2-(3′,5′-Dimethoxybenzylidene) cyclopentanone, a novel synthetic small-molecule compound, provides neuroprotective effects against ischemic stroke

Gu, Weiwei; Lu, Shiqi; Ni, Yicheng; Liu, Z.H.; Zhou, Xiaomei; Zhu, Yanfang; Luo, Yu; Li, X.; Li, L.S.; Sun, Wujin; Zhang, H.L.; Ao, Gui-Zhen

doi:10.1016/j.neuroscience.2015.11.052

Cited by 10 publications

(4 citation statements)

References 56 publications

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“…MTT assay is a well-established, widely used and easily reproducible method for the assessment of cell viability and cytotoxicity when cells are exposed to different substances [ 78 , 79 ]. Moreover, Rn decreased 15% (10 -6 M) and 20% (10 -5 M) LDH leakage in control astrocytes, suggesting less cell death [ 80 , 81 ]. In addition, Rn protected astrocytes from the harmful effects of Aβ 1–42 .…”

Section: Discussionmentioning

confidence: 99%

Effects of Ranolazine on Astrocytes and Neurons in Primary Culture

et al. 2016

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Ranolazine (Rn) is an antianginal agent used for the treatment of chronic angina pectoris when angina is not adequately controlled by other drugs. Rn also acts in the central nervous system and it has been proposed for the treatment of pain and epileptic disorders. Under the hypothesis that ranolazine could act as a neuroprotective drug, we studied its effects on astrocytes and neurons in primary culture. We incubated rat astrocytes and neurons in primary cultures for 24 hours with Rn (10−7, 10−6 and 10−5 M). Cell viability and proliferation were measured using trypan blue exclusion assay, MTT conversion assay and LDH release assay. Apoptosis was determined by Caspase 3 activity assay. The effects of Rn on pro-inflammatory mediators IL-β and TNF-α was determined by ELISA technique, and protein expression levels of Smac/Diablo, PPAR-γ, Mn-SOD and Cu/Zn-SOD by western blot technique. In cultured astrocytes, Rn significantly increased cell viability and proliferation at any concentration tested, and decreased LDH leakage, Smac/Diablo expression and Caspase 3 activity indicating less cell death. Rn also increased anti-inflammatory PPAR-γ protein expression and reduced pro-inflammatory proteins IL-1 β and TNFα levels. Furthermore, antioxidant proteins Cu/Zn-SOD and Mn-SOD significantly increased after Rn addition in cultured astrocytes. Conversely, Rn did not exert any effect on cultured neurons. In conclusion, Rn could act as a neuroprotective drug in the central nervous system by promoting astrocyte viability, preventing necrosis and apoptosis, inhibiting inflammatory phenomena and inducing anti-inflammatory and antioxidant agents.

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Section: Discussionmentioning

confidence: 99%

Effects of Ranolazine on Astrocytes and Neurons in Primary Culture

et al. 2016

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“…Proteins were extracted from ipsilateral cortical tissues or cultured astrocytes and used for Western blotting analysis as previously described [36]. Proteins were separated on 8%-12% SDS-PAGE gels and transferred to nitrocellulose membranes.…”

Section: Western Blotting Analysismentioning

confidence: 99%

RIPK1 inhibition contributes to lysosomal membrane stabilization in ischemic astrocytes via a lysosomal Hsp70.1B-dependent mechanism

Guo

Zhu

et al. 2023

Acta Pharmacol Sin

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Receptor-interacting protein kinase 1 (RIPK1) contributes to necroptosis. Our previous study showed that pharmacological or genetic inhibition of RIPK1 protects against ischemic stroke-induced astrocyte injury. In this study, we investigated the molecular mechanisms underlying RIPK1-mediated astrocyte injury in vitro and in vivo. Primary cultured astrocytes were transfected with lentiviruses and then subjected to oxygen and glucose deprivation (OGD). In a rat model of permanent middle cerebral artery occlusion (pMCAO), lentiviruses carrying shRNA targeting RIPK1 or shRNA targeting heat shock protein 70.1B (Hsp70.1B) were injected into the lateral ventricles 5 days before pMCAO was established. We showed that RIPK1 knockdown protected against OGD-induced astrocyte damage, blocked the OGD-mediated increase in lysosomal membrane permeability in astrocytes, and inhibited the pMCAO-induced increase in astrocyte lysosome numbers in the ischemic cerebral cortex; these results suggested that RIPK1 contributed to the lysosomal injury in ischemic astrocytes. We revealed that RIPK1 knockdown upregulated the protein levels of Hsp70.1B and increased the colocalization of Lamp1 and Hsp70.1B in ischemic astrocytes. Hsp70.1B knockdown exacerbated pMCAO-induced brain injury, decreased lysosomal membrane integrity and blocked the protective effects of the RIPK1-specific inhibitor necrostatin-1 on lysosomal membranes. On the other hand, RIPK1 knockdown further exacerbated the pMCAO- or OGD-induced decreases in the levels of Hsp90 and the binding of Hsp90 to heat shock transcription factor-1 (Hsf1) in the cytoplasm, and RIPK1 knockdown promoted the nuclear translocation of Hsf1 in ischemic astrocytes, resulting in increased Hsp70.1B mRNA expression. These results suggest that inhibition of RIPK1 protects ischemic astrocytes by stabilizing lysosomal membranes via the upregulation of lysosomal Hsp70.1B; the mechanism underlying these effects involves decreased Hsp90 protein levels, increased Hsf1 nuclear translocation and increased Hsp70.1B mRNA expression.

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“…The images were obtained by a confocal microscope (LSM 710; Carl Zeiss Co. Ltd., Oberkochen, Germany) and a fluorescent microscope (Olympus IX51; Olympus Co., Japan). Cells that were propidium iodide (PI)-negative and Annexin V-negative were considered as healthy; cells that were PI negative and Annexin V-positive were considered as apoptotic; and cells that were positive to both PI and Annexin V were considered as necrotic [45]. Five different regions were selected to calculate the percentage of necrotic and apoptosis rate.…”

Section: Detection Of Apoptosis and Necrosismentioning

confidence: 99%

Valproic Acid Inhibits Glial Scar Formation after Ischemic Stroke

Gao

Zeb

et al. 2022

Pharmacology

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Introduction: Cerebral ischemia induces reactive proliferation of astrocytes (astrogliosis) and glial scar formation. As a physical and biochemical barrier, the glial scar not only hinders spontaneous axonal regeneration and neuronal repair but also deteriorates the neuroinflammation in the recovery phase of ischemic stroke. Objectives: Previous studies have shown the neuroprotective effects of the valproic acid (2-n-propylpentanoic acid, VPA) against ischemic stroke, but its effects on the ischemia-induced formation of astrogliosis and glial scar are still unknown. As targeting astrogliosis has become a therapeutic strategy for ischemic stroke, this study was designed to determine whether VPA can inhibit the ischemic stroke-induced glial scar formation and to explore its molecular mechanisms. Methods: Glial scar formation was induced by an ischemia-reperfusion (I/R) model in vivo and an oxygen and glucose deprivation (OGD)-reoxygenation (OGD/Re) model in vitro. Animals were treated with an intraperitoneal injection of VPA (250 mg/kg/day) for 28 days, and the ischemic stroke-related behaviors were assessed. Results: Four weeks of VPA treatment could markedly reduce the brain atrophy volume and improve the behavioral deficits in rats’ I/R injury model. The results showed that VPA administrated upon reperfusion or 1 day post-reperfusion could also decrease the expression of the glial scar makers such as glial fibrillary acidic protein, neurocan, and phosphacan in the peri-infarct region after I/R. Consistent with the in vivo data, VPA treatment showed a protective effect against OGD/Re-induced astrocytic cell death in the in vitro model and also decreased the expression of GFAP, neurocan, and phosphacan. Further studies revealed that VPA significantly upregulated the expression of acetylated histone 3, acetylated histone 4, and heat-shock protein 70.1B in the OGD/Re-induced glial scar formation model. Conclusion: VPA produces neuroprotective effects and inhibits the glial scar formation during the recovery period of ischemic stroke via inhibition of histone deacetylase and induction of Hsp70.1B.

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2-(3′,5′-Dimethoxybenzylidene) cyclopentanone, a novel synthetic small-molecule compound, provides neuroprotective effects against ischemic stroke

Cited by 10 publications

References 56 publications

Effects of Ranolazine on Astrocytes and Neurons in Primary Culture

Effects of Ranolazine on Astrocytes and Neurons in Primary Culture

RIPK1 inhibition contributes to lysosomal membrane stabilization in ischemic astrocytes via a lysosomal Hsp70.1B-dependent mechanism

Valproic Acid Inhibits Glial Scar Formation after Ischemic Stroke

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