Abstract 94: Protection Against Blood-Brain Barrier Disruption in Focal Cerebral Ischemia by Docosahexaenoic Acid

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Sung-Ha Hong ◽  
Larissa Khoutorova ◽  
Daniela Anzola ◽  
Qiang Wu ◽  
Bokkyoo Jun ◽  
...  
Keyword(s):  
Docosahexaenoic Acid ◽  
Blood Brain Barrier ◽  
Cortical Area ◽  
Focal Cerebral Ischemia ◽  
Brain Barrier ◽  
Experimental Stroke ◽  
Lipid Mediator ◽  
Omega 3 ◽  
Physiological Variables ◽  
Blood Brain

INTRODUCTION: Docosahexaenoic acid (DHA; 22:6n-3) is an omega-3 essential fatty acid family member and the precursor of neuroprotectin D1, a lipid mediator which downregulates apoptosis and promotes cell survival. Recently, we have shown that DHA therapy improves functional and histological outcomes following experimental stroke. We examined the effect of DHA on blood-brain barrier (BBB) integrity after middle cerebral artery occlusion (MCAo) in rats. Damage to the BBB was judged by extravasation of Evans Blue (EB) dye. METHODS: Male SD rats were anesthetized with isoflurane and subjected to 2 h of MCAo by retrograde insertion of an intraluminal suture. DHA (5 mg/kg) or vehicle (saline) was administered IV at 3 h after the onset of MCAo and animals were sacrificed at 6, 24 or 72 h. Behavioral tests were performed at 5, 24, 48 or 72 h. EB (2% in saline, 4 ml/kg) was administered IV either at 5, 23 or 71 h after onset of MCAo. Fluorometric quantitation of EB was performed 1 h later in six brain regions. RESULTS: Physiological variables were stable and showed no significant differences between groups. In the 6 h series (n=9 per group), DHA decreased EB extravasation in the posterior ischemic hemisphere compared to saline (9.2±1.1 vs. 14.3± 1.5, respectively). In the 24 h series (n=8-9 per group), DHA improved behavioral scores on day 1 and decreased EB extravasation in the posterior ischemic hemisphere (4.9±0.41 vs. 8.5±1.0) and cortical area (3.0±0.4 vs. 8.6± 2.0, respectively) compared to saline. In the 72 h series (n=12 per group), DHA improved behavioral scores on days 1, 2 and 3, and decreased EB extravasation in the anterior (6.1±0.8 vs. 9.6±0.9), posterior (5.6±0.7 vs. 9.1±1.2, respectively) ischemic hemispheres compared to saline. In addition, EB extravasation was decreased by DHA in the cortical area (6.2±1.0 vs. 10.1±1.1) and total hemisphere (11.7±1.3 vs. 18.7±1.9, respectively) compared to vehicle. CONCLUSION: These data have demonstrated that DHA is an effective neuroprotective drug, diminishing BBB damage in a model of severe focal ischemia. Thus, it is reasonable to hypothesize that DHA may have potential use in treating focal ischemic stroke in the clinical setting. This study was supported by NIH, NINDS grant R01 NS065786 (LB) and R01 NS046741 (NGB).

Abstract 3098: Docosahexaenoic Acid Protects The Brain After Experimental Stroke By Modulating Protein Phosphorylation In The Penumbra

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Tiffany N Eady ◽  
Ludmila Belayev ◽  
Larissa Khoutorova ◽  
Kristal D Atkins ◽  
Nicolas G Bazan
Keyword(s):  
Docosahexaenoic Acid ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Experimental Stroke ◽  
Omega 3 ◽  
Western Blots ◽  
Behavioral Deficit ◽  
Physiological Variables ◽  
Cell Counts ◽  
Ischemic Core

Background and purpose: Docosahexaenoic acid (DHA), a member of the omega-3 essential fatty acid family, improves behavioral deficit and reduces infarct volume and brain edema after focal cerebral ischemia in rats. We hypothesize that DHA elicits neuroprotection by inducing protective cellular cascades, which in turn lead to cell survival. We used behavioral tests in conjunction with immunohistopathology and western blots to expand our understanding of the early mechanisms responsible for DHA-induced neuroprotection. Methods: Physiologically-controlled male Sprague-Dawley rats (304-370g) received 2h middle cerebral artery occlusion (MCAo) by intraluminal suture. Animals were treated with DHA (5mg/kg, iv) or saline (5ml/kg) at 3h after the onset of stroke. Behavioral function was evaluated at 1h after occlusion onset and at 24h on a grading scale of 0-12 (0=normal and 12=maximal deficit). GFAP (reactive astrocytes), ED-1 (activated microglia/microphages), and NeuN (neurons) were analyzed in the ischemic core and the penumbra regions (A, B and C) at 4 and 24h. Western blot/immunohistochemical analysis of pAKT, pGSK, and pS6 (proteins of the AKT signaling pathway) was conducted in the core and penumbra at 4 and 24h. Results: Physiological variables were stable and showed no significant differences between groups. Behavioral deficit was significantly improved by treatment with DHA compared to vehicle at 24h (7.3±0.5 vs. 10±0; p<0.001, respectively). DHA treatment significantly reduced the number of microglia cells in penumbra regions A and C (by 86% and 76%) and increased GFAP-positive cells in penumbra regions B and C (by 53% and 51%) at 24h after stroke. There were no significant differences in expression of cell markers between groups at 4h and in the ischemic core. DHA upregulated activation of AKT compared to vehicle at 4h (36% increase in p473 AKT and 79% increase in p308 AKT) and at 24h (114% increase in p473 AKT; 98% increase in p308 AKT). DHA also increased pS6 at 4h by 160% and pGSK at 24h by 61% as compared to vehicle-treated animals. DHA-treated animals had significantly higher p308 AKT cell counts in the penumbra at 4h (region A by182%, region B by 160% and region C by 103% increase). Conclusions: DHA treatment confers behavioral improvement, reduces microglial infiltration, increases astrocytosis at 24h, activates pro-survival AKT cascades as early as 4h, and has potential for the treatment of ischemic stroke.

Abstract T P222: Docosahexaenoic Acid as a Promising Neuroprotectant in Brain Ischemia: New Experimental Evidence

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Ludmila Belayev ◽  
Sung-Ha Hong ◽  
Larissa Khoutorova ◽  
Daniela Anzola ◽  
Andre Obenaus ◽  
...  
Keyword(s):  
Docosahexaenoic Acid ◽  
Evans Blue ◽  
Ex Vivo ◽  
Brain Regions ◽  
Saline Group ◽  
Experimental Stroke ◽  
Lipid Mediator ◽  
Omega 3 ◽  
Physiological Variables ◽  
Y Maze

Introduction: Docosahexaenoic acid (DHA; 22:6n-3) is an omega-3 essential fatty acid family member and the precursor of neuroprotectin D1, a lipid mediator which downregulates apoptosis and promotes cell survival. Recently, we have shown that DHA improved behavior in animals allowed to survive for 7 d after stroke. This study was conducted to establish whether the behavioral improvement induced by DHA persists with chronic survival. In addition, we examined the effect of DHA on blood-brain barrier (BBB) integrity using Evans Blue (EB) and FITC-dextran markers. METHODS: Physiologically-controlled SD rats received 2 h middle cerebral artery occlusion (MCAo). DHA (5 mg/kg; n=10) or vehicle (saline; n=9) was administered i.v. at 3 h after onset of MCAo. In behavioral studies, the composite 12-point neuroscore, rota-rod, Y-maze and beam walking test were conducted 1, 2 and 3 weeks after MCAo. Ex vivo imaging of the brains and histopathology were carried out on day 21. In BBB studies, fluorometric quantitation of Evans Blue (EB) was performed in six brain regions at 6, 24 or 72 h after stroke. FITC dextran leakage was analyzed on day 3 after MCAo. RESULTS: Physiological variables were stable and showed no significant differences between groups. DHA treatment significantly improved the 12-point neuroscore compared to vehicle on day 1 (by 16%), day 2 (by 19%), day 3 (by 22%), week 1 (by 20%), week 2 (by 22%) and week 3 (by 33%) respectively. Treatment with DHA prolonged latency time in the rota-rod test on weeks 1-3 (by 44-68%), enhanced the score in the balance beam (by 29%) and improved Y-maze performance by 19% compared to the saline group. DHA decreased EB extravasation in the posterior ischemic hemisphere at 6 h (by 34%), 24 h (by 42%) and 72 h (by 38%). EB extravasation was decreased by DHA in the cortex and total hemisphere as well. FITC dextran leakage was reduced by DHA treatment on day 3 by 68% compared to the saline group. CONCLUSION: DHA therapy accelerates long-lasting behavioral recovery and diminishes BBB damage in a model of experimental stroke. Thus, it is reasonable to hypothesize that DHA may have potential use in treating focal ischemic stroke in the clinical setting.

scholarly journals Can Natural Products Exert Neuroprotection without Crossing the Blood–Brain Barrier?

2021 ◽  
Vol 22 (7) ◽  
pp. 3356
Author(s):  
Manon Leclerc ◽  
Stéphanie Dudonné ◽  
Frédéric Calon
Keyword(s):  
Natural Products ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Omega 3 ◽  
Indirect Pathway ◽  
Brain Functions ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Peripheral Metabolism

The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood–brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut–microbiota–brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer’s disease.

scholarly journals Early Appearance of Activated Matrix Metalloproteinase-9 after Focal Cerebral Ischemia in Mice: A Possible Role in Blood—Brain Barrier Dysfunction

1999 ◽  
Vol 19 (9) ◽  
pp. 1020-1028 ◽  
Author(s):  
Yvan Gasche ◽  
Miki Fujimura ◽  
Yuiko Morita-Fujimura ◽  
Jean-Christophe Copin ◽  
Makoto Kawase ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Blood Brain Barrier ◽  
Focal Cerebral Ischemia ◽  
Vasogenic Edema ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Brain Barrier ◽  
Critical Event ◽  
Secondary Brain Injury ◽  
Blood Brain ◽  
Bbb Permeability

During cerebral ischemia blood–brain barrier (BBB) disruption is a critical event leading to vasogenic edema and secondary brain injury. Gelatinases A and B are matrix metalloproteinases (MMP) able to open the BBB. The current study analyzes by zymography the early gelatinases expression and activation during permanent ischemia in mice (n = 15). ProMMP-9 expression was significantly ( P < 0.001) increased in ischemic regions compared with corresponding contralateral regions after 2 hours of ischemia (mean 694.7 arbitrary units [AU], SD ± 238.4 versus mean 107.6 AU, SD ± 15.6) and remained elevated until 24 hours (mean 745,7 AU, SD ± 157.4). Moreover, activated MMP-9 was observed 4 hours after the initiation of ischemia. At the same time as the appearance of activated MMP-9, we detected by the Evan's blue extravasation method a clear increase of BBB permeability, Tissue inhibitor of metalloproteinase-1 was not modified during permanent ischemia at any time. The ProMMP-2 was significantly ( P < 0.05) increased only after 24 hours of permanent ischemia (mean 213.2 AU, SD ± 60.6 versus mean 94.6 AU, SD ± 13.3), and no activated form was observed. The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that MMP-9 may play an active role in early vasogenic edema development after stroke.

Effects of Inhibition of Nitric Oxide Synthase on Blood-Brain Barrier Transport in Focal Cerebral Ischemia

Pharmacology ◽  
1994 ◽  
Vol 48 (6) ◽  
pp. 367-373 ◽  
Author(s):  
Oak Za Chi ◽  
Hwu Meei Wei ◽  
Arabinda K. Sinha ◽  
Harvey R. Weiss
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Nitric Oxide Synthase ◽  
Blood Brain Barrier ◽  
Focal Cerebral Ischemia ◽  
Brain Barrier ◽  
Blood Brain ◽  
Oxide Synthase

The blood–brain barrier is continuously open for several weeks following transient focal cerebral ischemia

Neuroscience ◽  
2008 ◽  
Vol 153 (1) ◽  
pp. 175-181 ◽  
Author(s):  
D. Strbian ◽  
A. Durukan ◽  
M. Pitkonen ◽  
I. Marinkovic ◽  
E. Tatlisumak ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Blood Brain Barrier ◽  
Focal Cerebral Ischemia ◽  
Brain Barrier ◽  
Blood Brain ◽  
Transient Focal Cerebral Ischemia
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