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Lycium barbarum extracts protect the brain from blood-brain barrier disruption and cerebral edema in experimental stroke.

Yang D, Li SY, Yeung CM, Chang RC, So KF, Wong D, Lo AC - PLoS ONE (2012)

Bottom Line: LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content.Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains.Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation.

View Article: PubMed Central - PubMed

Affiliation: Eye Institute, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.

ABSTRACT

Background and purpose: Ischemic stroke is a destructive cerebrovascular disease and a leading cause of death. Yet, no ideal neuroprotective agents are available, leaving prevention an attractive alternative. The extracts from the fruits of Lycium barbarum (LBP), a Chinese anti-aging medicine and food supplement, showed neuroprotective function in the retina when given prophylactically. We aim to evaluate the protective effects of LBP pre-treatment in an experimental stroke model.

Methods: C57BL/6N male mice were first fed with either vehicle (PBS) or LBP (1 or 10 mg/kg) daily for 7 days. Mice were then subjected to 2-hour transient middle cerebral artery occlusion (MCAO) by the intraluminal method followed by 22-hour reperfusion upon filament removal. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, immunohistochemical analysis, and Western blot experiments. Evans blue (EB) extravasation was determined to assess blood-brain barrier (BBB) disruption after MCAO.

Results: LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content. Fewer apoptotic cells were identified in LBP-treated brains by TUNEL assay. Reduced EB extravasation, fewer IgG-leaky vessels, and up-regulation of occludin expression were also observed in LBP-treated brains. Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains.

Conclusions: Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation. The present study suggests that LBP may be used as a prophylactic neuroprotectant in patients at high risk for ischemic stroke.

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Reduced water content and blood-brain barrier (BBB) disruption in LBP-treated cerebral hemispheres.(A) Water content in vehicle and LBP-treated cerebral hemispheres 22 hours after reperfusion. White bars, contralateral hemisphere; filled bars, ipsilateral hemisphere. *P<0.05, ANOVA followed by Bonferroni's test, n = 7 each group. (B) Representative photographs of brains after Evans blue (EB) extravasation assay (left). Scale bar = 10 mm. Leakage of EB (blue area) indicated BBB breakdown after MCAO. LBP-treated ipsilateral hemisphere showed decreased EB extravasation (right). White bars, contralateral hemisphere; filled bars, ipsilateral hemisphere. *P<0.05, ANOVA followed by Bonferroni's test, n = 5 each group. (C) Representative IgG IHC showing leaky blood vessels in ipsilateral penumbral areas (interaural 1.98 mm). IgG signal leaked outside the blood vessel lumen (arrow head) in vehicle-treated brain. In LBP-treated brains, the outline of blood vessels was mostly intact and the IgG signal was present inside the vessel lumen. Inserts, higher magnification of typical blood vessels. Scale bar = 200 µm, inserts scale bar = 25 µm. (D) Quantification of blood vessel leakage in ipsilateral penumbral areas. Fewer leaky vessels were observed in LBP-treated brain when compared with the vehicle group. ***P<0.001, ANOVA followed by Bonferroni's test, n = 5 each group.
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pone-0033596-g003: Reduced water content and blood-brain barrier (BBB) disruption in LBP-treated cerebral hemispheres.(A) Water content in vehicle and LBP-treated cerebral hemispheres 22 hours after reperfusion. White bars, contralateral hemisphere; filled bars, ipsilateral hemisphere. *P<0.05, ANOVA followed by Bonferroni's test, n = 7 each group. (B) Representative photographs of brains after Evans blue (EB) extravasation assay (left). Scale bar = 10 mm. Leakage of EB (blue area) indicated BBB breakdown after MCAO. LBP-treated ipsilateral hemisphere showed decreased EB extravasation (right). White bars, contralateral hemisphere; filled bars, ipsilateral hemisphere. *P<0.05, ANOVA followed by Bonferroni's test, n = 5 each group. (C) Representative IgG IHC showing leaky blood vessels in ipsilateral penumbral areas (interaural 1.98 mm). IgG signal leaked outside the blood vessel lumen (arrow head) in vehicle-treated brain. In LBP-treated brains, the outline of blood vessels was mostly intact and the IgG signal was present inside the vessel lumen. Inserts, higher magnification of typical blood vessels. Scale bar = 200 µm, inserts scale bar = 25 µm. (D) Quantification of blood vessel leakage in ipsilateral penumbral areas. Fewer leaky vessels were observed in LBP-treated brain when compared with the vehicle group. ***P<0.001, ANOVA followed by Bonferroni's test, n = 5 each group.

Mentions: Decreased water content was found in ipsilateral hemispheres of LBP-treated mice, which indicated less cerebral edema (P<0.05 LBP10 group vs. vehicle group, Figure 3A). Water content of the contralateral hemispheres in all three groups was similar.


Lycium barbarum extracts protect the brain from blood-brain barrier disruption and cerebral edema in experimental stroke.

Yang D, Li SY, Yeung CM, Chang RC, So KF, Wong D, Lo AC - PLoS ONE (2012)

Reduced water content and blood-brain barrier (BBB) disruption in LBP-treated cerebral hemispheres.(A) Water content in vehicle and LBP-treated cerebral hemispheres 22 hours after reperfusion. White bars, contralateral hemisphere; filled bars, ipsilateral hemisphere. *P<0.05, ANOVA followed by Bonferroni's test, n = 7 each group. (B) Representative photographs of brains after Evans blue (EB) extravasation assay (left). Scale bar = 10 mm. Leakage of EB (blue area) indicated BBB breakdown after MCAO. LBP-treated ipsilateral hemisphere showed decreased EB extravasation (right). White bars, contralateral hemisphere; filled bars, ipsilateral hemisphere. *P<0.05, ANOVA followed by Bonferroni's test, n = 5 each group. (C) Representative IgG IHC showing leaky blood vessels in ipsilateral penumbral areas (interaural 1.98 mm). IgG signal leaked outside the blood vessel lumen (arrow head) in vehicle-treated brain. In LBP-treated brains, the outline of blood vessels was mostly intact and the IgG signal was present inside the vessel lumen. Inserts, higher magnification of typical blood vessels. Scale bar = 200 µm, inserts scale bar = 25 µm. (D) Quantification of blood vessel leakage in ipsilateral penumbral areas. Fewer leaky vessels were observed in LBP-treated brain when compared with the vehicle group. ***P<0.001, ANOVA followed by Bonferroni's test, n = 5 each group.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3306421&req=5

pone-0033596-g003: Reduced water content and blood-brain barrier (BBB) disruption in LBP-treated cerebral hemispheres.(A) Water content in vehicle and LBP-treated cerebral hemispheres 22 hours after reperfusion. White bars, contralateral hemisphere; filled bars, ipsilateral hemisphere. *P<0.05, ANOVA followed by Bonferroni's test, n = 7 each group. (B) Representative photographs of brains after Evans blue (EB) extravasation assay (left). Scale bar = 10 mm. Leakage of EB (blue area) indicated BBB breakdown after MCAO. LBP-treated ipsilateral hemisphere showed decreased EB extravasation (right). White bars, contralateral hemisphere; filled bars, ipsilateral hemisphere. *P<0.05, ANOVA followed by Bonferroni's test, n = 5 each group. (C) Representative IgG IHC showing leaky blood vessels in ipsilateral penumbral areas (interaural 1.98 mm). IgG signal leaked outside the blood vessel lumen (arrow head) in vehicle-treated brain. In LBP-treated brains, the outline of blood vessels was mostly intact and the IgG signal was present inside the vessel lumen. Inserts, higher magnification of typical blood vessels. Scale bar = 200 µm, inserts scale bar = 25 µm. (D) Quantification of blood vessel leakage in ipsilateral penumbral areas. Fewer leaky vessels were observed in LBP-treated brain when compared with the vehicle group. ***P<0.001, ANOVA followed by Bonferroni's test, n = 5 each group.
Mentions: Decreased water content was found in ipsilateral hemispheres of LBP-treated mice, which indicated less cerebral edema (P<0.05 LBP10 group vs. vehicle group, Figure 3A). Water content of the contralateral hemispheres in all three groups was similar.

Bottom Line: LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content.Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains.Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation.

View Article: PubMed Central - PubMed

Affiliation: Eye Institute, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.

ABSTRACT

Background and purpose: Ischemic stroke is a destructive cerebrovascular disease and a leading cause of death. Yet, no ideal neuroprotective agents are available, leaving prevention an attractive alternative. The extracts from the fruits of Lycium barbarum (LBP), a Chinese anti-aging medicine and food supplement, showed neuroprotective function in the retina when given prophylactically. We aim to evaluate the protective effects of LBP pre-treatment in an experimental stroke model.

Methods: C57BL/6N male mice were first fed with either vehicle (PBS) or LBP (1 or 10 mg/kg) daily for 7 days. Mice were then subjected to 2-hour transient middle cerebral artery occlusion (MCAO) by the intraluminal method followed by 22-hour reperfusion upon filament removal. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, immunohistochemical analysis, and Western blot experiments. Evans blue (EB) extravasation was determined to assess blood-brain barrier (BBB) disruption after MCAO.

Results: LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content. Fewer apoptotic cells were identified in LBP-treated brains by TUNEL assay. Reduced EB extravasation, fewer IgG-leaky vessels, and up-regulation of occludin expression were also observed in LBP-treated brains. Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains.

Conclusions: Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation. The present study suggests that LBP may be used as a prophylactic neuroprotectant in patients at high risk for ischemic stroke.

Show MeSH
Related in: MedlinePlus