Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke

Pu, Hongjian; Jiang, Xiaoyan; Hu, Xiaoming; Xia, Jinchao; Hong, Dandan; Zhang, Wenting; Gao, Yanqin; Shi, Yejie

doi:10.1007/s12975-016-0498-y

Cited by 37 publications

(25 citation statements)

References 76 publications

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“…In the current study, we extended the first injection of DHA to 2 h after reperfusion and further elevated brain n-3 PUFA levels in long term by FO dietary supplementation at 5 days after MCAO. Consistent with our recent finding that delayed DHA and FO treatments after MCAO promote cognitive recovery [25], the present study demonstrates long-term beneficial effect of n-3 PUFAs on white matter integrity and microglial responses. While DHA injections alone elicited some improvement in post-stroke histological and functional outcomes, such as improved sensorimotor recovery (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…Our recent study revealed beneficial effects of post-stroke DHA injections combined with FO dietary supplementation against stroke-induced cognitive decline [25]. In the present study, we investigated whether the delayed DHA and FO treatments ameliorate long-term sensorimotor deficits after ischemic stroke (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…docosahexaenoic acids (DHA), appears to be effective in ameliorating neurological deficits and reducing neuronal loss up to 7 days after cerebral ischemia [21–24]. We recently observed that repeated administration of n-3 PUFAs, beginning at 2 h after post-ischemic reperfusion, improved spatial learning and memory in a mouse stroke model, at least in part through enhancing the hippocampal integrity [25]. However, it remains unknown whether a post-stroke n-3 PUFA treatment regimen can promote white matter restoration and improve long-term sensorimotor function recovery.…”

Section: Introductionmentioning

confidence: 99%

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A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

Jiang

et al. 2016

Transl. Stroke Res.

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White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 hours after 60 minutes of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

Jiang

et al. 2016

Transl. Stroke Res.

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“…Another important restorative mechanism is oligodendrogenesis, which is essential for remyelination and white matter repair after TBI 49 . Following ischemic brain injury, delayed n-3 PUFA administration is capable of promoting angiogenesis and oligodendrogenesis, which are associated with improved functional recovery 50,51 . In the present study, we noticed an enhancement of post-TBI angiogenesis and oligodendrogenesis upon n-3 PUFA treatment that lasted up to 35 days after injury.…”

Section: Discussionmentioning

confidence: 99%

Repetitive and Prolonged Omega-3 Fatty Acid Treatment after Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery

Jiang

Wei

et al. 2017

Cell Transplant

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Traumatic brain injury (TBI) is one of the most disabling clinical conditions that could lead to neurocognitive disorders in survivors. Our group and others previously reported that prophylactic enrichment of dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) markedly ameliorate cognitive deficits after TBI. However, it remains unclear whether a clinically relevant therapeutic regimen with n-3 PUFAs administered after TBI would still offer significant improvement of long-term cognitive recovery. In the present study, we employed the decline of spatial cognitive function as a main outcome after TBI to investigate the therapeutic efficacy of post-TBI n-3 PUFA treatment and the underlying mechanisms. Mice were subjected to sham operation or controlled cortical impact, followed by random assignment to receive the following four treatments: (1) vehicle control; (2) daily intraperitoneal injections of n-3 PUFAs for 2 weeks, beginning 2 h after TBI; (3) fish oil dietary supplementation throughout the study, beginning 1 day after TBI; or (4) combination of treatments (2) and (3). Spatial cognitive deficits and chronic brain tissue loss, as well as endogenous brain repair processes such as neurogenesis, angiogenesis, and oligodendrogenesis, were evaluated up to 35 days after TBI. The results revealed prominent spatial cognitive deficits and massive tissue loss caused by TBI. Among all mice receiving post-TBI n-3 PUFA treatments, the combined treatment of fish oil dietary supplement and n-3 PUFA injections demonstrated a reproducible beneficial effect in attenuating cognitive deficits although without reducing gross tissue loss. Mechanistically, the combined treatment promoted post-TBI restorative processes in the brain, including generation of immature neurons, microvessels, and oligodendrocytes, each of which was significantly correlated with the improved cognitive recovery. These results indicated that repetitive and prolonged n-3 PUFA treatments after TBI are capable of enhancing brain remodeling and could be developed as a potential therapy to treat TBI victims in the clinic.

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“…Brain tissue was prepared and subjected to immunohistochemistry staining as before [32–33]. Primary antibodies include goat anti-CD206 (1:100; R&D System, Minneasolis, MN, USA), rabbit anti-Iba1 (1:1000, Wako, Richmond, VA, USA), F4/80 (1:200, Biolegend).…”

Section: Methodsmentioning

confidence: 99%

DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury

Wang

et al. 2016

Transl. Stroke Res.

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Stroke induces a catastrophic immune response that involves the global activation of peripheral leukocytes, especially T cells. The HLA-DRα1 domain linked to MOG-35-55 peptide (DRα1-MOG-35-55) is a partial major histocompatibility complex II (MHC II) construct which can inhibit neuroantigen-specific T cells and block binding of the cytokine/chemokine macrophage migration inhibitory factor (MIF) to its CD74 receptor on monocytes and macrophages. Here, we evaluated the therapeutic effect of DRα1-MOG-35-55 in a mouse model of permanent distal middle cerebral artery occlusion (dMCAO). DRα1-MOG-35-55 was administered to WT C57BL/6 mice by subcutaneous injection starting 4h after the onset of ischemia followed by 3 daily injections. We demonstrated that DRα1-MOG-35-55 post-treatment significantly reduced brain infarct volume, improved functional outcomes and inhibited the accumulation of CD4+ and CD8+ T cells and expression of pro-inflammatory cytokines in the ischemic brain 96h after dMCAO. In addition, DRα1-MOG-35-55 treatment shifted microglia/macrophages in the ischemic brain to a beneficial M2 phenotype without changing their total numbers in the brain or blood. This study demonstrates for the first time the therapeutic efficacy of the DRα1-MOG-35-55 construct in dMCAO across MHC class II barriers in C57BL/6 mice. This MHC independent effect obviates the need for tissue typing and will thus greatly expedite treatment with DRα1-MOG-35-55 in human stroke subjects. Taken together, our findings suggest that DRα1-MOG-35-55 treatment may reduce ischemic brain injury by regulating post-stroke immune responses in the brain and the periphery.

show abstract

Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke

Cited by 37 publications

References 76 publications

A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia

Repetitive and Prolonged Omega-3 Fatty Acid Treatment after Traumatic Brain Injury Enhances Long-Term Tissue Restoration and Cognitive Recovery

DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury

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