RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Tackling phlegm and improving blood circulation is vital in the treatment of ischemic stroke (IS), culminating in the development of Zhongfeng Decoction (ZFD), a method grounded in this approach and serving as an effective therapy for IS. Nonetheless, the defensive mechanism of the ZFD in preventing cerebral ischemia-reperfusion damage remains ambiguous. AIM OF THE STUDY: Determine the active ingredients in ZFD that have neuroprotective effects, and identify its mechanism of action against IS. MATERIALS AND METHODS: A cerebral ischemia model in rats was developed, utilizing TTC, Nissl staining, and an oxidative stress kit to evaluate the neuroprotective impact of ZFD on this rat model. Following this, an amalgamation of LC-MS and network pharmacology techniques was employed to pinpoint potential active components, primary targets, and crucial action mechanisms of ZFD in treating IS. Finally, key targets and signaling pathways were detected using qRT-PCR, ELISA, Western blotting, electron microscopy, and other methods. RESULTS: Through LC-MS and network analysis, 15 active ingredients and 6 hub targets were identified from ZFD. Analysis of pathway enrichment revealed that ZFD predominantly engages in the AGE-RAGE signaling route. Kaempferol, quercetin, luteolin, baicalein, and nobiletin in ZFD are the main active ingredients for treating IS. In vivo validation showed that ZFD can improve nerve damage in cerebral ischemic rats, reduce the mRNA expression of IL6, SERPINE1, CCL2, and TGFB1 related to inflammation. Furthermore, we also confirmed that ZFD can inhibit the protein expression of AGEs, RAGE, p-IKBα/IKBα, p-NF-κB p65/NF-κB p65, reduce autophagy levels, and thus decrease neuronal apoptosis. CONCLUSIONS: The mechanism of action of ZFD in treating IS primarily includes inflammation suppression, oxidative stress response alleviation, post-stroke cell autophagy and apoptosis regulation, and potential mediation of the AGE-RAGE signaling pathway. This study elucidates how ZFD functions in treating IS, establishing a theoretical basis for its clinical application.

Asunto(s)

Autofagia , Medicamentos Herbarios Chinos , Fármacos Neuroprotectores , Ratas Sprague-Dawley , Daño por Reperfusión , Transducción de Señal , Animales , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Medicamentos Herbarios Chinos/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Autofagia/efectos de los fármacos , Ratas , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Productos Finales de Glicación Avanzada/metabolismo

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.

Asunto(s)

Apoptosis , Estrés del Retículo Endoplásmico , Fármacos Neuroprotectores , Estrés Oxidativo , Ratas Sprague-Dawley , Daño por Reperfusión , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Estrés Oxidativo/efectos de los fármacos , Ratas , Células PC12 , Masculino , Fármacos Neuroprotectores/farmacología , Apoptosis/efectos de los fármacos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI. AIM OF THE STUDY: The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation. MATERIALS AND METHODS: Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT. RESULTS: NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI. CONCLUSION: This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.

Asunto(s)

Medicamentos Herbarios Chinos , Mitofagia , Farmacología en Red , Proteínas Quinasas , Daño por Reperfusión , Proteína p53 Supresora de Tumor , Animales , Masculino , Ratas , Isquemia Encefálica/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Mitofagia/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Células PC12 , Proteínas Quinasas/metabolismo , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas

RESUMEN

Ischaemic stroke is a common condition that can lead to cerebral ischaemia-reperfusion injury. Phillygenin (PHI), a natural bioactive compound derived from Forsythia suspensa, has been shown to play a crucial role in regulating inflammation across various diseases. However, its specific regulatory effects in ischaemic stroke progression remain unclear. In this study, we established a middle cerebral artery occlusion (MCAO) rat model. Treatment with PHI (50 or 100 mg/kg) significantly reduced cerebral infarction in MCAO rats. PHI treatment also mitigated the increased inflammatory response observed in these rats. Additionally, PHI suppressed microglial activation by reducing iNOS expression, a marker of M1-type polarization of microglia, and attenuated increased brain tissue apoptosis in MCAO rats. Furthermore, PHI's anti-inflammatory effects in MCAO rats were abrogated upon co-administration with GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor. In summary, PHI attenuated microglial activation and apoptosis in cerebral ischaemia-reperfusion injury through PPARγ activation, suggesting its potential as a therapeutic agent for mitigating cerebral ischaemia-reperfusion injury.

Asunto(s)

Apoptosis , Infarto de la Arteria Cerebral Media , Microglía , PPAR gamma , Ratas Sprague-Dawley , Daño por Reperfusión , Animales , PPAR gamma/metabolismo , Apoptosis/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Ratas , Masculino , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Lignanos

RESUMEN

Matrix metalloproteinases (MMPs) such as MMP-9, 3, and 2 degrade the cellular matrix and are believed to play a crucial role in ischemic stroke. We examined how the duration of ischemia (up to 4 h) and treatment with recombinant tissue plasminogen activator altered the comparative expression of these MMPs in experimental ischemic stroke with reperfusion. Both prolonged ischemia and r-tPA treatment markedly increased MMP-9 expression in the ischemic hemisphere (all p < 0.0001). The duration of ischemia and r-tPA treatment also significantly increased MMP-2 expression (p < 0.01-0.001) in the ischemic hemisphere (p < 0.01) but to a lesser degree than MMP-9. In contrast, MMP-3 expression significantly decreased in the ischemic hemisphere (p < 0.001) with increasing duration of ischemia and r-tPA treatment (p < 0.05-0001). MMP-9 expression was prominent in the vascular compartment and leukocytes. MMP-2 expression was evident in the vascular compartment and MMP-3 in NeuN+ neurons. Prolonging the duration of ischemia (up to 4 h) before reperfusion increased brain hemorrhage, infarction, swelling, and neurologic disability in both saline-treated (control) and r-tPA-treated mice. MMP-9 and MMP-2 expression were significantly positively correlated with, and MMP-3 was significantly negatively correlated with, infarct volume, swelling, and brain hemorrhage. We conclude that in experimental ischemic stroke with reperfusion, the duration of ischemia and r-tPA treatment significantly altered MMP-9, 3, and 2 expression, ischemic brain injury, and neurological disability. Each MMP showed unique patterns of expression that are strongly correlated with the severity of brain infarction, swelling, and hemorrhage. In summary, in experimental ischemic stroke in male mice with reperfusion, the duration of ischemia, and r-tPA treatment significantly altered the immunofluorescent expression of MMP-9, 3, and 2, ischemic brain injury, and neurological disability. In this model, each MMP showed unique patterns of expression that were strongly correlated with the severity of brain infarction, swelling, and hemorrhage.

Asunto(s)

Isquemia Encefálica , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 3 de la Matriz , Metaloproteinasa 9 de la Matriz , Activador de Tejido Plasminógeno , Animales , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Factores de Tiempo

RESUMEN

Agathisflavone is a flavonoid that exhibits anti-inflammatory and anti-oxidative properties. Here, we investigated the neuroprotective effects of agathisflavone on central nervous system (CNS) neurons and glia in the cerebellar slice ex vivo model of neonatal ischemia. Cerebellar slices from neonatal mice, in which glial fibrillary acidic protein (GFAP) and SOX10 drive expression of enhanced green fluorescent protein (EGFP), were used to identify astrocytes and oligodendrocytes, respectively. Agathisflavone (10 µM) was administered preventively for 60 min before inducing ischemia by oxygen and glucose deprivation (OGD) for 60 min and compared to controls maintained in normal oxygen and glucose (OGN). The density of SOX-10+ oligodendrocyte lineage cells and NG2 immunopositive oligodendrocyte progenitor cells (OPCs) were not altered in OGD, but it resulted in significant oligodendroglial cell atrophy marked by the retraction of their processes, and this was prevented by agathisflavone. OGD caused marked axonal demyelination, determined by myelin basic protein (MBP) and neurofilament (NF70) immunofluorescence, and this was blocked by agathisflavone preventative treatment. OGD also resulted in astrocyte reactivity, exhibited by increased GFAP-EGFP fluorescence and decreased expression of glutamate synthetase (GS), and this was prevented by agathisflavone pretreatment. In addition, agathisflavone protected Purkinje neurons from ischemic damage, assessed by calbindin (CB) immunofluorescence. The results demonstrate that agathisflavone protects neuronal and myelin integrity in ischemia, which is associated with the modulation of glial responses in the face of ischemic damage.

Asunto(s)

Animales Recién Nacidos , Cerebelo , Flavonoides , Fármacos Neuroprotectores , Animales , Fármacos Neuroprotectores/farmacología , Ratones , Cerebelo/metabolismo , Cerebelo/efectos de los fármacos , Flavonoides/farmacología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Glucosa/metabolismo , Biflavonoides

RESUMEN

OBJECTIVE: To study the efficacy and safety of the drug Picamilon with various therapy regimens in patients with stage II chronic cerebral ischemia (CCI). MATERIAL AND METHODS: An open cohort clinical study involved 50 patients diagnosed with stage II CCI aged 51 to 69 years (average age 62.2±8.98 years). Patients received Picamilon first parenterally 200 mg (100 mg/ml, 2 ml) intravenously for 10 days, then orally in 50 mg tablets 3 times a day for 60 days. The total duration of therapy in the group was 70 days. The study included 3 visits (before treatment, after completion of the course, 1.5 months after completion of treatment). The dynamics of cognitive status according to the Montreal Cognitive Assessment Scale, vegetative disorders according to the A.M. Vane scale, neurological disorders according to the A.I. Fedin scale, and sleep quality according to the Ya. I. Levin scale were compared. The state of cerebral blood flow and endothelium was studied before and after treatment: dopplerography of cranial vessels, assessment of the level of methylated forms of arginine (ADMA, MMA, SDMA) and their ratios. The registration of adverse events against the background of therapy and the tolerability of treatment by patients was also carried out. RESULTS: Against the background of Picamilon treatment, a significant positive dynamics of the MoCA scale results was observed in the general sample of patients, increasing in the delayed period (20.9, 24.6 and 25.9, p<0.0001 and p=0.0006); sleep normalization was observed in 55% of patients by Visit 2 and in 81% of patients by Visit 3 (p<0.0001 and p=0.0025). Improvement of neurological functions is noted in 84% of patients, the score on the Fedin A.I. scale significantly decreases after treatment from 17.4±9.34 to 8.06±6.84 (p<0.0001) and to 5.31±5.71 in the delayed period (p=0.0002). Normalization of vegetative status was observed in 38% of patients with stage II CCI, and in 60% of cases there was a decrease in the severity of vegetative dystonia syndrome (p=0.0001). Picamilon therapy has high efficacy in assessing clinical outcomes (100%), good tolerability in 98% of patients and is characterized by a favorable safety profile (in 92% of patients). Picamilon significantly affects the parameters of cerebral hemodynamics: increases the linear velocity of blood flow, reduces the thickness of the intima-media complex and the resistance index. It affects markers of NO metabolism and endothelial function: significantly reduces elevated levels of ADMA and ADMA/MMA and (ADMA+SDMA)/MMA ratios. CONCLUSION: The use of Picamilon is effective in patients with stage II CCI in the form of step therapy contributes to a significant regression of neurological deficit, cognitive impairment, improvement of sleep quality and autonomic function; improves vascular endothelial function, reduces the risk of cardiovascular complications. Picamilon is a pathogenetic therapy agent that prevents the progression of CCI.

Asunto(s)

Isquemia Encefálica , Humanos , Persona de Mediana Edad , Masculino , Femenino , Anciano , Isquemia Encefálica/tratamiento farmacológico , Resultado del Tratamiento , Enfermedad Crónica , Circulación Cerebrovascular/efectos de los fármacos , Cognición/efectos de los fármacos

RESUMEN

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is a prevalent neurological disorder, characterized by the oxidative stress and inflammatory response induced during the ischemia-reperfusion process, leading to significant damage to brain cells. Ginsenoside Rb1, a natural medicinal ingredient, possesses potential neuroprotective effects. This study aims to investigate the mechanism of action of ginsenoside Rb1 in CIRI and its protective effects on brain injury. METHODS: We utilized a mouse CIRI model and randomly divided the mice into control group, CIRI group, and ginsenoside Rb1 treatment group. The effects of Rb1 on brain tissue damage, apoptosis, expression of inflammatory factors, and pyroptotic cell numbers in CIRI mice were observed through triphenyl tetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, real-time reverse transcription polymerase chain reaction (qRT-PCR), and electron microscopy. In a cell model, the regulatory effect of Rb1 on oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cell pyroptosis via the nuclear respiratoty factor 2/tumor necrosis factor-α (TNF-α)-induced Protein 3 (TNFAIP3, aka A20)/eukaryotic translation elongation factor 1A2 (Nrf2/A20/eEF1A2) axis was detected using Western blot and TUNEL staining. Additionally, the impact of Nrf2 inhibitor ML385 and eEF1A2 overexpression on the neuroprotective effect of Rb1 was assessed. Using the comprehensive experimental methods mentioned above, the neuroprotective mechanism of Rb1 in CIRI was thoroughly evaluated. RESULTS: Our findings demonstrate that treatment with ginsenoside Rb1 alleviated behavioral deficits induced by CIRI and reduced pathological damage in brain tissue. Furthermore, ginsenoside Rb1 treatment notably decreased oxidative stress and the inflammatory response induced by CIRI, leading to lower levels of inflammatory factors (p < 0.05). Further experimental results indicated that ginsenoside Rb1 promoted antioxidant and anti-inflammatory responses by regulating the activity of the Nrf2/A20/eEF1A2 axis. Additionally, ginsenoside Rb1 inhibited the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, thereby reducing the release of inflammatory factors and the occurrence of cell apoptosis. CONCLUSION: Our study results suggest that ginsenoside Rb1 exerts neuroprotective effects and alleviates brain injury induced by CIRI by regulating the Nrf2/A20/eEF1A2 axis and inhibiting the activation of the NLRP3 inflammasome. These findings provide new treatment insights for CIRI and support ginsenoside Rb1's development as a therapeutic drug. However, despite the promising nature of our findings, further research is required to validate these discoveries and explore the feasibility and safety of ginsenoside Rb1 in clinical applications. We hope that our study can provide new directions and strategies for the treatment and prevention of CIRI, contributing to the development of neuroprotective drugs.

Asunto(s)

Ginsenósidos , Factor 2 Relacionado con NF-E2 , Daño por Reperfusión , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratones Endogámicos C57BL , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular

RESUMEN

BACKGROUND: Stroke is a type of acute brain damage that can lead to a series of serious public health challenges. Demonstrating the molecular mechanism of stroke-related neural cell degeneration could help identify a more efficient treatment for stroke patients. Further elucidation of factors that regulate microglia and nuclear factor (erythroid-derived 2)-like 1 (Nrf1) may lead to a promising strategy for treating neuroinflammation after ischaemic stroke. In this study, we investigated the possible role of pterostilbene (PTS) in Nrf1 regulation in cell and animal models of ischaemia stroke. METHODS: We administered PTS, ITSA1 (an HDAC activator) and RGFP966 (a selective HDAC3 inhibitor) in a mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R) and a model of microglial oxygen‒glucose deprivation/reperfusion (OGD/R). The brain infarct size, neuroinflammation and microglial availability were also determined. Dual-luciferase reporter, Nrf1 protein stability and co-immunoprecipitation assays were conducted to analyse histone deacetylase 3 (HDAC3)/Nrf1-regulated Nrf1 in an OGD/R-induced microglial injury model. RESULTS: We found that PTS decreased HDAC3 expression and activity, increased Nrf1 acetylation in the cell nucleus and inhibited the interaction of Nrf1 with p65 and p65 accumulation, which reduced infarct volume and neuroinflammation (iNOS/Arg1, TNF-α and IL-1ß levels) after ischaemic stroke. Furthermore, the CSF1R inhibitor PLX5622 induced elimination of microglia and attenuated the therapeutic effect of PTS following MCAO/R. In the OGD/R model, PTS relieved OGD/R-induced microglial injury and TNF-α and IL-1ß release, which were dependent on Nrf1 acetylation through the upregulation of HDAC3/Nrf1 signalling in microglia. However, the K105R or/and K139R mutants of Nrf1 counteracted the impact of PTS in the OGD/R-induced microglial injury model, which indicates that PTS treatment might be a promising strategy for ischaemia stroke therapy. CONCLUSION: The HDAC3/Nrf1 pathway regulates the stability and function of Nrf1 in microglial activation and neuroinflammation, which may depend on the acetylation of the lysine 105 and 139 residues in Nrf1. This mechanism was first identified as a potential regulatory mechanism of PTS-based neuroprotection in our research, which may provide new insight into further translational applications of natural products such as PTS.

Asunto(s)

Histona Desacetilasas , Accidente Cerebrovascular Isquémico , Ratones Endogámicos C57BL , Microglía , Enfermedades Neuroinflamatorias , Estilbenos , Animales , Histona Desacetilasas/metabolismo , Microglía/metabolismo , Microglía/efectos de los fármacos , Ratones , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Masculino , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Estilbenos/farmacología , Estilbenos/uso terapéutico , Modelos Animales de Enfermedad , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/complicaciones , Transducción de Señal/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo

RESUMEN

OBJECTIVE: This study aimed to further elucidate the mechanism of ginsenoside Rg1 in the treatment of cerebral ischemia-reperfusion. METHODS: In this study, we observed the apoptosis of RM cells (microglia) after oxygen-glucose deprivation/reoxygenation (OGD/R) modeling before and after Rg1 administration, changes in mitochondrial membrane potential, changes in the content of Reactive oxygen species (ROS) and inflammatory vesicles NLR Family Pyrin Domain Containing 3 (NLRP3), and the expression levels of autophagy-related proteins, inflammatory factors, and apoptosis proteins. We further examined the pathomorphological changes in brain tissue, neuronal damage, changes in mitochondrial morphology and mitochondrial structure, and the autophagy-related proteins, inflammatory factors, and apoptosis proteins expression levels in CI/RI rats before and after administration of Rg1 in vivo experiments. RESULTS: In vitro experiments showed that Rg1 induced mitochondrial autophagy, decreased mitochondrial membrane potential, and reduced ROS content thereby inhibiting NLRP3 activation, decreasing secretion of inflammatory factors and RM cell apoptosis by regulating the PTEN induced putative kinase 1(Pink1) /Parkin signaling pathway. In vivo experiments showed that Rg1 induced mitochondrial autophagy, inhibited NLRP3 activation, improved inflammatory response, and reduced apoptosis by regulating the Pink1/Parkin signaling pathway, and Rg1 significantly reduced the area of cerebral infarcts, improved the pathological state of brain tissue, and attenuated the neuronal damage, thus improving cerebral ischemia/reperfusion injury in rats. CONCLUSION: Our results suggest that ginsenoside Rg1 can ameliorate cerebral ischemia-reperfusion injury by modulating Pink1/ Parkin-mediated mitochondrial autophagy in microglia and inhibiting microglial NLRP3 activation.

Asunto(s)

Autofagia , Ginsenósidos , Microglía , Mitocondrias , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Quinasas , Daño por Reperfusión , Ubiquitina-Proteína Ligasas , Ginsenósidos/farmacología , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Autofagia/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ratas , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Masculino , Ratas Sprague-Dawley , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Apoptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología

RESUMEN

BACKGROUND: G protein-coupled receptor 68 (GPR68), an orphan receptor, has emerged as a promising therapeutic target for mitigating neuronal inflammation and oxidative damage. This study explores the protective mechanisms of GPR68 in cerebral ischemia-reperfusion injury (CIRI). METHODS: An in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was established. Mice received intraperitoneal injections of Ogerin, a selective GPR68 agonist. In vitro, GPR68 was overexpressed in SH-SY5Y and HMC3 cells, and the effects of oxygen-glucose deprivation/reperfusion (OGD/R) on cell viability were assessed using real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry. RESULTS: The expression of GPR68 was suppressed in cells subjected to OGD/R treatment, whereas its upregulation conferred protection to SH-SY5Y and HMC3 cells. In vivo, levels of GPR68 were reduced in brain tissues affected by MCAO/R, correlating with oxidative stress, inflammation, and neurological damage. Treatment with a GPR68 agonist decreased brain infarction, apoptosis, and dysregulated gene expression induced by MCAO/R. Mechanistically, GPR68 agonist treatment may inhibit the activation of the NF-κB/Hif-1α pathway, thereby reducing oxidative and inflammatory responses and enhancing protection against CIRI. CONCLUSIONS: This study confirms that the GPR68/NF-κB/Hif-1α axis modulates apoptosis, inflammation, and oxidative stress in CIRI, indicating that GPR68 is a potential therapeutic target for CIRI.

Asunto(s)

Subunidad alfa del Factor 1 Inducible por Hipoxia , FN-kappa B , Fármacos Neuroprotectores , Receptores Acoplados a Proteínas G , Daño por Reperfusión , Animales , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Ratones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , FN-kappa B/metabolismo , Fármacos Neuroprotectores/farmacología , Masculino , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Humanos , Transducción de Señal/efectos de los fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Línea Celular Tumoral

RESUMEN

Ischemic stroke is a serious condition that results in high rates of illness and death. Anaerobic glycolysis becomes the primary means of providing energy to the brain during periods of low oxygen levels, such as in the aftermath of an ischemic stroke. This process is essential for maintaining vital brain functions and has significant implications for recovery following a stroke. Energy supply by anaerobic glycolysis and acidosis caused by lactic acid accumulation are important pathological processes after ischemic stroke. Numerous natural products regulate glucose and lactate, which in turn modulate anaerobic glycolysis. This article focuses on the relationship between anaerobic glycolysis and ischemic stroke, as well as the associated signaling pathways and natural products that play a therapeutic role. These natural products, which can regulate anaerobic glycolysis, will provide new avenues and perspectives for the treatment of ischemic stroke in the future.

Asunto(s)

Productos Biológicos , Glucólisis , Accidente Cerebrovascular Isquémico , Transducción de Señal , Humanos , Glucólisis/fisiología , Glucólisis/efectos de los fármacos , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Animales , Anaerobiosis/fisiología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamiento farmacológico

RESUMEN

OBJECTIVE: To study the efficacy and safety of the use of the drug Picamilon with various therapy regimens in patients with stage I of chronic cerebral ischemia (CCI). MATERIAL AND METHODS: Material and methods. An open randomized comparative clinical trial included 44 patients with stage CCI aged 46 to 67 years (average age 55.6±6.76 years). Patients were randomized into two groups, patients of group 1 (n=23) received Picamilon orally in tablets of 50 mg 3 times/day for 60 days; group 2 (n=21) received Picamilon first parenterally at 100 mg i/m for 10 days, then in tablets of 50 mg 3 times/day for 50 days. The total duration of therapy was 60 days. The study included 4 visits (before treatment, 10 days later, 60 days later, 1.5 months after completion of treatment). The dynamics of cognitive status were assessed according to the Montreal Cognitive Function Assessment Scale (MoCA), vegetative disorders on the A.M. Wayne scale, neurological disorders on the A.I. Fedin scale, and sleep quality on the Ya.I. Levin scale. The study of the state of cerebral blood flow (dopplerography of intracranial vessels) and endothelial function (assessment of the level of methylation. RESULTS: During treatment, in the total sample of patients, there was a positive trend in the results of the MoCA scale, increasing in the delayed period (24.9/26.5/28.3 points, p=0.022 and p<0.001); improvement in sleep quality in 50% of patients by visit 3 and in 84% by visit 4, in the 2nd group the effect occurred in 28% of patients, in the 1st - in 11%, by the end of the study the effect was comparable (p=0.508). Improvement according to Fedin A.I. scale noted in 77% of patients, values decreased from 11.9±8.3 to 6±6.1 points (p<0.0001) and to 2.77±4.43 points by visit 4 (p<0.0001). Normalization of autonomic functions was observed in 29% of patients (p=0.024) without intergroup differences. Picamilon therapy showed high efficacy in terms of clinical outcomes (up to 89%), good tolerability (98% of patients) and a favorable safety profile (less than 8.6% of AEs). The use of Picamilon was accompanied by an increase in the linear velocity of blood flow, a decrease in the thickness of the intima-media complex and the resistance index; a decrease in elevated ADMA concentrations and ADMA/MMA and (ADMA+SDMA)/MMA ratios. CONCLUSION: The use of Picamilon is effective in patients with stage I CCI, contributes to a significant regression of neurological deficits, cognitive impairment, improved sleep quality and autonomic function; improves vascular endothelial function, reduces the risk of atherosclerosis and cardiovascular complications in patients. The optimal duration of therapy with Picamilon in stage I of chronic cerebral ischemia is 2 months.

Asunto(s)

Isquemia Encefálica , Humanos , Persona de Mediana Edad , Masculino , Femenino , Anciano , Resultado del Tratamiento , Isquemia Encefálica/tratamiento farmacológico , Pacientes Ambulatorios , Circulación Cerebrovascular/efectos de los fármacos

RESUMEN

Oltipraz (OPZ) is a synthetic dithiolethione and is considered a novel activator of nuclear factor E2-related factor 2 (Nrf2). Increasing evidence indicates that Nrf2 protects against cerebral ischemia/reperfusion (I/R) injury by antagonizing ferroptosis and lipid peroxidation. However, the protective effects of OPZ on cerebral I/R injury remain to be elucidated. We investigated the in vitro and in vivo neuroprotective effects of OPZ. Mice were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to construct an in vivo model and PC12 cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) to establish an in vitro model. OPZ administration reduced the infarct volume and brain water content, and alleviated the neurological deficit of MCAO/R mice. Moreover, OPZ ameliorated MCAO/R-induced oxidative stress by decreasing the levels of 4-HNE and MDA and increasing the activities of SOD and GSH. We also found that OPZ ameliorated MCAO/R-induced ferroptosis by increasing SLC7A11 and GPX4 protein expression and downregulating ACSL4 protein expression. Similarly, the in vitro results revealed that OGD/R-induced oxidative stress and ferroptosis. Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis.

Asunto(s)

Ferroptosis , Infarto de la Arteria Cerebral Media , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Fármacos Neuroprotectores , Estrés Oxidativo , Daño por Reperfusión , Tionas , Tiofenos , Animales , Ferroptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Tionas/farmacología , Tionas/uso terapéutico , Células PC12 , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Ratas , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Modelos Animales de Enfermedad , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/metabolismo , Pirazinas

RESUMEN

Ischemic stroke is a serious neurological disease involving multiple complex physiological processes, including vascular obstruction, brain tissue ischemia, impaired energy metabolism, cell death, impaired ion pump function, and inflammatory response. In recent years, there has been significant interest in cell membrane-functionalized biomimetic nanoparticles as a novel therapeutic approach. This review comprehensively explores the mechanisms and importance of using these nanoparticles to treat acute ischemic stroke with a special emphasis on their potential for actively targeting therapies through cell membranes. We provide an overview of the pathophysiology of ischemic stroke and present advances in the study of biomimetic nanoparticles, emphasizing their potential for drug delivery and precision-targeted therapy. This paper focuses on bio-nanoparticles encapsulated in bionic cell membranes to target ischemic stroke treatment. It highlights the mechanism of action and research progress regarding different types of cell membrane-functionalized bi-onic nanoparticles such as erythrocytes, neutrophils, platelets, exosomes, macrophages, and neural stem cells in treating ischemic stroke while emphasizing their potential to improve brain tissue's ischemic state and attenuate neurological damage and dysfunction. Through an in-depth exploration of the potential benefits provided by cell membrane-functionalized biomimetic nanoparticles to improve brain tissue's ischemic state while reducing neurological injury and dysfunction, this study also provides comprehensive research on neural stem cells' potential along with that of cell membrane-functionalized biomimetic nanoparticles to ameliorate neurological injury and dysfunction. However, it is undeniable that there are still some challenges and limitations in terms of biocompatibility, safety, and practical applications for clinical translation.

Asunto(s)

Materiales Biomiméticos , Membrana Celular , Accidente Cerebrovascular Isquémico , Nanopartículas , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Nanopartículas/química , Animales , Membrana Celular/metabolismo , Biomimética/métodos , Sistemas de Liberación de Medicamentos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo

RESUMEN

PURPOSE: To evaluate the neuroprotective effect of resveratrol, urapidil, and a combined administration of these drugs against middle cerebral artery occlusion (MCAO) induced ischemia/reperfusion (IR) injury model in rats. METHODS: Thirty-five rats were divided into five groups of seven animals each. Animals in IR, IR resveratrol (IRr), IR urapidil (IRu), and IR + combination of resveratrol and urapidil (IRc) were exposed to MCAO induced cerebral ischemia reperfusion injury model. Rats in IRr and IRu groups received 30-mg/kg resveratrol and 5-mg/kg urapidil respectively. Animals in IRc received a combined treatment of both drugs. At the end of the study, brain tissues were used for oxidative stress (malondialdehyde, glutathione, and superoxide dismutase), pro-apoptotic caspase-3, anti-apoptotic Bcl-2, and pro-inflammatory tumor necrosis factor-α cytokine level measurements. RESULTS: The MCAO model successfully replicated IR injury with significant histopathological changes, elevated tissue oxidative stress, and upregulated apoptotic and inflammatory protein expression in IR group compared to control group (p < 0.001). All parameters were significantly alleviated in IRr group compared to IR group (all p < 0.05). In IRu group, all parameters except for caspase-3 and Bcl-2 were also significantly different than IR group (all p < 0.05). The IRc group showed the biggest difference compared to IR group in all parameters (all p < 0.001). The IRc had higher superoxide dismutase and Bcl-2 levels, and lower caspase-3 levels compared to both IRr and IRu groups (all p < 0.05). Also, the IRc group had lower MDA and TNF-α levels compared to IRu group (all p < 0.05). CONCLUSIONS: The results indicate that combined treatment of resveratrol and urapidil may be a novel strategy to downregulate neurodegeneration in cerebral IR injury.

Asunto(s)

Modelos Animales de Enfermedad , Fármacos Neuroprotectores , Estrés Oxidativo , Daño por Reperfusión , Resveratrol , Estilbenos , Animales , Resveratrol/farmacología , Resveratrol/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Masculino , Estrés Oxidativo/efectos de los fármacos , Estilbenos/uso terapéutico , Estilbenos/farmacología , Quimioterapia Combinada , Ratas Wistar , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Resultado del Tratamiento , Ratas , Factor de Necrosis Tumoral alfa/análisis , Superóxido Dismutasa/análisis , Superóxido Dismutasa/metabolismo , Malondialdehído/análisis , Malondialdehído/metabolismo , Reproducibilidad de los Resultados , Apoptosis/efectos de los fármacos , Distribución Aleatoria , Isquemia Encefálica/tratamiento farmacológico , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Caspasa 3/metabolismo , Caspasa 3/análisis

RESUMEN

BACKGROUND: Clinically, ischemic reperfusion injury is the main cause of stroke injury. This study aimed to assess the effectiveness of fingolimod in suppressing inflammation caused by ischemic brain injury and explore its pharmacological mechanisms. METHODS: In total, 75 male Sprague-Dawley rats were randomly and equally assigned to five distinct groups: sham, middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, fingolimod low-dose (F-L), fingolimod medium-dose (F-M), and fingolimod high-dose (F-H). Neurobehavioral tests, 2,3,5-triphenyltetrazolium chloride staining, and the brain tissue drying-wet method were conducted to evaluate neurological impairment, cerebral infarction size, and brain water content. Enzyme-linked immunosorbent assay was employed to quantify pro-inflammatory cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) protein levels. Western blotting and immunohistochemical staining were performed to assess high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and nuclear factor kappa-B p65 (NF-κBp65) levels. RESULTS: Rats in the F-L, F-M, and F-H groups exhibited lower Longa scores, reduced infarction volumes, and decreased brain edema than those in the MCAO/R group. Additionally, the F-L, F-M, and F-H groups exhibited lower serum levels of IL-1ß, IL-6, and TNF-α than those of the MCAO/R group. Additionally, F-L, F-M, and F-H treatments resulted in decreased HMGB1, TLR4, and NF-κBp65 protein expression levels in the hippocampus of MCAO/R rats. CONCLUSIONS: Fingolimod was found to reduce ischemic brain injury in a dose-dependent manner. Moreover, it was also found to alleviate inflammation following ischemic brain injury via the HMGB1/TLR4/NF­κB signaling pathway.

Asunto(s)

Isquemia Encefálica , Clorhidrato de Fingolimod , Transducción de Señal , Animales , Masculino , Ratas , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Modelos Animales de Enfermedad , Clorhidrato de Fingolimod/farmacología , Clorhidrato de Fingolimod/administración & dosificación , Proteína HMGB1/metabolismo , Proteína HMGB1/efectos de los fármacos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/etiología , FN-kappa B/metabolismo , FN-kappa B/efectos de los fármacos , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/efectos de los fármacos

RESUMEN

A1 polarization of astrocytes mediated prolonged inflammation contributing to brain injury in ischemic stroke. We have previously shown that AD16 protects against neonatal hypoxic-ischemic brain damage in vivo and oxygen-glucose deprivation in vitro. More recently, AD16 has demonstrated safety, tolerability, and favorable pharmacokinetics in a randomized controlled phase I trial. In this study, we utilized a rat model of transient middle cerebral artery occlusion (tMCAO) to explore whether the anti-inflammatory compound AD16 protects against ischemic brain injury by regulating A1 polarization and its underlying mechanisms. Our results showed that AD16 treatment significantly reduced the brain infarcted volume and improved neurological function in tMCAO rats. GO analysis results show that differential genes among the Sham, tMCAO and AD16 treatment groups are involved in the regulation of cytokine and inflammatory response. KEGG enrichment pathways analysis mainly enriched in cytokine-cytokine receptor interaction, viral protein interaction with cytokine-cytokine receptor, TNF, chemokine, NF-κB and IL-17 signaling pathway. Furthermore, AD16 treatment decreased the permeability of the blood-brain barrier and suppressed neuroinflammation. AD16 treatment also significantly reduced the polarization of A1 and inhibited NF-κB and JAK2/STAT3 signaling pathways. This study demonstrates that AD16 protects against brain injury in ischemic stroke by reducing A1 polarization to suppress neuroinflammation through downregulating NF-κB and JAK2/STAT3 signaling. Our findings uncover a potential molecular mechanism for AD16 and suggest that AD16 holds promising therapeutic potential against cerebral ischemia.

Asunto(s)

Astrocitos , Enfermedades Neuroinflamatorias , Animales , Masculino , Ratas , Antiinflamatorios/farmacología , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Polaridad Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Fármacos Neuroprotectores/farmacología , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos

RESUMEN

Cerebral ischemia-reperfusion injury (CI/RI) is a leading cause of disability and mortality worldwide, with limited therapeutic options available. Erianin, a natural compound derived from traditional Chinese medicine, has been reported to possess anti-inflammatory and neuroprotective properties. This study aimed to investigate the therapeutic potential of Erianin in CI/RI and elucidate its underlying mechanisms. Network pharmacology analysis predicted that Erianin could target the PI3K/AKT pathway, which are closely associated with CI/RI. In vivo experiments using a rat model of CI/RI demonstrated that Erianin treatment significantly alleviated neurological deficits, reduced infarct volume, and attenuated neuronal damage. Mechanistically, Erianin inhibited microglial cell polarization towards the pro-inflammatory M1 phenotype, as evidenced by the modulation of specific markers. Furthermore, Erianin suppressed the expression of pro-inflammatory cytokines and mediators, such as TNF-α, IL-6, and COX-2, while enhancing the production of anti-inflammatory factors, including Arg1, CD206, IL-4 and IL-10. In vitro studies using oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated microglial cells corroborated the anti-inflammatory and anti-apoptotic effects of Erianin. Notably, Erianin inhibited the NF-κB signaling pathway by inhibiting p65 phosphorylation and preventing the nuclear translocation of the p65 subunit. Collectively, these findings suggest that Erianin represents a promising therapeutic candidate for CI/RI by targeting microglial cell polarization and inflammation.

Asunto(s)

Antiinflamatorios , Microglía , FN-kappa B , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Daño por Reperfusión , Transducción de Señal , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Ratas , Fosfatidilinositol 3-Quinasas/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Citocinas/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Modelos Animales de Enfermedad , Bibencilos , Fenol

RESUMEN

Chronic cerebral hypoperfusion (CCH) has been acknowledged as a potential contributor to cognitive dysfunction and brain injury, causing progressive demyelination of white matter, oligodendrocytes apoptosis and microglia activation. Nervonic acid (NA), a naturally occurring fatty acid with various pharmacological effects, has been found to alleviate neurodegeneration. Nonetheless, evidence is still lacking on whether NA can protect against neurological dysfunction resulting from CCH. To induce CCH in mice, we employed the right unilateral common carotid artery occlusion (rUCCAO) method, followed by oral administration of NA daily for 28 days after the onset of hypoperfusion. We found that NA ameliorated cognitive function, as evidenced by improved performance of NA-treated mice in both novel object recognition test and Morris water maze test. Moreover, NA mitigated demyelination and loss of oligodendrocytes in the corpus callosum and hippocampus of rUCCAO-treated mice, and prevented oligodendrocyte apoptosis. Furthermore, NA protected primary cultured murine oligodendrocytes against oxygen-glucose deprivation (OGD)-induced cell death in a concentration-dependent manner. These findings indicated that NA promotes oligodendrocyte maturation both in vivo and in vitro. Our findings suggest that NA offers protective effects against cerebral hypoperfusion, highlighting its potential as a promising treatment for CCH and related neurological disorders.

Asunto(s)

Apoptosis , Ratones Endogámicos C57BL , Fármacos Neuroprotectores , Oligodendroglía , Animales , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Ratones , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Apoptosis/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/metabolismo , Modelos Animales de Enfermedad , Cognición/efectos de los fármacos , Cuerpo Calloso/efectos de los fármacos , Cuerpo Calloso/patología , Enfermedad Crónica , Células Cultivadas