Stroke is one of the major medical concerns for United States military veterans. Stroke is devastating as currently no therapy is available to prevent stroke-induced neurological deficit. Prophylactic or therapeutic supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFAs) has recently emerged as a highly promising neuroprotective strategy for stroke. Epidemiological studies have shown an inverse association between n-3 PUFAs intake and risk of ischemic stroke. Supplementation with n-3 PUFAs, especially DHA, effectively reduces the extent of brain damage and neurological deficits in the acute phase of ischemic injury in experimental animals. However, the long-term effect of n-3 PUFAs on brain damage and post- stroke neurological recovery is unknown. We have recently created transgenic (Tg) mice over-expressing the C elegans fat-1 gene encoding an enzyme that converts endogenous n-6 to n-3 PUFAs. Our preliminary studies with fat-1 Tg mice have suggested two-phase (acute and delayed) beneficial effects of n-3 PUFAs on ischemic stroke. The fat-1 Tg mice at either young (3-month-old) or old age (15-month-old) were remarkably resistant to focal ischemic injury compared to their age-matched wild-type (Wt) littermates, showing reduced infarct size and improved neurological functional performance up to 14 days after middle cerebral artery occlusion. We have found that angiogenesis and neurogenesis were robustly enhanced after ischemia in 3-month old fat-1 Tg mice compared to Wt littermates, suggesting that n-3 PUFAs promote post-stroke neurovascular regeneration. Strikingly, we found that post-stroke angiogenesis and neurogenesis were profoundly impaired in aged mice, but almost fully restored by transgenic expression of fat-1. This proposal attempts to further explore the long-term protective effect of n-3 PUFAs on focal cerebral ischemia. The goal is to develop n-3 PUFA supplementation as a novel, clinically feasible prophylactic and/or therapeutic strategy to promote long-term neurological recovery after stroke through stimulating the generation of functional blood vessels and new neurons. The central hypothesis to be tested in the current proposal is that prophylactic or therapeutic n-3 PUFA treatment improves long-term neurological outcomes after stroke by stimulating and enhancing post-ischemia brain repair, including augmented neurogenesis and angiogenesis. The following specific objectives are proposed:
Aim 1. Test the hypothesis that n-3 PUFAs reduce long-term neurological deficits as well as brain tissue damage after focal cerebral ischemia in both young adult and aged mice. Two clinically applicable methods: 1) dietary delivery;and 2) augmented endogenous production of n-3 PUFAs via adeno-associated virus (AAV)-directed fat-1 gene expression, will be established to elevate brain levels of n-3 PUFAs. The effect of elevated n-3 PUFAs on ischemic brain injury induced by MCAO will be quantitatively evaluated. The endpoints of assessment include functional outcomes, infarct size, and white matter injury.
Aim 2. Test the hypothesis that n-3 PUFA treatment enhances cerebral neurovascular regeneration, including augmented angiogenesis and neurogenesis after cerebral ischemia in both young adult and aged mice. The proposed studies will quantitatively determine the effect of n-3 PUFAs on post-stroke neovascularization and on neural stem cell proliferation, migration, differentiation and neuronal replacement following ischemic stroke.

Public Health Relevance

NARRATIVE Stroke is one of the major medical concerns for United States military veterans. Stroke is devastating as currently no therapy is available to prevent stroke-induced neurological deficit. Prophylactic or therapeutic supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFAs) has recently emerged as a highly promising neuroprotective strategy for stroke. Supplementation with n-3 PUFAs, especially DHA, effectively reduces the extent of brain damage and neurological deficits in the acute phase of ischemic injury in experimental animals. However, the long-term effect of n-3 PUFAs on brain damage and post-stroke neurological recovery is unknown. Our preliminary studies have suggested two-phase (acute and delayed) beneficial effects of n-3 PUFAs on ischemic stroke. We have found evidence that n-3 PUFAs promote post-stroke neurovascular regeneration. Thus, the objective of the current proposal is to develop n-3 PUFA supplementation as a novel, clinically feasible prophylactic and/or therapeutic strategy to promote long-term neurological recovery after stroke. First, we will test the hypothesis that n-3 PUFAs reduce long-term neurological deficits as well as brain tissue damage after focal cerebral ischemia in both young adult and aged mice. Second, we will test the hypothesis that n-3 PUFA treatment enhances cerebral neurovascular regeneration.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01RX000420-01
Application #
8004760
Study Section
Spinal Cord Injury & Regenerative Medicine (RRD0)
Project Start
2011-02-01
Project End
2015-01-31
Budget Start
2011-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
033127569
City
Pittsburgh
State
PA
Country
United States
Zip Code
15206
Zhang, Wenting; Chen, Ruiying; Yang, Tuo et al. (2018) Fatty acid transporting proteins: Roles in brain development, aging, and stroke. Prostaglandins Leukot Essent Fatty Acids 136:35-45
Ma, Shubei; Wang, Jianyi; Wang, Yanling et al. (2018) Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia. Stroke 49:2453-2463
Jiang, Xiaoyan; Suenaga, Jun; Pu, Hongjian et al. (2018) Post-stroke administration of omega-3 polyunsaturated fatty acids promotes neurovascular restoration after ischemic stroke in mice: Efficacy declines with aging. Neurobiol Dis :
Li, Peiying; Stetler, R Anne; Leak, Rehana K et al. (2018) Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology 134:208-217
Cai, Mengfei; Zhang, Wenting; Weng, Zhongfang et al. (2017) Promoting Neurovascular Recovery in Aged Mice after Ischemic Stroke - Prophylactic Effect of Omega-3 Polyunsaturated Fatty Acids. Aging Dis 8:531-545
Cai, Wei; Zhang, Kai; Li, Peiying et al. (2017) Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect. Ageing Res Rev 34:77-87
Jiang, Xiaoyan; Pu, Hongjian; Hu, Xiaoming et al. (2016) A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia. Transl Stroke Res 7:548-561
Pu, Hongjian; Jiang, Xiaoyan; Hu, Xiaoming et al. (2016) Delayed Docosahexaenoic Acid Treatment Combined with Dietary Supplementation of Omega-3 Fatty Acids Promotes Long-Term Neurovascular Restoration After Ischemic Stroke. Transl Stroke Res 7:521-534
Zhang, Wenting; Zhang, Hui; Mu, Hongfeng et al. (2016) Omega-3 polyunsaturated fatty acids mitigate blood-brain barrier disruption after hypoxic-ischemic brain injury. Neurobiol Dis 91:37-46
Zhang, Wenting; Wang, Hailian; Zhang, Hui et al. (2015) Dietary supplementation with omega-3 polyunsaturated fatty acids robustly promotes neurovascular restorative dynamics and improves neurological functions after stroke. Exp Neurol 272:170-80

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