Autophagy Upregulation and Apoptosis Downregulation in DAHP and Triptolide Treated Cerebral Ischemia

It has previously been demonstrated that ischemic stroke activates autophagy pathways; however, the mechanism remains unclear. The aim of this study is to further investigate the role that autophagy plays in cerebral ischemia. 2, 4-diamino-6-hydroxy-pyrimidine (DAHP), for its nitric oxide synthase (...

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Bibliographic Details
Published in:Mediators of Inflammation 2015-01, Vol.2015 (2015), p.84-95-007
Main Authors: Fang, Marong, Ling, Shucai, Davies, Henry, Li, Weiyun, Hu, Zhiying, Gao, Keqiang, Yang, Yang, Rudd, John A.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - drug effects
Autophagy (Cytology)
Autophagy - genetics
Autophagy - physiology
Blotting, Western
Brain Ischemia - drug therapy
Cerebral ischemia
Diterpenes
Diterpenes - therapeutic use
Dosage and administration
Drug therapy
Epoxy Compounds - therapeutic use
Health aspects
Immunohistochemistry
In Situ Nick-End Labeling
Kinases
Magnetic Resonance Spectroscopy
Male
Mortality
Patient outcomes
Phenanthrenes - therapeutic use
Pyrimidines
Rats
Rats, Sprague-Dawley
Rodents
Stroke
Sugar Acids - therapeutic use
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Summary:It has previously been demonstrated that ischemic stroke activates autophagy pathways; however, the mechanism remains unclear. The aim of this study is to further investigate the role that autophagy plays in cerebral ischemia. 2, 4-diamino-6-hydroxy-pyrimidine (DAHP), for its nitric oxide synthase (NOS) inhibiting neuroprotective effect, and triptolide (TP), for its anti-inflammatory property, were selected to administer pre middle cerebral artery occlusion (MCAO). The drugs were administered 12 hours prior to MCAO. Both magnetic resonance imaging (MRI) and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that the drugs reduce the area of infarction. Immunoblotting analysis revealed increases in Beclin-1 and myeloid cell leukelia-1(Mcl-1) in treated rats. This could be a contributing factor to the reduction in autophagy induced damage. Immunochemistry and western blot showed that mTOR expression in treated rats was marginally different 24 h after injury, and this could also be significant in the mechanism. Furthermore, terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP nick end labeling (TUNEL) staining proved that the drugs are effective in reducing apoptosis. The upregulation of Beclin-1 and Mcl-1 and downregulation of Bcl-2, caspase-3, and the Bcl-2/Beclin-1 ratio infer that the neuroprotective effect of DAHP and TP act via the mediation of autophagy and apoptosis pathways.
ISSN:0962-9351
1466-1861
DOI:10.1155/2015/120198