Abstract
Background Cerebral ischemic stroke is a refractory disease which seriously endangers human health. Remote ischemic perconditioning (RiPerC) by which the sublethal ischemic stimulus is administered during the ischemic event is beneficial after an acute stroke. However, the regulatory mechanism of RiPerC that relieves cerebral ischemic injury is still not completely clear. Methods In the present study, we investigated the regulatory mechanism of RiPerC in a rat model of ischemia induced by the middle cerebral artery occlusion (MCAO). Forty-eight adult male Sprague-Dawley (SD) rats were injected intracerebroventricularly with miR-98 agomir, miR-98 antagomir, or their negative controls (agomir-NC, antagomir-NC) 2 h before MCAO or MCAO+RiPerC followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. The expression of miR-98, PIK3IP1, and tight junction proteins in rat hippocampus and cerebral cortex tissues was detected by quantitative polymerase chain reaction (qPCR) and Western blot (WB). Enzyme-linked immunosorbent assay (ELISA) was used to assess the IL-1β, IL-6, and TNF-α levels in the rat serum. Results The results showed that in MCAO group, the expression of PIK3IP1 was upregulated, but decreased after RiPerC treatment. Then, we found that PIK3IP1 was a potential target of miR-98. Treatment with miR-98 agomir decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control rats. But treating with miR-98 antagomir in RiPerC group, the protective effect on cerebral ischemia injury was canceled. Conclusion Our finding indicated that RiPerC inhibited the MCAO-induced expression of PIK3IP1 through upregulated miR-98, thereby reducing the apoptosis induced by PIK3IP1 through the PI3K/AKT signaling pathway, thus reducing the cerebral ischemia-reperfusion injury.
Highlights
Cerebral ischemic stroke is a refractory disease which seriously endangers human health
The results showed that miR-98 antagomir suppressed the Remote ischemic perconditioning (RiPerC)-mediated induction of miR-98. miR-98 antagomir canceled the protective effect of RiPerC, as evidenced by increased infarct volumes (Figures 3(a) and 3(b)), enhanced neurological deficit (Figure 3(c)), and greater levels of inflammatory cytokines (Figures 3(f)–3(h)), suggesting miR-98 mediates the effect of RiPerC on cerebral ischemic injury
TUNEL staining was performed to determine apoptosis of hippocampus in each rat group, the results indicated that the apoptosis rate in the middle cerebral artery occlusion (MCAO) injected with miR-98 agomir was lower than the MCAO injected with NC agomir group (Figure 4(a))
Summary
Cerebral ischemic stroke is a refractory disease which seriously endangers human health. The regulatory mechanism of RiPerC that relieves cerebral ischemic injury is still not completely clear. We investigated the regulatory mechanism of RiPerC in a rat model of ischemia induced by the middle cerebral artery occlusion (MCAO). The results showed that in MCAO group, the expression of PIK3IP1 was upregulated, but decreased after RiPerC treatment. Treatment with miR-98 agomir decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control rats. Treating with miR-98 antagomir in RiPerC group, the protective effect on cerebral ischemia injury was canceled. Our finding indicated that RiPerC inhibited the MCAO-induced expression of PIK3IP1 through upregulated miR-98, thereby reducing the apoptosis induced by PIK3IP1 through the PI3K/AKT signaling pathway, reducing the cerebral ischemia-reperfusion injury
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