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Aging and Disease    2017, Vol. 8 Issue (5) : 531-545     DOI: 10.14336/AD.2017.0520
Original Article |
Promoting Neurovascular Recovery in Aged Mice after Ischemic Stroke - Prophylactic Effect of Omega-3 Polyunsaturated Fatty Acids
Mengfei Cai1,Wenting Zhang1,*,Zhongfang Weng2,R. Anne Stetler1,2,3,Xiaoyan Jiang2,Yejie Shi2,3,Yanqin Gao1,2,*,Jun Chen1,2,3,*
1State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, and Collaborative Innovation Center, Fudan University, Shanghai 200032, China
2Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
3Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA
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The aged population is among the highest at risk for ischemic stroke, yet most stroke patients of advanced ages (>80 years) are excluded from access to thrombolytic treatment by tissue plasminogen activator, the only FDA approved pharmacological therapy for stroke victims. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) robustly alleviate ischemic brain injury in young adult rodents, but have not yet been studied in aged animals. This study investigated whether chronic dietary supplementation of n-3 PUFAs protects aging brain against cerebral ischemia and improves long-term neurological outcomes. Aged (18-month-old) mice were administered n-3 PUFA-enriched fish oil in daily chow for 3 months before and up to 8 weeks after 45 minutes of transient middle cerebral artery occlusion (tMCAO). Sensorimotor outcomes were assessed by cylinder test and corner test up to 35 days and brain repair dynamics evaluated immunohistologically up to 56 days after tMCAO. Mice receiving dietary supplementation of n-3 PUFAs for 3 months showed significant increases in brain ratio of n-3/n-6 PUFA contents, and markedly reduced long-term sensorimotor deficits and chronic ischemic brain tissue loss after tMCAO. Mechanistically, n-3 PUFAs robustly promoted post-ischemic angiogenesis and neurogenesis, and enhanced white matter integrity after tMCAO. The Pearson linear regression analysis revealed that the enhancement of neurogenesis and white matter integrity both correlated positively with improved sensorimotor activities after tMCAO. This study demonstrates that prophylactic dietary supplementation of n-3 PUFAs effectively improves long-term stroke outcomes in aged mice, perhaps by promoting post-stroke brain repair processes such as angiogenesis, neurogenesis, and white matter restoration.

Keywords docosahexaenoic acid      eicosapentaenoic acid      angiogenesis      neurogenesis      white matter restoration     
Corresponding Authors: Wenting Zhang,Yanqin Gao,Jun Chen   
Just Accepted Date: 28 May 2017   Issue Date: 26 September 2017
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Mengfei Cai
Wenting Zhang
Zhongfang Weng
R. Anne Stetler
Xiaoyan Jiang
Yejie Shi
Yanqin Gao
Jun Chen
Cite this article:   
Mengfei Cai,Wenting Zhang,Zhongfang Weng, et al. Promoting Neurovascular Recovery in Aged Mice after Ischemic Stroke - Prophylactic Effect of Omega-3 Polyunsaturated Fatty Acids[J]. A&D, 2017, 8(5): 531-545.
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Figure 1.  Lipid profiles are altered in the forebrains of aged mice by dietary PUFA supplementation

Mice were maintained on a low n-3 PUFA (N3L) or high n-3 PUFA (N3H) diet for 3 months, and forebrains were then processed for lipid analysis. (A) Lipid profiles in mouse forebrains expressed as the percent of total fatty acids (TFA), and included profiles of saturated fatty acids (SFA), mono-unsaturated fatty acids (MUFA), and poly-unsaturated fatty acids (PUFA). (B) The ratio of forebrain n-3 to n-6 fatty acids increased in N3H-fed mice. (C) Specific n-3 PUFAs content expressed as pmol/mg; the n-3 PUFAs include α-linolenic acid (ALA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). (D) Specific n-6 PUFAs content expressed as pmol/mg: the n-6 PUFAs include arachidonic acid (AA), docosatetraenoic acid (DTA), dihomo-γ-linolenic acid (DGLA) and γ-linoleic acid (GLA). Data are mean ± SEM, n=4 per group; *p≤0.05, **p≤0.01 vs. N3L.

Figure 2.  Dietary n-3 PUFAs supplementation protects against long-term behavioral deficits and infarct induced by ischemic brain injury in aged mice

(A) Diagram of the experimental timeline. 18-month-old (18 mo) mice were fed either the standard chow or chow supplemented with n-3 PUFAs enriched fish oil, then subjected to 45 min of transient MCAO at 21 months (21 mo) of age. After MCAO, the mice were maintained on the same diet as prior to MCAO until the end of the study (56 days after MCAO). Pre-training for behavioral tests occurred 3 days before 45 min transient MCAO or sham operation. BrdU was injected daily starting 3 days after MCAO through day 10 after MCAO. Sensorimotor function was evaluated up to 35 days after MCAO. Mice were sacrificed 56 days after MCAO for histological assessments. (B) Regional cerebral blood flow measured by laser Doppler during and after MCAO showed no difference between N3L and N3H groups for the duration and extent of ischemic induction. (C, D) Tissue loss from N3L- and N3H-fed mice 56 days after MCAO was measured by MAP2 immunostaining. Representative images of MAP2 staining at 56 days after MCAO are shown, where the dashed lines illustrate chronic brain infarct (MAP2-negative area). Scale bar=1mm. (E) The corner test and cylinder test performance over 35 days after MCAO demonstrated impairments in both groups of MCAO mice. The N3H-fed mice showed significantly improved performance compared to ischemic mice fed the N3L diet. All data are presented as mean ± SEM, n=7 per group, #p≤0.05, ##p≤0.01 vs.; *p≤0.05, **p≤0.01 vs. N3L tMCAO.

Figure 3.  Dietary n-3 PUFAs enhances angiogenesis after MCAO in aged mice

Mice were injected with BrdU daily over 3-10 days following 45 min MCAO, then processed for immunohistology for BrdU and CD31 at 56 days following MCAO. (A) Representative images of CD31 and BrdU double-labeling within the peri-infart region (striatum) of vehicle and n-3 PUFAs treated brains at 56 days after MCAO. Arrow: BrdU+/CD31+ cells. Scale bar=50 μm. (B) Representative high power confocal images of BrdU+/CD31+ co-localization in the striatum at 56 days after MCAO. Scale bar=10 μm. (C) An image stained with MAP2 to designate the infarct area. Analysis of angiogenesis was derived from the regions marked by the blue boxes in the peri-infarct striatum. (D-F) Quantification of post-stroke generated (BrdU+/CD31+) vessels, vessel (CD31+) length, and number of all vessels (CD31+ vessels) at 56 days after cerebral ischemia. Data are presented as mean ± SEM, N3L group, n = 5; N3H group, n=6. *p≤0.05 vs. N3L, #p≤0.05, ##p≤0.01 vs. sham. (G, H) Pearson linear regression analysis was performed to correlate the performance of corner test (G) and cylinder test (H) at 21-35 days after MCAO with the number of BrdU+/CD31+ cells in striatum at 56 days after MCAO.

Figure 4.  Dietary supplementation of n-3 PUFAs increase the presence of matured neural progenitor cells after ischemia in aged mice

(A) Representative images of mature neurons (NeuN+, red) and BrdU+ (green) cells in the striatum after MCAO. Scale bar=50 μm. Arrow: NeuN+/BrdU+ cells. (B) Quantification of BrdU+/NeuN+ cells at 56 days after cerebral ischemia. Data are presented as mean ± SEM, n = 5-6 mice per group at each time point. ***p≤0.001 vs. N3L. (C, D) Pearson linear regression analysis was performed to correlate the performance of corner test (C) and cylinder test (D) at 21-35 days after MCAO with the number of NeuN+/BrdU+ cells in striatum at 56 days after MCAO. N3L group, n = 5; N3H group, n=6.

Figure 5.  n-3 PUFAs supplementation decreases demyelination after MCAO in aged mice

(A) Representative images of SMI-32 and MBP double staining in striatum (STR) and in corpus callosum (CC) of aged mice 56 days after MCAO. The dashed white line indicates the border between the cortex and corpus callosum. Scale bar=50 μm. (B) Diagram to indicate the infarct core, infarct border and peri-infarct regions. The blue and purple boxes indicate the areas used for histological assessments for STR and CC, respectively. (C, D) Quantification of SMI-32/MBP ratio in the striatum (C) and corpus callosum (D). Data are presented as mean ± SEM, n = 5 per group, **p≤0.01 vs. N3L. ##p≤0.01 vs. sham. (E-H) Pearson linear regression analysis was performed to correlate asymmetric rate of forelimb use in corner test (E, G) and cylinder test (F, H) at 21-35 days after MCAO with the ratio of SMI-32/MBP in STR (E, F) or CC (G, H) 56 days after MCAO. N3L group, n = 5; N3H group, n=6.

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