Introduction: Cerebrovascular Accident (CVA), is a neurological disorder whose pathophysiology of ischemic side occurs along with the development of a central inflammatory process. Omega-3 fatty acids appear as a potential agent in the prevention and treatment of the repercussions of this ischemic event, presenting the potential for neuroprotection in successive studies.

Objective: We aim to carry out a systematic review of the literature about the neuroprotective potential of omega-3 in terms of preventive and therapeutic aspects in ischemic CVA.

Method: From a search in the electronic databases PubMed and Scopus following the items of Guidelines for Systematic Reviews and Meta-analyzes (PRISMA), 12 published articles were included in the final sample and applied for discussion according to the literature.

Results: The studies pointed out the decrease in omega-3 as prejudicial to the regeneration of nervous tissues, as well as the neuroprotective role of omega-3 in cerebral ischemia after ischemia-reperfusion injury in animal models.

Conclusion: Reduction of cerebral edema, promotion of angiogenesis, preservation of the integrity of the blood-brain barrier and tissue protection were observed. Therefore, a greater understanding of the molecular role of omega-3 fatty acids and their consequences for supplementation in humans is needed.

• Cerebral ischemia

• Omega-3 Polyunsaturated Fatty Acids

• Neuroprotection

de Alencar Viana Melo L, Costa Silva AM, Ribeiro Grangeiro SE, Neto WM, Neto LL, et al. (2021) The Neuroprotective Potential of Omega-3 in Terms of Preventive and Therapeutic Aspects in Ischemic CVA. Ann Psychiatry Ment Health 9(2): 1166.

Cerebrovascular Accident (CVA), is one of the neurological disorders with the highest mortality and permanent sequelae rates [1]. Among 240 causes of mortality, CVA is the second globally, surpassed only by ischemic heart disease (IHD), and the continuity of the rates is projected until 2030. Survivors of this morbidity may be affected by organic and psychological functional complications, requiring temporary or permanent assistance that demands high human and economic costs. Globally, the gross numbers of new stroke events increased from 6.8 million in 1990 to 11.9 million in 2017 [2].

There are two types of CVA: ischemic and hemorrhagic. Briefly, the first includes atherothrombotic cerebral infarction, cardioembolic stroke and lacunar infact, while the second, intracerebral hemorrhage and subarachnoid hemorrhage. Both have common risk factors, such as smoking, alcoholism, chronic arterial disease and previous strokes. In addition, studies suggest the influence of some genetic component on Cerebrovascular Accident [3].

Analyzing the pathophysiological pathway of CVA, the important role of neuroinflammation in the pathogenesis of ischemic stroke and the installation of brain injury are understood. Experimentally, focal cerebral ischemia induces time-dependent recruitment and activation of inflammatory cells, including neutrophils, T cells and macrophages. The inhibition of the neuroinflammatory response decreases the extent of the infarction and provides less neurological deficit in the experimental lesion [4]. Polyunsaturated fatty acids (PUFAs), are able to partially inhibit many aspects of inflammation, including leukocyte chemotaxis, expression of adhesion molecules and leukocyte-endothelial adhesive interactions, eicosanoid production and production of inflammatory substances [5].

Regarding the biochemical characteristics, PUFAs of the omega-3 family include α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). The oils that contain these fatty acids (FAs), or some of them, originate mainly from plant sources or are modified in plants, as well as marine, algae and unicellular sources [6].

Under the neuroprotective perspective of omega-3 PUFAs, studies have linked the effects of EPA to the suppression of oxidative stress and endothelial activation which were induced after cerebral ischemia. In this context, there is an evaluation of the anti-inflammatory and antinociceptive actions of omega-3 polyunsaturated fatty acid (n-3 PUFA), whose suggested mechanisms may involve the inhibition of cyclooxygenases and microglial activation, leading to a reduced release of pro-inflammatory cytokines, such as TNF-α [7].

Later studies by Nobre et al [7], also demonstrated that the administration of low doses (5mg and 10mg/kg), of omega-3 caused a protective effect in rats against global ischemic injuries, a potential attributed to their anti-inflammatory properties [7]. This article, therefore, aims to conduct a systematic review of the literature on the neuroprotective potential of omega-3 in ischemic CVA, given the important findings that can contribute to mitigate the effects of this serious public health problem.

A systematic revision was made, following the PRISMA protocol (Preferred Reporting Items for Systematic Reviews and Meta-Analysis).

Inclusion criteria

The inclusion criteria were studies published in English, Portuguese, french and german suitability for the purpose of this review, methodological rigor applied and full-text available for free. Review articles, as well as comments on literature, editorials, communications and letters to the editor were excluded. We had no restrictions related to study design, methodological quality, or language. The language problem was solved through a reasonable degree of comparability, which allowed us to systematically analyze the selected evidence, its critical evaluation process, and its success in including relevant studies in other languages.

We classify assessments according to their level of inclusion of studies in other languages. Reviews that excluded non-English studies with an explicit justification in the research question or research objectives were categorized as justified by R1 (that is, justified in English), while those that excluded non-English studies without justification were categorized as restricted to RR1 (that is, languages that are not restricted to English). Reviews that did not explicitly exclude studies that were not in English were categorized as RR1-open, unless they successively included studies that were not in English, in which case they were RR1-inclusive. Finally, revisions that did not declare language criteria were considered to be RR1-open.

Literature research and selection of articles

To search for studies, the following databases were used: The keywords “ cerebral ischemia ”; “ Stroke”; “Omega-3 fatty acids ”; “DHA”; “EPA”; “Neuroprotection” and “neurological function” were applied to identify articles published between January 2015 and March 2020.

Data extraction and methodological quality assessment

One researcher (MLRN), extracted data and another verified the extraction. Two researchers (MEPN and AOC) independently assessed the methodological quality of systematic reviews using the AMSTAR tool and qualitative studies using the CASP checklist (Critical Appraisal Skills Programme – CASP, 2020). A researcher (FT) assessed the quality of cross-sectional studies using the JBI Prevalence or the JBI Cross-sectional analytical checklist and longitudinal studies using the JBI Cohort checklist (Johanna Briggs Institute).

Data presentation and analysis

We summarized the results narratively. We described interventions and outcomes based on the information provided in the studies. When studies showed neuroprotective properties of omega-3 in ischemic cerebrovascular accident results in numbers without numbers, we extracted them using online software (https://apps.automeris.io/wpd/). We decided not to perform a quantitative analysis of summaries of the associations between the various correlates and health factors, due to a combination of heterogeneity in the measures and lack of control groups, and an embraced lack of descriptions necessary to confirm sufficient homogeneity. We rated the certainty of the evidence using the GRADE approach – (Grading of Recommendations Assessment, Development and Evaluations.

In the post-stroke period, the metabolic demand of tissues increases considerably, leading the patient to lack several essential nutrients, such as omega-3[8]. This malnutrition slows down and impairs the regeneration of brain tissue. To reverse this situation, studies have shown how long-chain omega-3 fatty acids (DHA and EPA) [9], and their alpha-linoleic acid precursor (ALA) [8], administered, respectively, by injections and by food supplementation have neuroprotective properties. As much as there are disagreements regarding these studies, such as the statement by Berressem et al. [9], that there is a reduction in the infarcted area in the action of omega-3 and the statement by Bourourou et al. [8], that the neuroprotective effect is due to the improvement in learning and memory and not to the reduction of the infarcted area, both confirm mechanisms by which omega-3 has the beneficial effects in the post-stroke period.

The administration of a single dose, in female rats, of a long-chain omega-3 lipid emulsion (Omegaven 10% ®, OGV) containing fish oil (DHA 18mg/ml; EPA21mg/ml) and alpha-tocopherol (0,2mg/ml) demonstrated great efficacy in the acute treatment of ischemic stroke. When this treatment is performed exclusively with EPA, it has been shown to be ineffective in the hypoxia-ischemia brain injury model, unlike DHA, which showed great efficacy in the same experiment; however, EPA demonstrated effects such as vasodilation and better fluidity of the membrane, which, in combination with DHA, it can enhance the neuroprotective effects [9]. Studies by Nobre et al. [7], demonstrate that small doses (5 and 10 mg/kg/ day, orally) of omega-3 fatty acids administered for seven days show neuroprotective action, showing reversal of biological changes resulting from cerebral ischemia, such as the presence of anxiety, loss of spatial memory, and decreased expression of pro- inflammatory cytokines in the studied nervous tissue.

Cerebral ischemia in neonates may have its consequences mitigated with the administration of omega-3 polyunsaturated fatty acids (n-3 PUFA) [10-12], with various pathophysiological mechanisms for this interaction being described in the literature. Zhang et al. [12], inferred that a n-3 PUFA enrichment diet, in the period from the second day of pregnancy to two weeks after delivery, acts in maintaining the integrity of the blood-brain barrier in Sprague-Dawley rats. This is due to the suppression of the activity and of the synthesis of matrix metalloproteinases, enzymes that play a role in the degradation of the basement membrane proteins and the stock junction, and that, when their production is suppressed, the levels of pro-inflammatory cytokines such as TNF-alpha and IL-1beta are also suppressed.

Zhang et al. [11], also presents another mechanism by which n-3 PUFA acts in a neuroprotective manner, in which the dietary supplementation of n-3 PUFA enriched in female rats on the second day of gestation will considerably increase the content of this fatty acid in the cerebral cortex, suppressing, by n-3 PUFA, the inflammatory response, in addition to promoting phosphatidylserine biosynthesis in neuronal cell membranes. Phosphatidylserine acts as a protective factor for cell survival, as it preserves and increases a survival path called PI3K/Akt, which has been increasingly linked to neuronal survival in post-ischemic damage. Another study that reports the protective action of omega-3 in cerebral ischemia, in Zhang et al. [10], states that n-3 PUFAs show a decrease in their amount after CVA due to the increased metabolic demand. However, when omega-3 supplementation occurs, the neuroprotective effect occurs by partially suppressing the inflammatory response mediated by microglia.

In addition, Mayurasakorn et al. [13], describes that mice that, at 10 days of age, experienced brain damage due to ischemia showed short (24 hours), and long term (8 to 9 weeks),improvement in the neurological progress after treatment with two administrations via intraperitoneal doses (0.375 g n-3 TG/ kg/dose), of tri-DHA, and not of tri-EPA. One administration was performed immediately after the ischemic damage and the other after 1 hour. Such improvement was associated with an increase in DHA in brain mitochondria and bioactive metabolites derived from DHA in brain tissue. This fact was associated with mitochondria that suffered hypoxia-ischemia becoming resistant to calcium-induced membrane permeability (Ca2+), reduced oxidative brain damage and permanent neuroprotection. This corroborates the studies by Zhang et al. [10], Zhang et al. [11], Zhang et al. [12].

The presence of a low proportion of n-3 polyunsaturated fatty acids (n-3 PUFAs), may be associated with ischemic and hemorrhagic damage, in cerebral small vessel diseases (CSVD), including the total score, which measures the severity of the disease. Thus, a diet rich in n-3 PUFA, could reduce the severity of CSVDs, regardless of their hemorrhagic or ischemic origin [14].

In a population-based study in South Korea with 220 patients, high levels of n-3 PUFAs in the blood were associated with better executive functions and beneficial effects on the white matter microstructure, while low levels of n-3 PUFAs were related to more serious changes in white matter. One of the protection mechanisms would be the production of anti-inflammatory molecules, resolvins and protectins, through the lipoxygenase or cyclooxygenase pathways. In addition, n-3 PUFA had an effect on the stabilization of atheromatous plaques and lesser macrophage infiltration in patients waiting for a carotid endarterectomy who were treated with fish oil [14]. In contrast, in 3 independent prospective cohorts, which included different samples of men aged 40 to 65 and women aged 30 to 55, performed in the United States, it was found that not all active forms of n-3 PUFA, acid eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), have the same effectiveness in reducing risk of total ischemia, atherothrombotic and cardioembolic CVA [15].

Thus, among the types of ischemic infarction, circulating DHA is inversely associated with atherothrombotic stroke, whereas DPA, with cardioembolic stroke. However, EPA was not associated with a lower risk of ischemic CVA, total atherothrombotic or cardioembolic. It was found that higher levels of DHA represented 47% lower risk when assessing atherothrombotic stroke, without significant relevance of circulating DPA and EPA in these cases. When considering cardioembolic stroke, patients with the highest levels of DPA, compared to the lowest levels, had 42% lower risk, without significant relevance of the amounts of blood DHA and EPA in such cases [15].

DHA is also a precursor to neuroprotectin D1, a docosanoid anti-inflammatory derivative which reduces apoptosis, promoting cell survival in ischemic stroke models [16].

Furthermore, Lin et al. [17], suggests that DHA would also act in the hemorrhagic transformation (HT), a feared complication of ischemic stroke, frequent after the use of thrombolytic therapy. In this sense, DHA would act in order to reduce the risk of HT, which is increased due to hyperglycemia after focal ischemic injury. The studies by Lin et al. [17], used adult male rats that received 50% dextrose injection (6 ml/kg intraperitoneal) in order to induce hyperglycemia and, consequently, HT, 10 min before suffering a middle cerebral artery occlusion. Treatment with DHA (10mg/ kg), 5min before reperfusion reduced HT, decreased the volume of infarction, in addition to having demonstrated better neurological progress after seven days. It was also confirmed that DHA inhibited the inflammatory reaction mediated by ICAM- 1, a transmembrane protein in endothelial cells that facilitates leukocyte transmigration and adhesion. DHA also acted by inhibiting the collagen type IV degradation, in order to stabilize the blood-brain barrier, since collagen IV is the main component of capillary endothelial cells.

Still under this bias, Sumiyoshi et al. [18], evaluated that in ovariectomized female rats that were subjected, after the eleventh week of life, to cerebral ischemia due to middle cerebral artery occlusion, there is an increase in the expression of HMG- 1, a DNA-binding ubiquitous nuclear protein that is released by necrotic cells and secreted by activated leukocytes. Such protein has relevance in post-ischemia damage, acting as an activator of antigen-presenting cells through the receptor for advanced glycation end products (RAGE), and toll-like receptors (TLRs), triggering and exacerbating the inflammatory response. It has also been shown that a pretreatment with EPA supplementation (500 mg/kg/day, orally), for 4 weeks attenuates these changes regardless of estrogen levels, which may point to a future treatment in cases of human women affected by stroke and who are in the post-menopausal stage. EPA, in addition to having antiarrhythmic, anticoagulant, antioxidant, and anti- inflammatory actions, is also an agonist of the PPARγ receptor, which modulates the immune system of the central nervous system by inhibiting the activation of macrophages and by modulating the release of pro- inflammatory mediators [18].

In a study with an animal model of oxygen-glucose ischemia/ reperfusion injury or oxygen-glucose deprivation/reperfusion (OGD / R), fat-1 type rats, that is, those with a higher level of endogenous n-3 PUFA, were fed with 10% corn oil. Shi et al. [14], then, demonstrated that both endogenous and exogenous n-3 PUFA increased the survival of a culture of cortical neurons after OGD / R. In this model, the fat-1 gene increased the expression of neuronal n-3 PUFA, including the active forms DPA and DHA. Thus, when comparing fat-1 rats with wild-type rats (WT), it was found that WT neurons showed cellular damage and neuritis 24h after OGD/R considerably greater than fat-1 neurons. In addition, lower intracellular accumulation of reactive oxygen species (ROS) in fat-1 neurons was attested, which points to inhibition of ROS activation by endogenous n-3 PUFA. There was also greater expression of cleaved caspase-3 in WT neurons. In the exogenous administration of DHA and GSH, there was also a significant reduction in ROS activation. Such neuroprotection is directly related to the elimination of ROS and positive regulation of anti-apoptotic proteins. Recently, it was discovered that DHA modulates neuronal defenses by activating the expression of GSH in brain cells. The observations also showed a significant improvement in the integration of motor and sensory functions, 2 weeks after OGD / R, in fat-1 rats.

Shi et al. [19], added that, by combining n-3 PUFA treatment, especially DHA, with Lycium barbarum Polysaccharide (LBP),better results can be obtained in the rescue of cortical neurons after OGD/R, particularly by activating the TrkB receptor and alleviating intracellular Ca2+ overload. In this context, studies have pointed out the role of n-3 PUFA in inhibiting the release of Ca2+ by the endoplasmic reticulum. However, in this research, treatment with only LBP proved to have limited influence on the control of Ca2+ overload. Furthermore, the observations demonstrated that LBP and n-3 PUFA perform neuroprotection by activating the anti-apoptotic Bcl-2 cascade, a fact that also contributes to maintaining Ca2+ homeostasis in the endoplasmic reticulum. This study, for the first time, also reported that LBP can perform neuronal protection from apoptosis by modulating the neurotrophin pathway, which is initiated from the cell membrane. However, contrary to Shi et al. [14], it was stated that there are inconsistencies in the dietary supplementation of n-3 PUFA in animal studies due to the variance of the component in the diet, in addition to a certain neglect of the relevance in the proportion between n-3 PUFA and n-6 PUFA [19-27].

Omega-3 can possibly act as a neuroprotective agent in several ways, playing an important supporting role in the prevention and/or treatment of CVA. Studies have shown its vasodilator activity, providing improvement in spatial memory and learning and decreased depression and anxiety after global ischemia in animals.

Its anti-inflammatory potential has also been reported, decreasing the activation of microglia and release of pro- inflammatory mediators, restoring mitochondrial function and reestablishing glucose level in brain tissue. Studies also report that omega-3 can act to reduce cerebral edema, promote angiogenesis, preserve blood-brain barrier integrity and protect tissue by reducing reactive oxygen species. This study was limited due to the existence of few records in the literature that address the direct relationship between protective properties of omega-3 and ischemic stroke, in addition to sparse research that includes human models. Thus, there is a need for further research in the area, in order to provide greater understanding about the molecular action of omega-3 fatty acids and their role in supplementation in humans.

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A total of 335 articles were designated for screening using the search strategy. After screening by title and abstract, 47 articles were selected for full-text evaluation. Out of these studies, 35 were excluded due to the unsuitability for the objective of this review. Thus, 12 articles were included for study and discussion in the literature (Figure 1).

Figure 1: Flowchart summarizing the search strategy for studies

The main characteristics of the included studies are presented in Table 1. This review included

12 studies published between 2015 and 2017, carried out between Brazil, China, the United States, Germany, South Korea, France and Japan (Table 1).

Evaluation of the methodological quality of the included studies

The most common methodological weaknesses in all the studies arose from insufficient reporting: samples, scenarios, and recruitment procedures were often not fully described.

Interventions in mental health

Eight studies reported the urgent need to implement interventions in order to prevent or reduce neuroprotective properties of omega-3 in ischemic cerebrovascular accident. Four studies demonstrate the need for interventions to organizational adjustments in the reduce neuroprotective properties of omega-3 in ischemic cerebrovascular accident.