**7. Roles of EPA and DHA in resolution of inflammation after SAH**

Consensus has emerged on the pressing need to find a multipronged therapeutic intervention to address the various deleterious effects of early brain injury (EBI) after SAH [51]. Nonetheless, the loss of brain DHA after SAH is likely to be an unrecognized effect of EBI, and in turn loss of DHA may represent a critical event in the pathogenesis of secondary brain injury after SAH. Depending on the severity of SAH, the cumulative burden of brain DHA loss may be massive and decreases endogenous neuroprotective capacity in the short term [12, 36]. Thus, unresolved homeostatic disturbances within the cerebral microenvironment may lead to neurovascular uncoupling, which may spread over the cerebral cortex in the most severe cases [52]. The loss of an entire series of signaling events required for maintenance of neurovascular network integrity may further increase the risk of focal injury, diffuse cerebral atrophy, and functional sequelae [37]. In this context, it is reasonable to assume that large-artery vasospasm may paradoxically be a compensatory mechanism to preserve tissue oxygen availability in the presence of progressive microvascular failure, i.e., when capillary transit time heterogeneity substantially increases [3, 31]. Unresolved inflammation may also induce hyperproliferation of arachnoid cap cells, which increases the risk of hydrocephalus [4]. Uncontrolled systemic complications, such as severe cardiopulmonary dysfunction, may further aggravate homeostatic disturbances and have devastating consequences on brain function [53].

Theoretically, EPA, DHA, and their respective SPMs possess the bioactive capacity to counteract the major homeostatic disturbances that occur after SAH. EPA-RvEs could reduce thromboinflammation at the cerebral microvasculature by inhibiting vasoconstriction, leukocyte transendothelial migration, and platelet aggregation [15, 26]. DHA and its derivatives may trigger the critical signals required to maintain functional neurovascular coupling and cell survival [16, 36, 37]. DHA-induced upregulation of the enzyme heme oxygenase 1 (HO-1) may accelerate the clearance of subarachnoid clots and thus decrease hemeinduced cerebral inflammation [54]. SMPs may attenuate inflammation-induced hyperproliferation of arachnoid cap cells, further contributing to diminish the risk of hydrocephalus. SPMs may also provide multi-organ protection and enhance the immune response against infections.

Furthermore, the promising role of DHA derivatives in reducing microglial polarization toward an inflammatory phenotype may offer a novel approach to reduce the brain inflammation induced by neurosurgical trauma in surgically treated SAH patients [55]. Neurogenesis has also been identified in SAH patients, and thus DHA could represent a novel therapeutic strategy to improve neurological recovery by stimulating neurogenesis [56]. Moreover, subtle changes on microvascular function and synaptogenesis induced by EPA and DHA may improve cognitive function and mood and thus increase the likelihood of complete functional recovery of SAH patients.
