2-(3′, 5′-Dimethoxybenzylidene) cyclopentanone, a novel synthetic small-molecule compound, provides neuroprotective effects against ischemic stroke. (1st March 2016)

• Record Type: Journal Article
• Authors: Gu, W.W.; Lu, S.Q.; Ni, Y.; Liu, Z.H.; Zhou, X.Y.; Zhu, Y.M.; Luo, Y.; Li, X.; Li, L.S.; Sun, W.Z.; Zhang, H.L.; Ao, G.Z.
• Is Part Of: Neuroscience. Volume 316(2016)
• Page Start: 26
• Page End: 40
• Publication Date: 2016-03-01
• Subjects: COX cyclooxygenase -- DMBC 2-(3′, 5′-Dimethoxybenzylidene) cyclopentanone -- DTBHP 3, 5-di-tert-butyl-4-hydroxyphenyl -- GFAP glial fibrillary acid protein -- LDH lactate dehydrogenase -- 5-LOX 5-Lipoxygenase -- MAP 2 Microtubule-associated protein 2 -- MCA middle cerebral artery -- OGD oxygen–glucose deprivation -- PI propidium iodide -- pMCAO permanent middle cerebral artery occlusion -- rCBF relative cerebral blood flow -- tPA tissue plasminogen activator -- TTC 2, 3, 5-triphenyltetrazolium chloride; 2-(3′, 5′-Dimethoxybenzylidene) cyclopentanone -- cerebral ischemia -- neuroprotection -- astrocyte -- HT 22 cell -- cathepsin B; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.11.052
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: 2-(3′, 5′-Dimethoxybenzylidene) (DMBC) produces neuroprotection against pMCAO insult. DMBC directly protects HT22 cell and astrocytes against OGD insult. DMBC inhibits the ischemia or OGD-induced activation of cathepsin B. DMBC treatment blocks the ischemia or OGD-induced release of cathepsin B. Abstract: 2-(3′, 5′-Dimethoxybenzylidene) cyclopentanone (DMBC) is a novel small-molecule compound synthesized by our group. Here, we found that in rat models of permanent middle cerebral artery occlusion (pMCAO), intraperitoneal injection (ip) of DMBC at 1 h after ischemia reduced infarct volume, improved neurological deficits and increased the protein levels of microtubule-associated protein 2 (MAP 2) and glial fibrillary acid protein (GFAP) in the ischemic cortex. Post-treatment of DMBC still produced neuroprotective effects even when administered at 6 h after ischemia. In the oxygen–glucose deprivation (OGD)-induced astrocytes or HT22 cell injury, DMBC treatment decreased the OGD-induced lactate dehydrogenase (LDH) leakage and increased the GFAP levels in astrocytes. In addition, Annexin-V-Fluos staining analysis revealed that DMBC treatment attenuated both OGD-induced apoptosis and necrosis in astrocytes. Western blotting analysis showed DMBC treatment inhibited the ischemia or OGD-induced increases in active cathepsin B in the ischemic cortex or in astrocytes or HT22 cells. Immunofluorescence analysis demonstrated that DMBC treatment blocked the ischemia or OGD-induced release of cathepsin B from the lysosomes into the cytoplasm in the ischemic cortex or in astrocytes or HT22 cells. Taken together, our results indicate that DMBC can offer neuroprotective effects against cerebral ischemia with an extended therapeutic window and its mechanism might be associated with inhibition of the cathepsin B activation.