Inhibition of p70 ribosomal S6 kinase 1 (S6K1) by PF-4708671 decreased infarct size in early cerebral ischemia-reperfusion with decreased BBB permeability

It is not clear whether inhibition of p70 ribosomal S6 kinase 1 (S6K1) is neuroprotective in cerebral ischemia-reperfusion. Decreasing blood-brain barrier (BBB) disruption has been associated with a better neuronal outcome in cerebral ischemia. We hypothesized that inhibition of S6K1 would decrease BBB disruption and infarct size in the early stage of cerebral ischemia-reperfusion. Middle cerebral artery occlusion (MCAO) was performed in rats under isoflurane anesthesia with controlled ventilation. 75 mg/kg of PF-4708671, an S6K1 inhibitor, was administered intraperitoneally 15 min after MCAO. After 1 h of MCAO and 2 h of reperfusion, the transfer coefficient (K-i) of C-14-alpha-aminoisobutyric acid and the volume of H-3-dextran distribution were determined to assess the degree of BBB disruption. At the same time point, phosphorylated Rictor (pT1135) and the infarct size were measured to evaluate S6K1 activity. In the PF-4708671 treated rats, the K-i of the ischemic-reperfused cortex was lower than the untreated rats (-22%, P < 0.05) and the volume of dextran distribution was significantly lower in most brain regions. With PF-4708671, a significant decrease in pT1135 Rictor was observed and the percentage of cortical infarct out of total cortical area was decreased (11.6 +/- 2.0% vs 7.2 +/- 1.1%, P < 0.0001). Our data demonstrate that PF-4708671 decreased the size of the cortical infarct in the ischemic-reperfused cortex with a decrease in BBB disruption suggesting that inhibition of S6K1 may induce neuronal survival in early cerebral ischemia-reperfusion and that a decrease of BBB disruption could be one of the contributing factors.