Research led by Nicolas Bazan, MD, PhD, Boyd Professor and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, and Ludmila Belayev, MD, LSU Health New Orleans Professor of Neuroscience, Neurology and Neurosurgery, has unlocked a key fundamental mechanism in the communication between brain cells when confronted with stroke.
They report that DHA not only protected neuronal cells and promoted their survival, but also helped maintain their integrity and stability.
The discovery provides potential new clinical targets and specific molecules for the treatment of ischemic stroke and other cardiovascular diseases.
Their findings are published online in CNS Neuroscience & Therapeutics.
Brain cells talk to one another. This synchronized cell-to-cell crosstalk regulates neuroinflammation and the immune system, which are activated in the brain at the onset of stroke, Alzheimer’s, Parkinson’s, and other diseases.
The researchers found that in the model of stroke, docosahexaenoic acid (DHA) affects the levels of two proteins crucial to communication between brain cells — mesencephalic astrocyte-derived neurotrophic factor (MANF) and triggering receptor expressed on myeloid cells-2 (TREM2).
They discovered that treatment with DHA reduced the size of the damaged brain area, initiated repair mechanisms and greatly improved neurological and behavioral recovery.
These findings provide a major conceptual advance of broad relevance for neuronal cell survival, brain function and, particularly, stroke and neurodegenerative diseases.
DHA is made from omega-3 very long chain polyunsaturated fatty acids (VLC-PUFAs,n-3).
It is found in fatty, cold-water fish like salmon. Among other benefits, DHA is essential for normal brain function in adults and for the growth and development of the brain in babies.
“Our findings contribute greatly to our understanding of cellular interactions engaging neurons, astrocytes, and microglia to sustain synaptic circuitry, set neurogenesis in motion, and initiate restoration to pathological derangements,” notes Dr. Bazan, who also holds the Ernest C. and Ivette C. Villere Chair at LSU Health New Orleans.
These findings advance the understanding of how the complexity and resiliency of the human brain is sustained, mainly when confronted with adversities as in stroke.
A key factor is how neurons communicate among themselves. These novel molecules participate in delivering messages to the overall synaptic organization to ensure the accurate flow of information through neuronal circuits.
“We know how neurons make synaptic connections with other neurons; however, these connections have to be malleable in order to change to the appropriate strength through experience,” explains Dr. Belayev.
“It’s like an orchestra,” says Bazan. “You need a conductor, and this is the role that DHA plays. Such a large-scale complexity first requires violinists, or in this case, synapses, which are highly sensitive sites of stroke injury that become messengers to target vulnerable cells.”
Co-authors include Sung-Ha Hong, Raul S. Freitas, Hemant Menghani, Shawn J. Marcell, Larissa Khoutorova, Pranab K. Mukherjee, and Reinaldo B. Oria. Dr. Menghani was supported by the Department of Pediatrics Hematology-Oncology Section at LSU Health New Orleans and Children’s Hospital of New Orleans. Raul S. Freitas is a graduate student from the Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil. Shawn J. Marcell is an LSU Health New Orleans medical student.
Funding: The research was supported by grants from the National Institute of Neurological Disorders and Stroke 1R01NS109221 and 1R01NS104117.
he n-3 polyunsaturated fatty acids (PUFAs) are a class of essential fatty acids required for normal biological activity and function in living organisms.
The n-3 PUFAs are poorly synthesized in the human body, and they are composed of marine fish-derived agents such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
It is well known that n-3 PUFAs reduce the risk of cardiovascular diseases through multiple actions, including an anti-inflammatory effect, reduction of platelet aggregation, and stabilization of atherosclerotic plaques [19,20,21,22,23,24].
Thus, less dietary intake of n-3 PUFAs can result in an increase in the incidence of cardiovascular diseases.
Considerable insight has been gained into the n-3 PUFAs, through their dietary intake and their use as therapy for the risk of cardiovascular diseases.
However, the association of ingestion of n-3 PUFAs with stroke burden has not been adequately studied.
The current article reviews the associations of dietary n-3 PUFA intake with stroke and the effects of treatment with n-3 PUFAs on stroke in the previous high-impact studies, and moreover, the mechanistic role of n-3 PUFAs and their metabolites related to stroke burden was investigated.
Biological Effects of Omega-3 PUFAs for Stroke
Omega-3 PUFAs and Their Metabolites
EPA competitively inhibits prostaglandin E2 formation by cyclooxygenase (COX) 1/2 from AA, and it produces less-inflammatory prostaglandin E3, thereby showing an anti-inflammatory effect, inhibition of monocyte adhesion and platelet aggregation, and improvement of endothelial injury [67,68].
EPA also decreases the production of mediators and enzymes from inflammatory cells such as macrophages and stabilizes atherosclerotic plaques [22,23,24]. There is evidence that DHA suppresses inflammation more potently than EPA [69,70].
Importantly, EPA and DHA are metabolized via the COX and lipoxygenase pathways into a new class of lipid mediators [67,68]. Specialized pro-resolving lipid mediators, including resolvins, maresins, and protectins, are synthesized from n-3 PUFAs.
In the metabolism of EPA, 18-hydroxyeicosapentaenoic acid (18-HEPE) is converted from EPA in the cyclooxygenase-2 or cytochrome P450 pathways, and further metabolized to the resolvin E series including resolvin E1, E2, and E3 (Figure 2) [71,72].
In the metabolism of DHA, 12-lipoxygenase converted DHA to maresins, while the resolvin D-series were converted from DHA to the intermediate 17S-hydroperoxy-DHA by 15-lipoxygenase and further metabolized by 5-lipoxygenase.
Protectins were converted from DHA by 15-lipoxygenase. These metabolites have powerful anti-inflammatory effects. In experimental stroke models, it has been shown that maresins, protectins, and resolvin D-series derived from DHA exerted an anti-inflammatory response, ameliorated stroke injuries, and induced neurogenesis and angiogenesis [73,74,75,76].
Treatment with Omega-3 PUFAs in Experimental Stroke
So far, underlying molecular mechanisms after supplementation with n-3 PUFAs have been studied in vivo and in vitro. In a middle cerebral artery occlusion (MCAO) model in rodents, it was shown that treatment with n-3 PUFAs prior to MCAO [77,78,79,80], after MCAO [81,82], and both  decreased infarct volume and improved neurological deficits and motor function.
In vitro, n-3 PUFAs suppressed lipopolysaccharide-induced nitric oxide and tumor necrosis factor-α release and the inflammatory response, altered the shift from M1 to M2 phenotype, enhanced myelin phagocytosis in cultured microglia, and activated nuclear factor E2-related factor 2 and upregulated heme oxygenase-1 in neurons [82,84,85].
With regard to neuroprotective effects of EPA, suppression of oxidative stress and endothelial Rho-kinase activation were induced after ischemia . In ovariectomized rats subjected to transient MCAO, EPA regulated post-ischemic high mobility group box 1/toll-like receptor 9 pathway proliferator-activated receptor gamma-dependently and -independently .
On the other hand, DHA reduced the expansion of infarct area due to a subsequent inflammatory response elicited by ischemia, via the promotion of conversion from 15-lipoxygenase-1 to neuroprotectin D1, exhibiting cell-protective, anti-inflammatory, and anti-apoptotic responses .
Other studies showed that DHA induced neurological recovery and reduced infarct size by diminishing blood-brain-barrier damage, regulating microglial infiltration, and reducing oxidative stress and activating AKT cascades in neurons [85,87,88] (Figure 2).
Role of Omega-3 PUFAs and Their Metabolites before and after Stroke
The aforementioned data indicated that various anti-inflammatory effects, anti-oxidative stress, diminishing blood–brain-barrier damage, and regulation of signaling pathways have been implicated in the mechanisms of the roles of n-3 PUFAs against brain injury after stroke, which were clearly shown in vivo and in vitro in rodents.
It is reasonable that treatment with PUFAs prior to stroke displayed a protective effect against ischemic injury, which might be consistent with the results from previous epidemiological and other studies, showing partial effects for reduction of stroke burden.
Likewise, a beneficial effect of n-3 PUFA treatment immediately after stroke could indicate that the n-3 PUFAs are potential candidates for acute stroke therapy (Figure 3).
In clinical trials involving stroke patients, no evidence has been available on the effects of n-3 PUFA supplementation for stroke outcome. Future research may facilitate the development of possible treatment agents for ischemic stroke in humans.
Original Research: Open access
“DHA modulates MANF and TREM2 abundance, enhances neurogenesis, reduces infarct size, and improves neurological function after experimental ischemic stroke” by Ludmila Belayev, Sung‐Ha Hong, Raul S. Freitas, Hemant Menghani, Shawn J. Marcell, Larissa Khoutorova, Pranab K. Mukherjee, Madigan M. Reid, Reinaldo B. Oria, Nicolas G. Bazan. CNS Neuroscience & Therapeutics.