Puerarin attenuates locomotor and cognitive deficits as well as hippocampal neuronal injury through the PI3K/Akt1/GSK-3β signaling pathway in an in vivo model of cerebral ischemia
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Jinhao Tao1,*, Yuehua Cui3,4,*, Yu Duan3, Nan Zhang2, Congmin Wang5 and Fayong Zhang2
1Pediatric Emergency and Critical Care Center, Children’s Hospital of Fudan University, Shanghai, P.R. China
2Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University, Shanghai, P.R. China
3Department of Neurosurgery, Huadong Hospital Affiliated to Fudan University, Shanghai, P.R. China
4Department of Basic Medical Sciences, University of Arizona, Tucson, AZ, USA
5Department of Neurology, Affiliated Hospital of Hebei University of Engineering, Handan, P.R. China
*These authors contributed equally to this work
Congmin Wang, email: [email protected]
Fayong Zhang, email: [email protected]
Keywords: cerebral ischemia/reperfusion; puerarin; hippocampus; Akt; GSK-3β
Received: June 17, 2017 Accepted: October 14, 2017 Published: November 07, 2017
Ischemic stroke causes irreversible damage to the brain. The hippocampus is a vulnerable region and plays an important role in cognition and locomotor activity. Puerarin is a phytoestrogen that has beneficial effects in treating neurological disorders. How puerarin protects against hippocampal injury and its molecular mechanisms remain to be elucidated. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with puerarin alone or together with LY294002 (an PI3K inhibitor) before ischemia/reperfusion (I/R). The open- and closed-field tasks and Morris water maze (MWM) test were used to assess the effects of puerarin on anxiety-like behavioral and cognitive impairment following I/R. Hematoxylin-eosin staining(HE) was used to examine the survival of hippocampal CA1 pyramidal neurons, and immunoblotting was performed to examine the expression of the related proteins. By using the rat model for transient I/R, we demonstrated that puerarin pretreatment significantly increased the travelling distance and number of crossings in the open- and closed-field tests, reduced latency and increased the proportion of distance and time in zone IV in the MWM. The number of live cells in the hippocampus is sharply increased by puerarin pretreatment.We further observed that the levels of phosphorylated Akt1, GSK-3β and MCL-1were elevated and those of cleaved-caspase-3 were reduced in the puerarin-treatment group. Notably, the PI3K inhibitor LY294002 counteracted all of the effects of puerarin. Our findings suggest that puerarin protects the hippocampus from I/R damage by activating the PI3K/Akt1/GSK-3β/MCL-1 signaling pathway.
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