Abstract
Our previous studies have provided evidences that calycosin can protect the brain from ischemia/reperfusion injury, but its mechanisms is not fully understand. Transient receptor potential canonical 6 (TRPC6) has a critical role in promoting neuronal survival against cerebral ischemic injury. The aim of the present study is to test whether calycosin protects against cerebral ischemic injury through TRPC6-CREB pathway. In vivo, rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h and then treated with different doses of calycosin at the onset of reperfusion. In vitro, primary cultured neurons were treated by calycosin, then exposed to 2 h oxygen glucose deprivation (OGD) followed by 24 h reoxygenation. Our results showed that treatment with calycosin protected against ischemia-induced damages by increasing TRPC6 and P-CREB expression and inhibiting calpain activation. The neuroprotection effect of calycosin was diminished by inhibition or knockdown of TRPC6 and CREB. These findings indicated that the potential neuroprotection mechanism of calycosin was involved with TRPC6-CREB pathway.
Highlights
Calycosin, a major isoflavonoid in Radix Astragali Mongolici, was reported to exhibit anti-oxidative, anti-inflammatiry, tumor suppressive and osteogenic properties[17,18,19,20]
The results showed that the number of necrotic neurons of the ischemic penumbral cortex in middle cerebral artery occlusion (MCAO) group was significantly increased at 24 h after reperfusion compared to that of the sham group (P < 0.01)
We found that: (1) Cerebral ischemia obviously led to intracellular Ca2+ overload, activated calpain, and decreased the expressions of Transient receptor potential canonical 6 (TRPC6) and P-cAMP response element-binding protein (CREB). (2) Treatment with calycosin protected the brain against ischemic injury through up-regulating TRPC6 and P-CREB expression and inhibiting calpain activation in both in vitro and in vivo model of ischemia
Summary
A major isoflavonoid in Radix Astragali Mongolici, was reported to exhibit anti-oxidative, anti-inflammatiry, tumor suppressive and osteogenic properties[17,18,19,20]. Ameliorate diabetes-induced cognitive impairments via PI3K/Akt/GSK-3β signaling pathway[21]. Calycosin acts as a Ca2+ channel blocker, which may block voltage-dependent Ca2+ channel and receptor-operated Ca2+channel[22]. In our previous study[23], we firstly confirmed that pre-treatment with calycosin has a potential neuroprotective effect on ischemia and reperfusion-induced cerebral damage in rats. Whether calycosin will provide neuroprotection when given after the onset of stroke and what is the key mechanism underlying its neuroprotective effect still need to be explored. The present study is aimed to investigate the effect of calycosin post-treatment on cerebral ischemic injury and the role of TRPC6-CREB pathway in this phenomenon
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