Docosanoids Promote Neurogenesis and Angiogenesis, Blood-Brain Barrier Integrity, Penumbra Protection, and Neurobehavioral Recovery After Experimental Ischemic Stroke

Abstract

Docosahexaenoic acid (DHA) and neuroprotectin D1 (NPD1) are neuroprotective after experimental ischemic stroke. To explore underlying mechanisms, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo) and treated with DHA (5 mg/kg, IV) or NPD1 (5 μg/per rat, ICV) and vehicles 1 h after. Neuro-behavioral assessments was conducted on days 1, 2, and 3, and on week 1, 2, 3, or 4. BrdU was injected on days 4, 5, and 6, immunohistochemistry was performed on week 2 or 4, MRI on day 7, and lipidomic analysis at 4 and 5 h after onset of stroke. DHA improved short- and long-term behavioral functions and reduced cortical, subcortical, and total infarct volumes (by 42, 47, and 31%, respectively) after 2 weeks and reduced tissue loss by 50% after 4 weeks. DHA increased the number of BrdU/Ki-67, BrdU/DCX, and BrdU/NeuN cells in the cortex, subventricular zone, and dentate gyrus and potentiated NPD1 synthesis in the penumbra at 5 h after MCAo. NPD1 improved behavior, reduced lesion volumes, protected ischemic penumbra, increased NeuN, GFAP, SMI-71-positive cells and vessels, axonal regeneration in the penumbra, and attenuated blood-brain barrier (BBB) after MCAo. We conclude that docosanoid administration increases neurogenesis and angiogenesis, activates NPD1 synthesis in the penumbra, and diminishes BBB permeability, which correlates to long-term neurobehavioral recovery after experimental ischemic stroke.

Available Therapeutics after a Stroke: Current and Promising Options

“…Dietary administration with docosahexaenoic acid (DHA) has also proven to have anti-inflammatory and neuroprotective effects in cerebral ischemia through the reduction of proinflammatory cytokine expression, such as TNF-α, IL-1β and IL-6; even, a decrease in macrophage and microglial activation and a decrease in leukocyte infiltration to the lesion site [70]. Similar observations were made by Cai et al who noted that macrophage, neutrophil, and T and B lymphocyte infiltration was significantly decreased, besides stimulating an anti-inflammatory macrophage (M2) activation [71]; DHA is also capable of inducing neurogenesis and angiogenesis [72], which makes it a promising molecule for future experimental research.…”

“…Belayev et al [72] trials in Alzheimer's patients with mild cognitive decline have shown improvements in verbal memory after being treated with a ketogenic diet [73]. Dietary administration with docosahexaenoic acid (DHA) has also proven to have anti-inflammatory and neuroprotective effects in cerebral ischemia through the reduction of proinflammatory cytokine expression, such as TNF-α, IL-1β and IL-6; even, a decrease in macrophage and microglial activation and a decrease in leukocyte infiltration to the lesion site [70].…”

The Anti-Inflammatory Role of Omega-3 Polyunsaturated Fatty Acids Metabolites in Pre-Clinical Models of Psychiatric, Neurodegenerative, and Neurological Disorders

“…PD1 also reduced frequency and seizure duration and prevented weight loss (54). Additionally, intravenous injection of PD1 and its aspirin-triggered isomer (AT-PD1) improved neurological recovery in rat models of ischemic stroke using middle cerebral artery occlusion (51,53).…”

“…Cellular outcomes were investigated in nine studies both in vivo and in vitro, predominantly using models of AD and ischemia. Intravenous administration of PD1 in vivo reduced immunoglobulin G (IgG) immunoreactivity in the cortex, subcortex, and whole right hemisphere of rats subject to ischemic stroke (53). It also inhibited astrocyte and microglia activation in the penumbra of ischemic rats (51).…”

Aneurysmal Subarachnoid Hemorrhage and Resolution of Inflammation

“…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].…”