Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll‐like receptor 4 signaling pathway

ABSTRACT Inflammation plays a key role in the progression of subarachnoid hemorrhage (SAH). Here, we examined the effects of astaxanthin (ATX) on the inflammatory response and secondary damage after SAH and the underlying mechanisms of action. In vivo , a prechiasmatic cistern injection model was established in rats and mice. In addition, neuron‐microglia cocultures were exposed to oxyhemoglobin to mimic SAH in vitro . Western blotting revealed that protein expression of TLR4 was markedly increased in microglia at 24 h after SAH, with consequent increases in the downstream molecules myeloid differentiation factor 88 and NF‐κB. Treatment with ATX significantly inhibited the TLR4 activation, increased sirtuin 1 expression, and inhibited the subsequent inflammatory response both in vivo and in vitro . ATX also significantly decreased high‐mobility group box 1 nuclear translocation and secretion in neurons, an effect that was reversed by the sirtuin 1‐specific inhibitor sirtinol. ATX administered 4 h after SAH ameliorated cerebral inflammation, brain edema, and neuronal death and improved neurologic function. ATX reduced neuronal death but did not improve neurologic function in TLR4 knockout mice. These results suggest that ATX reduces the proinflammatory response and secondary brain injury after SAH, primarily by increasing sirtuin 1 levels and inhibiting the TLR4 signaling pathway.—Zhang, X., Lu, Y., Wu, Q., Dai, H., Li, W., Lv, S., Zhou, X., Zhang, X., Hang, C., Wang, J. Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll‐like receptor 4 signaling pathway. FASEB J. 33, 722–737 (2019). www.fasebj.org