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Eur J Pharmacol. 2019 Jul 15;855:202-207. doi: 10.1016/j.ejphar.2019.05.010. Epub 2019 May 4.

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

Author information

1
Department of Anesthesiology and Perioperative Medicine, Rutgers Robert Wood Johnson Medical School, 125 Paterson Street, Suite 3100, New Brunswick, NJ, 08901-1977, USA. Electronic address: chi@rwjms.rutgers.edu.
2
Department of Anesthesiology and Perioperative Medicine, Rutgers Robert Wood Johnson Medical School, 125 Paterson Street, Suite 3100, New Brunswick, NJ, 08901-1977, USA.
3
Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
4
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ, 08854, USA.

Abstract

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 (Ki) of 14C-α-aminoisobutyric acid and the volume of 3H-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 Ki 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.

KEYWORDS:

(14)C-α-aminoisobutyric acid; Blood-brain barrier; Brain protection; Cerebral ischemia-reperfusion; PF-4708671; S6K1 inhibitor

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