophagy.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"179 ","pages":"Article 105808"},"PeriodicalIF":4.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enriched environment treatment promotes neurofunctional recovery by regulating the ALK5/Smad2/3/Gadd45β signaling pathway in rats with cerebral ischemia /reperfusion injury","authors":"Gang Liu ,&nbsp;Chenchen Xie ,&nbsp;Jiani Li ,&nbsp;Xia Jiang ,&nbsp;Hao Tang ,&nbsp;Changqing Li ,&nbsp;Keming Zhang","doi":"10.1016/j.neuint.2024.105806","DOIUrl":"10.1016/j.neuint.2024.105806","url":null,"abstract":"<div><p>It has been demonstrated that an enriched environment (EE) treatment can alter neuroplasticity in neurodegenerative diseases. However, the role of EE treatment in ischemic stroke remains unclear. Previous findings have revealed that EE treatment can promote cerebral activin-receptor-like-kinase-5 (ALK5) expression after cerebral ischemia/reperfusion (I/R) injury. ALK5 has been identified as a potential mediator of neuroplasticity through its modulation of Smad2/3 and Gadd45β. Therefore, the aim of this study was to investigate whether EE treatment could promote neurofunctional recovery by regulating the ALK5/Smad2/3/Gadd45β pathway. The study utilized the rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). The ALK5/Smad2/3/Gadd45β signaling pathway changes were evaluated using western blotting (WB). Brain injury was assessed by infarct volume and neurobehavioral scores. The effect of EE treatment on neurogenesis was evaluated using Doublecortin (DCX) and Nestin, axonal plasticity with biotinylated dextran amine (BDA) nerve tracing, and dendritic plasticity was assessed using Golgi-Cox staining. EE treatment has been demonstrated to modulate the Smad2/3/Gadd45β pathway by regulating the expression of ALK5. The protective effects of EE treatment on brain infarct volume, neurological function, newborn neurons, dendritic and axonal plasticity following cerebral I/R injury were counteracted by ALK5 silencing. EE treatment can enhance neurofunctional recovery after cerebral I/R injury, which is achieved by regulating the ALK5/Smad2/3/Gadd45β signaling pathway to promote neuroplasticity.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"178 ","pages":"Article 105806"},"PeriodicalIF":4.4,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141638491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The flavonoid fisetin reduces multiple physiological risk factors for dementia","authors":"Pamela Maher","doi":"10.1016/j.neuint.2024.105805","DOIUrl":"10.1016/j.neuint.2024.105805","url":null,"abstract":"<div><p>Dementia is a growing problem around the globe as the world's population continues to age. Multiple studies have identified potentially modifiable risk factors for the development of dementia suggesting that addressing some or all of these risk factors might have a significant impact on the aging population worldwide. However, this is not always as straightforward as it seems since many of these risk factors are currently treated with drugs specific to the risk factor. Moreover, since people can have multiple risk factors, addressing each of them individually could be highly problematic as it would likely lead to negative outcomes associated with polypharmacy and, in the long term, could do significant harm. A potential alternative is to identify compounds that have shown efficacy against a number of these different risk factors. As discussed in this review, there is strong evidence that the flavonol fisetin is one such compound. In animal studies it has shown efficacy against many of the risk factors that have been associated with an increased risk of developing dementia and also exhibits direct neuroprotective effects. Thus, further human research on fisetin in the context of dementia risk factors is clearly warranted.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"178 ","pages":"Article 105805"},"PeriodicalIF":4.4,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential anxiolytic therapeutics from Hybanthus enneaspermus (L.) F. Muell. - mitigate anxiety by plausibly modulating the GABAA-Cl- channel","authors":"Liesl Maria Fernandes e Mendonça ,&nbsp;Arun Bhimrao Joshi ,&nbsp;Anant Bhandarkar ,&nbsp;Shamshad Shaikh ,&nbsp;Samantha Fernandes ,&nbsp;Himanshu Joshi ,&nbsp;Shrinivas Joshi","doi":"10.1016/j.neuint.2024.105804","DOIUrl":"10.1016/j.neuint.2024.105804","url":null,"abstract":"<div><p>Anxiety is a commonly prevailing psychological disorder that requires effective treatment, wherein phytopharmaceuticals and nutraceuticals could offer a desirable therapeutic profile. <em>Hybanthus enneaspermus</em> (L.) F. Muell. is a powerful medicinal herb, reportedly effective against several ailments, including psychological disorders. The current research envisaged evaluating the anxiolytic potential of the ethanolic extract of <em>Hybanthus enneaspermus</em> (EEHE) and its toluene insoluble biofraction (ITHE) employing experimental and computational approaches. Elevated Plus Maze, Light and Dark Transition, Mirror Chamber, Hole board and Open field tests were used as screening models to assess the antianxiety potential of 100, 200 and 400 mg/kg body weight of EEHE and ITHE in rats subjected to social isolation, using Diazepam as standard. The brains of rats exhibiting significant anxiolytic activity were dissected for histopathological and biochemical studies. Antioxidant enzymes like catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, glutathione reductase; and neurotransmitters <em>viz</em>. monoamines (serotonin, noradrenaline, dopamine), Gamma-aminobutyric acid (GABA), and glutamate were quantified in the different regions of rats’ brain (cortex, hippocampus, pons, medulla oblongata, cerebellum). Chromatographic techniques were used to isolate phytoconstituents from the fraction exhibiting significant activity that were characterized by spectroscopic methods and subjected to <em>in silico</em> molecular docking. ITHE at 400 mg/kg body weight significantly mitigated anxiety in all the screening models (<em>p</em> &lt; 0.05), reduced the inflammatory vacuoles and necrosis (<em>p</em> &lt; 0.05) and potentiated the antioxidant enzymes (<em>p</em> &lt; 0.05). It enhanced the monoamines and GABA levels while attenuating glutamate levels (<em>p</em> &lt; 0.01) in the brain. Three significant flavonoids <em>viz.</em> Quercitrin, Rutin and Hesperidin were isolated from ITHE. <em>In silico</em> docking studies of these flavonoids revealed that the compounds exhibited substantial binding to the GABA_A receptor. ITHE displayed a promising pharmacological profile in combating anxiety and modulating oxidative stress, attributing its therapeutic virtues to the flavonoids present.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"178 ","pages":"Article 105804"},"PeriodicalIF":4.4,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating the biosynthesis and TLR4-interaction of lipopolysaccharide as an approach to counter gut dysbiosis and Parkinson's disease: Role of phyto-compounds","authors":"Rubina Roy ,&nbsp;Diwakar Kumar ,&nbsp;Pallab Bhattacharya ,&nbsp;Anupom Borah","doi":"10.1016/j.neuint.2024.105803","DOIUrl":"10.1016/j.neuint.2024.105803","url":null,"abstract":"<div><p>The prevalence of the world's second leading neurodegenerative disorder Parkinson's disease (PD) is well known while its pathogenesis is still a topical issue to explore. Clinical and experimental reports suggest the prevalence of disturbed gut microflora in PD subjects, with an abundance of especially Gram-negative bacteria. The endotoxin lipopolysaccharide (LPS) released from the outer cell layer of these bacteria interacts with the toll-like receptor 4 (TLR4) present on the macrophages and it stimulates the downstream inflammatory cascade in both the gut and brain. Recent research also suggests a positive correlation between LPS, alpha-synuclein, and TLR4 levels, which indicates the contribution of a parallel LPS-alpha-synuclein-TLR4 axis in stimulating inflammation and neurodegeneration in the gut and brain, establishing a body-first type of PD. However, owing to the novelty of this paradigm, further investigation is mandatory. Modulating LPS biosynthesis and LPS-TLR4 interaction can ameliorate gut dysbiosis and PD. Several synthetic LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase; LPS-synthesizing enzyme) inhibitors and TLR4 antagonists are reported to show beneficial effects including neuroprotection in PD models, however, are not devoid of side effects. Plant-derived compounds have been long documented for their benefits as nutraceuticals and thus to search for effective, safer, and multitarget therapeutics, the present study focused on summarizing the evidence reporting the potential of phyto-compounds as LpxC inhibitors and TLR4 antagonists. Studies demonstrating the dual potential of phyto-compounds as the modulators of LpxC and TLR4 have not yet been reported. Also, very few preliminary studies have reported LpxC inhibition by phyto-compounds. Nevertheless, remarkable neuroprotection along with TLR4 antagonism has been shown by curcumin and juglanin in PD models. The present review thus provides a wide look at the research progressed to date in discovering phyto-compounds that can serve as LpxC inhibitors and TLR4 antagonists. The study further recommends the need for expanding the search for potential candidates that can render dual protection by inhibiting both the biosynthesis and TLR4 interaction of LPS. Such multitarget therapeutic intervention is believed to bring fruitful yields in countering gut dysbiosis, neuroinflammation, and dopaminergic neuron damage in PD patients through a single treatment paradigm.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"178 ","pages":"Article 105803"},"PeriodicalIF":4.4,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current multi-scale biomaterials for tissue regeneration following spinal cord injury","authors":"Yuang Zhang ,&nbsp;Zhonghuan Wu ,&nbsp;Junfeng Wu ,&nbsp;Tingdong Li ,&nbsp;Fugui Jiang ,&nbsp;Biao Yang","doi":"10.1016/j.neuint.2024.105801","DOIUrl":"10.1016/j.neuint.2024.105801","url":null,"abstract":"<div><p>Spinal cord injury (SCI) may cause loss of motor and sensory function, autonomic dysfunction, and thus disrupt the quality of life of patients, leading to severe disability and significant psychological, social, and economic burden. At present, existing therapy for SCI have limited ability to promote neural function recovery, and there is an urgent need to develop innovative regenerative approaches to repair SCI. Biomaterials have become a promising strategy to promote the regeneration and repair of damaged nerve tissue after SCI. Biomaterials can provide support for nerve tissue by filling cavities, and improve local inflammatory responses and reshape extracellular matrix structures through unique biochemical properties to create the optimal microenvironment at the SCI site, thereby promoting neurogenesis and reconnecting damaged spinal cord tissue. Considering the importance of biomaterials in repairing SCI, this article reviews the latest progress of multi-scale biomaterials in SCI treatment and tissue regeneration, and evaluates the relevant technologies for manufacturing biomaterials.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"178 ","pages":"Article 105801"},"PeriodicalIF":4.4,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stroke triggers dynamic m6A reprogramming of cerebral circular RNAs","authors":"Suresh L. Mehta ,&nbsp;Hadjer Namous ,&nbsp;Raghu Vemuganti","doi":"10.1016/j.neuint.2024.105802","DOIUrl":"10.1016/j.neuint.2024.105802","url":null,"abstract":"<div><p>We previously showed that stroke alters circular RNA (circRNA) expression profiles. Many circRNAs undergo epitranscriptomic modifications, particularly methylation of adenosine to form N⁶-methyladenosine (m⁶A). This modification significantly influences the circRNA metabolism and functionality. Hence, we currently evaluated if transient focal ischemia in adult C57BL/6J mice alters the m⁶A methylation of circRNAs. Changes in m⁶A were profiled in the peri-infarct cortex following immunoprecipitation coupled with microarrays. Correlation and gene ontology analyses were performed to understand the association of m⁶A changes with circRNA regulation and functional implications after stroke. Many circRNAs showed differential regulation (up or down) after stroke, and this change was highest at 24h of reperfusion. Notably, most circRNAs differentially regulated after stroke also exhibited temporal changes in m⁶A modification patterns. The majority of circRNAs that showed post-stroke differential m⁶A modifications were derived from protein-coding genes. Hyper-than hypomethylation of circRNAs was most prevalent after stroke. Gene ontology analysis of the host genes suggested that m⁶A-modified circRNAs might regulate functions such as synapse-related processes, indicating that m⁶A epitranscriptomic modification in circRNAs could potentially influence post-stroke synaptic pathophysiology.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"178 ","pages":"Article 105802"},"PeriodicalIF":4.4,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocyte-secreted lipocalin-2 elicits bioenergetic failure-induced neuronal death that is causally related to high fatality in a mouse model of hepatic encephalopathy","authors":"Ching-Yi Tsai,&nbsp;Chin-Lai Lee,&nbsp;Jacqueline C.C. Wu","doi":"10.1016/j.neuint.2024.105800","DOIUrl":"10.1016/j.neuint.2024.105800","url":null,"abstract":"<div><p>Hepatic encephalopathy (HE) is a neurological complication arising from acute liver failure with poor prognosis and high mortality; the underlying cellular mechanisms are still wanting. We previously found that neuronal death caused by mitochondrial dysfunction in rostral ventrolateral medulla (RVLM), which leads to baroreflex dysregulation, is related to high fatality in an animal model of HE. Lipocalin-2 (Lcn2) is a secreted glycoprotein mainly released by astrocytes in the brain. We noted the presence of Lcn2 receptor (Lcn2R) in RVLM neurons and a parallel increase of <em>Lcn2</em> gene in astrocytes purified from RVLM during experimental HE. Therefore, our guiding hypothesis is that Lcn2 secreted by reactive astrocytes in RVLM may underpin high fatality during HE by eliciting bioenergetic failure-induced neuronal death in this neural substrate. In this study, we first established the role of astrocyte-secreted Lcn2 in a liver toxin model of HE induced by azoxymethane (100 μg/g, ip) in C57BL/6 mice, followed by mechanistic studies in primary astrocyte and neuron cultures prepared from postnatal day 1 mouse pups. In animal study, immunoneutralization of Lcn2 reduced apoptotic cell death in RVLM, reversed defunct baroreflex-mediated vasomotor tone and prolonged survival during experimental HE. In our primary cell culture experiments, Lcn2 produced by cultured astrocytes and released into the astrocyte-conditioned medium significantly reduced cell viability of cultured neurons. Recombinant Lcn2 protein reduced cell viability, mitochondrial ATP (mitoATP) production, and pyruvate dehydrogenase (PDH) activity but enhanced the expression of pyruvate dehydrogenase kinase (PDK) 1, PDK3 and phospho-PDHA1 (inactive PDH) through MAPK/ERK pathway in cultured neurons, with all cellular actions reversed by Lcn2R knockdown. Our results suggest that astrocyte-secreted Lcn2 upregulates PDKs through MAPK/ERK pathway, which leads to reduced PDH activity and mitoATP production; the reinforced neuronal death in RVLM is causally related to baroreflex dysregulation that underlies high fatality associated with HE.</p></div>","PeriodicalId":398,"journal":{"name":"Neurochemistry international","volume":"178 ","pages":"Article 105800"},"PeriodicalIF":4.4,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}