Abstract
Previous studies have demonstrated that activation of Akt may alleviate early brain injury (EBI) following subarachnoid hemorrhage (SAH). This study is undertaken to determine whether iron metabolism is involved in the beneficial effect of Akt activation after SAH. Therefore, we used a novel molecule, SC79, to activate Akt in an experimental Sprague–Dawley rat model of SAH. Rats were randomly divided into four groups as follows: sham, SAH, SAH + vehicle, SAH + SC79. The results confirmed that SC79 effectively enhanced the defense against oxidative stress and alleviated EBI in the temporal lobe after SAH. Interestingly, we found that phosphorylation of Akt by SC79 reduced cell surface transferrin receptor-mediated iron uptake and promoted ferroportin-mediated iron transport after SAH. As a result, SC79 administration diminished the iron content in the brain tissue. Moreover, the impaired Fe-S cluster biogenesis was recovered and loss of the activities of the Fe-S cluster-containing enzymes were regained, indicating that injured mitochondrial functions are restored to healthy levels. These findings suggest that disrupted iron homeostasis could contribute to EBI and Akt activation may regulate iron metabolism to relieve iron toxicity, further protecting neurons from EBI after SAH.
Highlights
Stroke is a major cause of morbidity and mortality worldwide
subarachnoid hemorrhage (SAH) can induce reactive oxidative species (ROS) production and increase the lipid peroxidation; we examined the levels of ROS and MDA
The production of both ROS and MDA significantly increased after SAH, which was markedly reduced by treatment with SC79 (Figure 1B,C)
Summary
Stroke is a major cause of morbidity and mortality worldwide. subarachnoid hemorrhage (SAH) accounts for only 5% of all strokes, it often leads to high mortality [1]. The pathogenesis of EBI resulted from various mechanisms, including oxidative stress and inflammation after SAH [2]. Another study has indicated that antioxidant butin attenuates oxidative stress by activating Nrf2-mediated SOD2 induction via the PI3K/Akt signaling pathway [8]. SC79, a novel Akt activator described by Jo et al [11], binds to the PH domain of Akt to cause a conformational change that favors its activation. Their results have demonstrated that SC79 suppresses excitotoxicity and alleviates stroke-induced neuronal death. In view of the above facts, we evaluated whether iron metabolism is involved in the beneficial effect of Akt activation after SAH
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