Neurochemical Research最新文献

{"title":"Glia-related Acute Effects of Risperidone and Haloperidol in Hippocampal Slices and Astrocyte Cultures from Adult Wistar Rats: A Focus on Inflammatory and Trophic Factor Release.","authors":"Amanda da Silva, Larissa Daniele Bobermin, Camila Leite Santos, Rômulo Rodrigo de Souza Almeida, Lílian Juliana Lissner, Tiago Marcon Dos Santos, Marina Seady, Marina Concli Leite, Angela T S Wyse, Carlos-Alberto Gonçalves, André Quincozes-Santos","doi":"10.1007/s11064-024-04273-y","DOIUrl":"https://doi.org/10.1007/s11064-024-04273-y","url":null,"abstract":"<p><p>Antipsychotics are drugs commonly prescribed to treat a variety of psychiatric conditions. They are classified as typical and atypical, depending on their affinity for dopaminergic and serotonergic receptors. Although neurons have been assumed to be the major mediators of the antipsychotic pharmacological effects, glia, particularly astrocytes, have emerged as important cellular targets for these drugs. In the present study, we investigated the effects of acute treatments with the antipsychotics risperidone and haloperidol of hippocampal slices and astrocyte cultures, focusing on neuron-glia communication and how antipsychotics act in astrocytes. For this, we obtained hippocampal slices and primary astrocyte cultures from 30-day-old Wistar rats and incubated them with risperidone or haloperidol (1 and 10 μM) for 30 min and 24 h, respectively. We evaluated metabolic and enzymatic activities, the glutathione level, the release of inflammatory and trophic factors, as well as the gene expression of signaling proteins. Haloperidol increased glucose metabolism; however, neither of the tested antipsychotics altered the glutathione content or glutamine synthetase and Na⁺K⁺-ATPase activities. Haloperidol induced a pro-inflammatory response and risperidone promoted an anti-inflammatory response, while both antipsychotics seemed to decrease trophic support. Haloperidol and risperidone increased Nrf2 and HO-1 gene expression, but only haloperidol upregulated NFκB and AMPK gene expression. Finally, astrocyte cultures confirmed the predominant effect of the tested antipsychotics on glia and their opposite effects on astrocytes. Therefore, antipsychotics cause functional alterations in the hippocampus. This information is important to drive future research for strategies to attenuate antipsychotics-induced neural dysfunction, focusing on glia.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":"22"},"PeriodicalIF":3.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666801","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":"Exploring α-synuclein Interaction Partners and their Potential Clinical Implications for Parkinson's Disease.","authors":"Yingfei Chen, Yanan Gu, Can Cao, Qiuying Zheng, Lili Sun, Wenyong Ding, Li Ma, Cui Wang, Wenli Zhang","doi":"10.1007/s11064-024-04250-5","DOIUrl":"https://doi.org/10.1007/s11064-024-04250-5","url":null,"abstract":"<p><p>Alpha-synuclein aggregates are strongly associated with Parkinson's disease (PD), a degenerative neurological disorder characterized by a progressive loss in motor functions. Our study aimed to unravel the potential interaction partners of α-synuclein for exploring the synucleinpathy of PD related to α-synuclein aggregates. α-synuclein was expressed in E.coli and purified by affinity chromatography followed by isolation and identification of its interaction partners using pulldown assay coupled with LC-MS/MS. The impacts of the identified interaction partners on PD were evaluated based on GSE205450 dataset. Consequently, 157 proteins were identified by the criteria of unique peptide = 5. Four proteins including ACO2, ANT1, ATP5F1B and CKB were confirmed using immunostaining coupled with α-synuclein-pulldown assay. Transcriptomics assay showed that the dominant biological processes influenced by α-synuclein interaction partners with differential expression were energy metabolism. Together with GSE205450, Western blot assay showed that α-synuclein interaction partners involved in energy metabolism were down-regulated in PD patients and the MPTP-lesioned mice. ROC curves indicated their clinical implications as diagnostic indices of PD. Using ANT1 as an example, we found that protein aggregates formed by ANT1 and α-synuclein predominantly solely appeared in the cells and mice with PD-like variations. Thereby, low levels of the interaction partners of α-synuclein associated with energy metabolism were associated with PD pathogenesis via forming protein aggregates. This study provides an insight into developing innovative targets on PD based on synucleinpathy.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":"23"},"PeriodicalIF":3.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666799","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":"Alterations in Circular RNAs circOprm1 and circSerpini in the Striatum are Associated with Changes in Spatial Working Memory Performance after Morphine Dependence and Withdrawal in Rats.","authors":"Shamseddin Ahmadi, Abdulbaset Vali, Samira Amiri, Danesh Rostami, Mohammad Majidi, Karim Rahimi","doi":"10.1007/s11064-024-04284-9","DOIUrl":"https://doi.org/10.1007/s11064-024-04284-9","url":null,"abstract":"<p><p>Modulating role of circRNAs and microRNAs in neurobiological changes induced by drug exposure remains unclear. We examined alterations in some circRNAs and microRNAs in the striatum after morphine dependence and withdrawal and their associations with the changes in spatial working memory performance. Male Wistar rats were used in which 10 days morphine exposure induced dependence. Withdrawal effects were assessed 30 days after stopping morphine exposure. Spatial working memory was assessed using a Y maze test on days 1 and 10 of the drug exposure and 30 days after withdrawal. The gene and protein expression were assessed after dependence and withdrawal. The results revealed that 10 days morphine exposure impaired working memory, which partially reinstated after withdrawal. After 10 days morphine exposure, significant increases in Oprm1 gene and OPRM1 protein levels were detected, which persisted even after withdrawal. The expression of circOprm1 and miR-339-3p decreased in the morphine-dependent group, but they returned to normal levels after withdrawal. The expression of Tlr4 gene and TLR4 protein levels decreased after dependence. While Tlr4 mRNA levels returned to normal after withdrawal, TLR4 protein levels remained lower than the control group. In the morphine-dependent group, both Serpini1 and circSerpini expression significantly increased, but they restored after withdrawal. Expression of miR-181b-3p, miR-181b-5p, miR-181c-3p, and miR-181c-5p decreased after dependence, but they reinstated after withdrawal. It can be concluded that circOprm1 and circSerpini via regulating the OPRM1 and TLR4 expression in the striatum are associated with the neuroadaptation underlying spatial working memory after both morphine dependence and withdrawal.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":"20"},"PeriodicalIF":3.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666798","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 P38MAPK Pathway Mediates the Destruction of the Blood-Brain Barrier in Anti-NMDAR Encephalitis Mice.","authors":"Dayuan Lao, Zhuowei Gong, Taiyan Li, Xuean Mo, Wen Huang","doi":"10.1007/s11064-024-04270-1","DOIUrl":"https://doi.org/10.1007/s11064-024-04270-1","url":null,"abstract":"<p><p>The clinical manifestations of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may be closely related to the integrity of the blood-brain barrier (BBB). The P38 mitogen-activated protein kinase (P38MAPK) pathway plays a protective role in neurodegenerative diseases. However, whether the P38MAPK pathway is involved in the underlying mechanism of tight junction (TJ) protein disruption and neuronal damage has not been elucidated. Therefore, in this study, a mouse model of anti-NMDAR encephalitis was established by active immunization with NMDAR NR1_356-385 peptides. The critical pathways of P38MAPK were screened by interaction network and co-enrichment analysis. The role of P38MAPK pathways was investigated by the injection of P38MAPK inhibitor SB203580 (10 mg/kg, i.p.). Compared with the control group, the expression of occludin and zonula occludens (ZO)-1 in NMDAR NR1_356-385 group mice was downregulated, and the structure and function of BBB were damaged. However, after the intervention of SB203580, the activation of the P38MAPK was inhibited, the expression of matrix metalloproteinase 9 (MMP9) was reduced, and the function of BBB was improved. Meanwhile, inhibiting the P38MAPK pathway reversed the degradation of NMDAR NR1, while reducing the expression of the glial fibrillary acidic protein (GFAP) and pro-inflammatory factor tumor necrosis factor (TNF-α). It also relieved the damage of neuron-specific nucleus (NeuN), thus alleviating psychobehavioral symptoms. In conclusion, our results suggested that the P38MAPK pathway is involved in BBB destruction and neurobehavioral change in mice with anti-NMDAR encephalitis. Targeting the P38MAPK pathway may be a promising option for the treatment of anti-NMDAR encephalitis.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":"21"},"PeriodicalIF":3.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666802","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":"Atractylenolide-I Attenuates MPTP/MPP+‑Mediated Oxidative Stress in Parkinson’s Disease Through SIRT1/PGC‑1α/Nrf2 Axis","authors":"Ya Gao,&nbsp;Shuyue Li,&nbsp;Shuming Zhang,&nbsp;Yidan Zhang,&nbsp;Jian Zhang,&nbsp;Yuan Zhao,&nbsp;Cui Chang,&nbsp;Xuan Gao,&nbsp;Ling Chen,&nbsp;Guofeng Yang","doi":"10.1007/s11064-024-04258-x","DOIUrl":"10.1007/s11064-024-04258-x","url":null,"abstract":"<div><p>Parkinson’s disease (PD) is typically marked by motor dysfunction accompanied by loss of dopaminergic (DA) neurons and aggravated oxidative stress in the substantia nigra pars compacta (SNpc). Atractylenolide-I (ATR-I) is a potent antioxidant sesquiterpene with neuroprotective properties. However, whether ATR-I plays a neuroprotective role against oxidative stress in PD remains unclear. The objective of this study was to explore the mechanism of antioxidant action of ATR-I in PD models both in vivo and in vitro. Here, we show that ATR-I alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice. Moreover, ATR-I treatment effectively reduced DA neuron loss and increased tyrosine hydroxylase expression in the SNpc of MPTP-induced mice. Additionally, ATR-I inhibited oxidative stress (as manifested by elevated superoxide dismutase and glutathione peroxidase activities, and reduced malondialdehyde content) in MPTP-induced mice and attenuated reactive oxygen species levels in 1-methyl-4-phenylpyridinum (MPP⁺)-treated SH-SY5Y cells. Finally, ATR-I upregulated expressions of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), NF-E2-related factor-2 (Nrf2), and heme oxygenase-1 in MPTP-induced mice and MPP⁺-treated SH-SY5Y cells, but had little effect on these factors in the presence of the SIRT1 inhibitor EX527. Taken together, these findings indicated that the important antioxidant role of ATR-I in MPTP/MPP⁺-mediated oxidative stress and the pathogenesis of PD through the SIRT1/PGC-1α/Nrf2 axis, highlighting its potential as a therapeutic option for PD.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646580","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":"AMP-Activated Protein Kinase Treatment Ameliorates Chronic Restraint Stress Induced Memory Impairment in Early Adolescent Rat by Restoring Metabolite Profile and Synaptic Proteins","authors":"Koilmani Emmanuvel Rajan,&nbsp;Baskaran Nishanthini,&nbsp;Swamynathan Sowndharya","doi":"10.1007/s11064-024-04285-8","DOIUrl":"10.1007/s11064-024-04285-8","url":null,"abstract":"<div><p>Recent studies highlight the role of brain metabolites in regulation of neuronal signals and behaviour. To understand the underlying mechanism, brain metabolites and associated signaling molecules were examined in early adolescent rat experienced CRS. Rats were tested for their learning and memory ability, and their metabolite profile was evaluated using Gas chromatography-mass spectrometry (GC-MS). Differences in metabolites were examined by variable importance in projection (VIP) and multivariate analysis. Ingenuity Pathway Analysis (IPA) and KEGG ID were performed for the identified metabolites. We found that CRS altered the metabolites that were involved in biosynthesis of steroid hormone, aminoacyl t-RNA, L-Dopa biosynthesis, and metabolism of tyrosine, fatty acid, and purine. Further analysis showed reduction of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, a metabolite involved in purine metabolism) an AMP kinase activator, influenced the hypoxanthine-guanine phosphoribosyltransferase (HPRT), serotonin transporter (SERT), postsynaptic density protein (PSD) -95, its phosphorylation and brain-derived neurotrophic factor (BDNF) in CRS animals, which displayed deficit in memory. The AICAR treated CRS rats showed improved memory and altered metabolites and other molecules (HPRT, SERT, PSD-95 and BDNF) levels were restored. Our analysis revealed that CRS induced changes in metabolites possibly altered synaptic plasticity and memory in which HPRT, SERT-PSD95-BDNF associated pathway involved. Taken together, our observation provides initial insight into how stress differently influences the metabolic pathway, and associated behaviour. Further study will help to develop pharmacological intervention strategies.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646576","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":"Naringenin Protected Against Blood Brain Barrier Breakdown after Ischemic Stroke through GSK-3β/ β-Catenin Pathway","authors":"Yanping Yang,&nbsp;Liang Li,&nbsp;Liang Yu,&nbsp;Ying Xia,&nbsp;Zongping Fang,&nbsp;Shiquan Wang","doi":"10.1007/s11064-024-04259-w","DOIUrl":"10.1007/s11064-024-04259-w","url":null,"abstract":"<div><p>Protection against blood-brain barrier (BBB) dysfunction is key to reduce the cerebral ischemia injury as its breakdown causes edema formation and extravasation of blood components and immune cells. The maintenance of BBB integrity requires the GSK-3β/β-catenin pathway activity. Naringenin (NAR), an effective monomer from Chinese herbal medicine, had potent protective effect on brain inflammatory and oxidative injury. However, whether NAR could protect the integrity of BBB during cerebral ischemia injury and the involvement of GSK-3β/β-catenin pathway in the beneficial effect of NAR was unknown. Therefore, mouse middle cerebral artery occlusion/reperfusion (IR) model was employed to answer these questions. NAR was intraperitoneally administrated once daily for 6 days immediately after IR with the dose of 10 mg/kg. BBB damage was evaluated with Evans blue. Protein levels of GSK-3β and β-catenin in vascular endothelial cells at penumbra were assessed with western blotting and immunofluorescence. The experimental data suggested that NAR improved neurological deficits, decreased the percentage of infarct volumes and neuronal apoptosis at 7d after IR. NAR improved BBB damage as evidenced by a lower permeability of Evans blue dye and upregulation of tight junction proteins such as zonula occludens-1(ZO-1), Occludin and Claudin-5. Importantly, GSK-3β/β-catenin pathway activity was related to the improvement of BBB integrity rendered by NAR. Our findings demonstrated that NAR might become a potential therapeutic drug for IR.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646602","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":"l-Proline Alters Energy Metabolism in Brain Cortical Tissue Slices","authors":"Abhijit Das,&nbsp;Gregory Gauthier-Coles,&nbsp;Stefan Bröer,&nbsp;Caroline D. Rae","doi":"10.1007/s11064-024-04262-1","DOIUrl":"10.1007/s11064-024-04262-1","url":null,"abstract":"<div><p>L-Proline (<span>l</span>-Pro) is a non-essential amino acid which, in high concentrations, can cause neurological problems including seizures, although the causative mechanism for this is unclear. Here, we studied the impact of physiological levels of proline on brain energy metabolism and investigated the metabolism of <span>l</span>-Pro itself, using the cortical brain tissue slice and stable isotope labelling from [1-¹³ C]glucose and [1,2-¹³ C]acetate detected by NMR spectroscopy and LCMS. <span>l</span>-Pro was actively taken up by the slices and significantly reduced the total metabolic pools of all measured metabolites with glutamine the least affected, while reducing net flux of ¹³C into glycolytic byproducts (lactate and alanine). Conversely, net flux into Krebs cycle intermediates was increased, suggesting that L-Pro at lower concentrations was driving increased mitochondrial activity in both neurons and glia at the expense of glycolysis and metabolic pool sizes. As there was no evidence of metabolism of [1-¹³ C] <span>l</span>-Pro in slices under normo-glycemic conditions, the effect of proline on metabolism was not due to displacement of metabolites by added <span>l</span>-Pro. Comparison of the metabolic fingerprint generated by <span>l</span>-Pro in slices metabolizing [3-¹³ C]pyruvate with that generated by ligands active in the GABAergic system suggested that <span>l</span>-Pro may engender effects similar to that of the inhibitory neurotransmitter and metabolite γ-aminobutyric acid (GABA), in line with previous suggestions that <span>l</span>-Pro may be a GABA mimetic in addition to its role as a modulator of mitochondrial metabolism.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646585","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":"Acute Behavioral and Neurochemical Effects of Sulpiride in Adult Zebrafish","authors":"David S. Galstyan,&nbsp;Andrey S. Lebedev,&nbsp;Nikita P. Ilyin,&nbsp;Maria S. Papulova,&nbsp;Nikita I. Golushko,&nbsp;Valeria V. Tishkina,&nbsp;Daryna K. Saklakova,&nbsp;Daniil Martynov,&nbsp;Tatiana O. Kolesnikova,&nbsp;Dennis B. Rosemberg,&nbsp;Murilo S. De Abreu,&nbsp;Konstantin A. Demin,&nbsp;Allan V. Kalueff","doi":"10.1007/s11064-024-04268-9","DOIUrl":"10.1007/s11064-024-04268-9","url":null,"abstract":"<div><p>Affective and psychotic disorders are highly prevalent and severely debilitating mental illnesses that often remain untreated or treatment-resistant. Sulpiride is a common antipsychotic (neuroleptic) drug whose well-established additional (e.g., antidepressant) therapeutic effects call for further studies of a wider spectrum of its CNS effects. Here, we examined effects of acute 20-min exposure to sulpiride (50–200 mg/L) on anxiety- and depression-like behaviors, as well as on brain monoamines, in adult zebrafish (<i>Danio rerio</i>). Overall, sulpiride exerted overt anxiolytic-like effects in the novel tank test and showed tranquilizing-like effects in the zebrafish tail immobilization test, accompanied by lowered whole-brain dopamine and its elevated turnover, without affecting serotonin or norepinephrine levels and their turnover. Taken together, these findings support complex behavioral pharmacology of sulpiride in vivo and reconfirm high sensitivity of zebrafish-based screens to this and, likely, other related clinically active neuroleptics.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643632","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":"Inhibition of PCSK9 Protects against Cerebral Ischemia‒Reperfusion Injury via Attenuating Microcirculatory Dysfunction","authors":"Yuanfei Luo,&nbsp;Linying Yuan,&nbsp;Zhihui Liu,&nbsp;Weichen Dong,&nbsp;Li Huang,&nbsp;Anyu Liao,&nbsp;Yi Xie,&nbsp;Rui Liu,&nbsp;Wenya Lan,&nbsp;Yulong Cai,&nbsp;Wusheng Zhu","doi":"10.1007/s11064-024-04272-z","DOIUrl":"10.1007/s11064-024-04272-z","url":null,"abstract":"<div><p>Proprotein convertase substilin/kexin type 9 (PCSK9), a pivotal protein regulating lipid metabolism, has been implicated in promoting microthrombotic formation and inflammatory cascades, thereby contributing to cardiovascular ischemia/reperfusion (I/R) injury. However, its involvement in cerebral I/R injury and its potential role in microcirculation protection remain unexplored. In this investigation, we utilized a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate ischemic stroke. Different concentrations of evolocumab (1, 5, 10 mg/kg, i.v.), a PCSK9 inhibitor, were administered to assess its impact. Immunofluorescence staining was employed to analyze changes in the expression of occludin, claudin-5, thrombocyte, ICAM-1, VCAM-1, and CD45, providing insights into blood-brain barrier integrity, platelet adhesion, and immune cell infiltration. Moreover, the Morris water maze and elevated plus maze were utilized to evaluate neurological and behavioral functions in MCAO/R mice, shedding light on the effects of PCSK9 inhibition. Our findings revealed a surge in plasma PCSK9 levels post-MCAO/R, peaking at 24 h post-reperfusion. Evolocumab (10 mg/kg) treatment significantly mitigated brain infarction and neurological deficits, evidenced by enhanced locomotor function and reduced post-stroke anxiety. However, it did not ameliorate cognitive impairment following MCAO/R. Additionally, evolocumab administration led to diminished leakage of evans blue solution and upregulated expression of occludin and claudin-5. Thrombocyte, ICAM-1, VCAM-1, and CD45 levels were notably reduced in the penumbral area post-evolocumab treatment. These protective effects are speculated to be mediated through the inhibition of the ERK/NF-κB pathway. The PCSK9 inhibitor evolocumab holds promise as a therapeutic agent during the acute phase of stroke, exerting its beneficial effects by modulating the ERK/NF-κB signaling pathway.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638302","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}