Synergetic Effects of Caspase 3 and μ-Calpain in XIAP-Breakdown upon Focal Cerebral Ischemia

The purpose of this study was to enhance our understanding of the mechanisms of neuronal death after focal cerebral ischemia and the neuroprotective effects of tamoxifen (TMX). The phosphorylation state of 31 protein kinases/signaling proteins and superoxide anion (O2−) production in the contralateral and ipsilateral cortex was measured after permanent middle cerebral artery occlusion (pMCAO) in ovariectomized rats treated with placebo or TMX. The study revealed that pMCAO modulated the phosphorylation of a number of kinases/proteins in the penumbra at 2 h after pMCAO. Of significant interest, phospho-ERK1/2 (pERK1/2) was elevated significantly after pMCAO. TMX attenuated the elevation of pERK1/2, an effect correlated with reduced infarct size. In situ detection of O2− production showed a significant elevation at 1–2 h after pMCAO in the ischemic cortex with enhanced oxidative damage detected at 24 h. ERK activation may be downstream of free radicals, a suggestion supported by the findings that cells positive for O2− had high pERK activation and that a superoxide dismutase (SOD) mimetic, tempol, significantly attenuated pERK activation after MCAO. TMX treatment significantly reduced the MCAO-induced elevation of O2− production, oxidative damage, and proapoptotic caspase-3 activation. Additionally, pMCAO induced a significant reduction in the levels of manganese SOD (MnSOD), which scavenge O2−, an effect largely prevented by TMX treatment, thus providing a potential mechanistic basis for the antioxidant effects of TMX. As a whole, these studies suggest that TMX neuroprotection may be achieved via an antioxidant mechanism that involves enhancement of primarily MnSOD levels, with a corresponding reduction of O2− production, and downstream kinase and caspase-3 activation.

Download Full-text

Effects of Low-Dose Lidocaine on Cytochrome C Release and Caspase-3 Activation after Transient Focal Cerebral Ischemia in Rats

Anesthesiology ◽

10.1097/00000542-200209002-00800 ◽

2002 ◽

Vol 96 (Sup 2) ◽

pp. A800

Author(s):

Baiping Lei ◽

Susanna Popp ◽

Christine Capuano-Waters ◽

James E. Cottrell ◽

Ira S. Kass

Keyword(s):

Cerebral Ischemia ◽

Cytochrome C ◽

Low Dose ◽

Caspase 3 ◽

Focal Cerebral Ischemia ◽

Cytochrome C Release ◽

Transient Focal Cerebral Ischemia

Download Full-text

Abstract WP97: Neuroprotective Effect of Progranulin Against Focal Cerebral Ischemia via Inhibition of Proteolysis of TDP-43 by Caspase-3

Stroke ◽

10.1161/str.47.suppl_1.wp97 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Toriyabe Masafumi ◽

Masato Kanazawa ◽

Misaki Koyama ◽

Minami Miura ◽

Tetsuya Takahashi ◽

...

Keyword(s):

Cerebral Ischemia ◽

Growth Factor ◽

Caspase 3 ◽

Focal Cerebral Ischemia ◽

Neuroprotective Effect ◽

Neuronal Cells ◽

Interleukin 10 ◽

Full Length ◽

Expression Level ◽

Vascular Protection

Introduction: We previously demonstrated that progranulin (PGRN), a glycoprotein growth factor, may be a novel therapeutic target that provides vascular protection and anti-neuroinflammation properties related in part to vascular endothelial growth factor and interleukin 10, respectively. We also found that PGRN could provide neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43 (TDP-43), although its exact mechanism remains poorly understood. The purpose of this study is to determine the mechanism of neuroprotection by PGRN against ischemic neuronal injury. Methods: The middle cerebral artery of adult PGRN knock-out (KO) mice (C57BL/6 background) and wild-type (WT) mice was occluded for 90 minutes. Immunohistochemical analysis using an antibody against TDP-43 was performed to investigate the subcellular localization of TDP-43 after ischemia. We also performed Western blot analysis to investigate the expression levels of TDP-43 and activated caspase-3 using cerebral cortex tissues from a rat autologous thromboembolic model with delayed tissue plasminogen activator (tPA) treatment (4 hours after ischemia). Results: Twenty-four hours after reperfusion, neuronal cells showing cytoplasmic redistribution of TDP-43 were more frequently observed in PGRN KO mice than in WT mice (P<0.01). In a rat autologous thromboembolic model with delayed tPA treatment, the expression level of full-length of TDP-43 decreased 24 hours after ischemia via proteolytic degradation. However, intravenous administration of recombinant PGRN with delayed tPA treatment inhibited the decrease in the expression level of full-length TDP-43 as well as the increase in the expression level of activated caspase-3 compared with that of the control protein. Conclusion: This study demonstrated that PGRN might protect neuronal cells against focal cerebral ischemia via inhibition of proteolysis and abnormal cytoplasmic redistribution of TDP-43 by caspase-3.

Download Full-text

Neuroprotective Effect of DAHP via Antiapoptosis in Cerebral Ischemia

Behavioural Neurology ◽

10.1155/2018/5050469 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Yanhua Qin ◽

Weiming Hu ◽

Yang Yang ◽

Zhiying Hu ◽

Weiyun Li ◽

...

Keyword(s):

Nitric Oxide ◽

Brain Injury ◽

Cerebral Ischemia ◽

Caspase 3 ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Tunel Staining ◽

Cox 2

Aberrant production of nitric oxide following inducible nitric oxide synthase (iNOS) expression has been implicated in cell death and contributes to ischemic brain injury. Tetrahydrobiopterin (BH4) is an essential cofactor of NOS activity. Herein, we evaluated antiapoptotic and anti-inflammatory effects of diamino-6-hydroxypyrimidine (DAHP), a guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) inhibitor on focal cerebral ischemia-reperfusion injury by middle cerebral artery occlusion and reperfusion (MCAO) and investigated the underlying mechanism. Sprague-Dawley rats were divided into five groups. Experimental groups were subjected to 1.5 h transient MCAO. T2-weighted imaging was performed to evaluate brain edema lesions in the stroke rats. Infarct volume was estimated by 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24 h reperfusion. Western blotting and immunohistochemistry were performed to detect iNOS, caspase-3, Bcl-2, COX-2, and TNF-α protein expressions. Apoptosis was determined by TUNEL staining. T2 hyperintensity changes were observed in primary ischemic region. DAHP pretreatment significantly suppressed iNOS overexpression, caspase-3, and TNF-α. There was also attenuation of neuronal apoptosis with decrement in proteins Bcl-2 and COX-2 expressions. On the basis of our results, we hypothesize DAHP to have a neuroprotective function against focal cerebral ischemia and might attenuate brain injury by decreasing reactive oxygen species (ROS) production, subsequently inhibiting apoptosis.

Download Full-text