**6. Loss of brain DHA after SAH**

To date, three clinical studies have examined the loss of DHA from the brain after SAH. Pilitsis et al. conducted the first observational study to analyze free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) [12]. The concentrations of ARA, DHA, linoleic acid, myristic acid, oleic acid, and palmitic acid were measured over the first 14 days following SAH in 20 patients. A cohort of 73 patients with no evidence of acute neurological disease served as the control group. Compared to control patients, the concentrations of all FFAs tested were significantly elevated in CSF during the first 2 days after SAH, with a significant secondary increase in FAA concentrations at 8–10 days. The concentrations of DHA exhibited a biphasic increase and remained significantly elevated (200–600%) throughout the first 14 days after SAH.

Increased levels of free DHA in CSF after SAH are likely to be the result of the cleavage of DHA from membrane phospholipids by either direct structural damage or an increase in phospholipase A2 activity in response to neuroinflammation. DHA can also be readily oxidized due to its high degree of unsaturation and excessive generation of free radicals following SAH [45]. Such nonenzymatic oxidation of DHA generates F4-neuroprostanes (F4-NPs), which represent a lipid marker of oxidative stress in the CNS. Two clinical studies confirmed that the concentrations of F4-NPs in CSF significantly increased within the first 24 hours following SAH compared to control patients [46, 47]. Hsieh et al. also showed the concentrations of F4-NPs in CSF remained significantly elevated throughout the first 10 days after SAH and suggested a positive correlation exists between F4-NP concentrations and clinical outcome at 3 months after SAH. Despite the limited number of patients analyzed, these studies provided valuable evidence that substantial loss of brain DHA occurs after SAH.

Moreover, it is highly likely that SAH may increase metabolic consumption of DHA though increased generation of neuroprotective derivatives. This potential additional source of DHA loss has not yet been evaluated but could be significant. Net cumulative DHA loss from the brain (DHA loss + DHA consumption) following SAH may be massive in some cases and is likely to impose a severe burden on the brain.

#### **6.1 Selective brain malnutrition**

A current Western diet may provide sufficient amounts of FAs to compensate for the loss of other FAs, but not DHA. Current Western diets are characterized by very low intakes of long-chain omega-3 FAs and high intakes of other FAs, especially omega-6 FAs such as ARA and linoleic acid [48]. Thus, a significant imbalance between brain DHA loss and inadequate nutritional intake of omega-3 FAs may persist over the long term in SAH patients, hindering the recovery of DHA accretion in the brain required for normal neuronal function [35, 36].

Loss of EPA after SAH has not yet been examined; however, it is reasonable to assume that depletion of EPA from cerebral endothelial membranes may play a significant role in microvascular dysfunction after SAH. Indeed, EPA seems to have a more potent effect than DHA in the treatment of mood disorders, though the underlying mechanisms remain elusive [22].

We coined the term "selective brain malnutrition" to describe the pathological consequences of EPA and DHA loss following SAH on the structure and function of the brain. This novel hypothesis of selective brain malnutrition offers a plausible explanation for some of the intriguing clinical features of SAH, including diffuse cerebral atrophy and the frequently observed long-lasting functional sequelae, such

**243**

function [53].

immune response against infections.

**7.1 Clinical rationale for omega-3 FAs therapy in SAH**

recovery of SAH patients.

*Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation*

as cognitive dysfunction and mood disorders, that occur even in the absence of focal injury [5, 49]. Importantly, a higher omega-3 index has been associated with larger total brain and hippocampal volumes in observational studies in humans [50].

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

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

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

The theoretical framework described above provides scientific rationale for future clinical trials of omega-3 FAs in SAH patients. The disappointing results

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

*DOI: http://dx.doi.org/10.5772/intechopen.88297*

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

To date, three clinical studies have examined the loss of DHA from the brain after SAH. Pilitsis et al. conducted the first observational study to analyze free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) [12]. The concentrations of ARA, DHA, linoleic acid, myristic acid, oleic acid, and palmitic acid were measured over the first 14 days following SAH in 20 patients. A cohort of 73 patients with no evidence of acute neurological disease served as the control group. Compared to control patients, the concentrations of all FFAs tested were significantly elevated in CSF during the first 2 days after SAH, with a significant secondary increase in FAA concentrations at 8–10 days. The concentrations of DHA exhibited a biphasic increase and remained significantly elevated (200–600%) throughout the first

Increased levels of free DHA in CSF after SAH are likely to be the result of the cleavage of DHA from membrane phospholipids by either direct structural damage or an increase in phospholipase A2 activity in response to neuroinflammation. DHA can also be readily oxidized due to its high degree of unsaturation and excessive generation of free radicals following SAH [45]. Such nonenzymatic oxidation of DHA generates F4-neuroprostanes (F4-NPs), which represent a lipid marker of oxidative stress in the CNS. Two clinical studies confirmed that the concentrations of F4-NPs in CSF significantly increased within the first 24 hours following SAH compared to control patients [46, 47]. Hsieh et al. also showed the concentrations of F4-NPs in CSF remained significantly elevated throughout the first 10 days after SAH and suggested a positive correlation exists between F4-NP concentrations and clinical outcome at 3 months after SAH. Despite the limited number of patients analyzed, these studies provided valuable evidence that substantial loss of brain

Moreover, it is highly likely that SAH may increase metabolic consumption of DHA though increased generation of neuroprotective derivatives. This potential additional source of DHA loss has not yet been evaluated but could be significant. Net cumulative DHA loss from the brain (DHA loss + DHA consumption) following SAH may be massive in some cases and is likely to impose a severe burden

A current Western diet may provide sufficient amounts of FAs to compensate for the loss of other FAs, but not DHA. Current Western diets are characterized by very low intakes of long-chain omega-3 FAs and high intakes of other FAs, especially omega-6 FAs such as ARA and linoleic acid [48]. Thus, a significant imbalance between brain DHA loss and inadequate nutritional intake of omega-3 FAs may persist over the long term in SAH patients, hindering the recovery of DHA accretion

Loss of EPA after SAH has not yet been examined; however, it is reasonable to assume that depletion of EPA from cerebral endothelial membranes may play a significant role in microvascular dysfunction after SAH. Indeed, EPA seems to have a more potent effect than DHA in the treatment of mood disorders, though the

We coined the term "selective brain malnutrition" to describe the pathological consequences of EPA and DHA loss following SAH on the structure and function of the brain. This novel hypothesis of selective brain malnutrition offers a plausible explanation for some of the intriguing clinical features of SAH, including diffuse cerebral atrophy and the frequently observed long-lasting functional sequelae, such

in the brain required for normal neuronal function [35, 36].

underlying mechanisms remain elusive [22].

**6. Loss of brain DHA after SAH**

14 days after SAH.

DHA occurs after SAH.

**6.1 Selective brain malnutrition**

on the brain.

**242**

as cognitive dysfunction and mood disorders, that occur even in the absence of focal injury [5, 49]. Importantly, a higher omega-3 index has been associated with larger total brain and hippocampal volumes in observational studies in humans [50].
