**9. Experimental models and clinical interventional studies of omega-3 FAs in SAH**

### **9.1 Experimental models**

To date, only two preclinical studies of omega-3 FAs in experimental models of SAH have been published. Yin et al. suggested that pre-treatment with omega-3 FAs by oral gavage elicited anti-inflammatory and anti-apoptotic effects in a rat model of SAH [66]. Zhang et al. showed intravenous administration of DHA may prevent oxidative stress-induced apoptosis by improving mitochondrial dynamics in a rat model of SAH induced by endovascular perforation [67]. However, the scarcity of preclinical studies on omega-3 FAs in SAH contrasts with the large number of experimental studies on ischemic stroke. The effects of omega-3 FAs (or specific derivatives) in neural tissue have been widely examined in experimental ischemiareperfusion models [55, 68, 69]. These studies have consistently shown that omega-3 FAs significantly reduce cerebral infarction volume by around 40–50% and are associated with a drastic decrease in the neuroinflammatory response [70, 71]. Interestingly, the long-term neurobehavioral recovery in experimental models of ischemic stroke is associated with neuroprotective effects of DHA on both gray and white matter [55]. It is noteworthy that one of these studies used a specific FOLE that is widely approved for clinical use [70].

#### **9.2 Clinical studies**

A limited number of omega-3 FAs interventional studies have been performed in SAH patients [13, 72–74]. The main characteristics and findings of these studies are summarized in **Table 1**. Two studies utilized EPA and DHA, and only one study included a parenteral regimen. In total, 229 patients with SAH have received an omega-3 FAs intervention; most patients were surgically treated (*n* = 223). Although two studies were published as RCTs, one study had significant methodological shortcomings in the randomization process that conferred a high risk of selection bias [74]. While these preliminary clinical studies reported encouraging results (see **Table 1**), high-quality RCTs are needed to confirm the benefits of omega-3 FAs in SAH patients.
