Arc regulates brain damage and neuroinflammation via Sirt1 signaling following subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) accounts for only 5 % of all stroke cases, but carries a heavy burden of morbidity and mortality. Activity regulated cytoskeleton associated protein (Arc) is an immediate early gene (IEG)-coded postsynaptic protein that is involved in synaptic plasticity. Increasing evidence and our previous studies have shown that Arc might be involved in the pathological mechanism of various neurological diseases, such as traumatic brain injury (TBI). In this study, we investigated the level of Arc in cerebrospinal fluids (CSF) of aSAH patients and its potential role in brain damage following experimental SAH model. We found that the levels of Arc in aSAH patients' CSF positively correlated with Hunt-Hess (H&H) grades. Knockdown of endogenous Arc expression by small interfere RNA (siRNA) significantly increased brain edema and oxidative stress following SAH. The results of immunostaining in brain sections showed that knockdown of Arc enhanced activation of microglia and astrocytes. In congruent, generation of inflammatory cytokines following SAH was increased by Si-Arc transfection. The results of western blot analysis showed that knockdown of Arc inhibited the expression of Sirt1 and Nrf2, which was accompanied by decreased enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px). In addition, activation of sirtuin 1 (Sirt1) via agonist SRT2104 markedly decreased the brain damage and neuroinflammation induced by Arc knockdown. In conclusion, knockdown of endogenous Arc could aggravate brain damage and neuroinflammation following experimental SAH, and Arc levels in aSAH patients' CSF might be a potential indicator of brain damage and prognosis.