Nanoliposomes Reduce Stroke Injury Following Middle Cerebral Artery Occlusion in Mice

Background and Purpose: Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phosphatidylcholine, cholesterol, and monosialogangliosides (nanoliposomes) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that nanoliposomes will preserve human neuroblastoma (SH-SY5Y) and human brain microvascular endothelial cells viability following oxygen-glucose deprivation (OGD)–reoxygenation and will reduce injury in mice following middle cerebral artery occlusion. Methods: SH-SY5Y and human brain microvascular endothelial cells were exposed to oxygen-glucose deprivation–reoxygenation (3 hours 0.5%–1% oxygen and glucose-free media followed by 20-hour ambient air/regular media) without or with nanoliposomes (300 µg/mL). Viability was measured (calcein-acetoxymethyl fluorescence) and protein expression of antioxidant proteins HO-1 (heme oxygenase-1), NQO1 (NAD[P]H quinone dehydrogenase 1), and SOD1 (superoxide dismutase 1) were measured by Western blot. C57BL/6J mice were treated with saline (n=8) or nanoliposomes (10 mg/mL lipid, 200 µL, n=7) while undergoing 60-minute middle cerebral artery occlusion followed by reperfusion. Day 2 postinjury neurological impairment score and infarction size were compared. Results: SH-SY5Y and human brain microvascular endothelial cells showed reduced viability post–oxygen-glucose deprivation–reoxygenation that was reversed by nanoliposomes. Nanoliposomes increased protein expressions of HO-1, NQO1 in both cell types and SOD1 in human brain microvascular endothelial cells. Nanoliposomes-treated mice showed reduced neurological impairment and brain infarct size (18.8±2% versus 27.3±2.3%, P =0.017) versus controls. Conclusions: Nanoliposomes reduced stroke injury in mice subjected to middle cerebral artery occlusion likely through induction of an antioxidant protective response. Nanoliposome is a candidate novel agent for stroke.

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Abstract 166: Endothelial Overexpression of LOX-1 Increases Stroke Size in vivo

Circulation Research ◽

10.1161/res.113.suppl_1.a166 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Alexander Akhmedov ◽

Remo D Spescha ◽

Francesco Paneni ◽

Giovani G Camici ◽

Thomas F Luescher

Keyword(s):

Endothelial Cells ◽

Ischemic Stroke ◽

Endothelial Dysfunction ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Oxidized Ldl ◽

Artery Occlusion ◽

Cerebral Artery Occlusion ◽

The Brain

Background— Stroke is one of the most common causes of death and long term disability worldwide primarily affecting the elderly population. Lectin-like oxidized LDL receptor 1 (LOX-1) is the receptor for oxidized LDL identified in endothelial cells. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO. Accumulating evidence suggests that LOX-1 is involved in endothelial dysfunction, inflammation, atherogenesis, myocardial infarction, and intimal thickening after balloon catheter injury. Interestingly, a recent study demonstrated that acetylsalicylic acid (aspirin), which could prevent ischemic stroke, inhibited Ox-LDL-mediated LOX-1 expression in human coronary endothelial cells. The expression of LOX-1 was increased at a transient ischemic core site in the rat middle cerebral artery occlusion model. These data suggest that LOX-1 expression induces atherosclerosis in the brain and is the precipitating cause of ischemic stroke. Therefore, the goal of the present study was to investigate the role of endothelial LOX-1 in stroke using experimental mouse model. Methods and Results— 12-week-old male LOX-1TG generated recently in our group and wild-type (WT) mice were applied for a transient middle cerebral artery occlusion (MCAO) model to induce ischemia/reperfusion (I/R) brain injury. LOX-1TG mice developed 24h post-MCAO significantly larger infarcts in the brain compared to WT (81.51±8.84 vs. 46.41±10.13, n=7, p < 0.05) as assessed morphologically using Triphenyltetrazolium chloride (TTC) staining. Moreover, LOX-1TG showed higher neurological deficit in RotaRod (35.57±8.92 vs. 66.14±10.63, n=7, p < 0.05) and Bederson tests (2.22±0.14 vs. 1.25±0.30, n=9-12, p < 0.05) - two experimental physiological tests for neurological function. Conclusions— Thus, our data suggest that LOX-1 plays a critical role in the ischemic stroke when expressed at unphysiological levels. Such LOX-1 -associated phenotype could be due to the endothelial dysfunction. Therefore, LOX-1 may represent novel therapeutic targets for preventing ischemic stroke.

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Willed‑movement training reduces middle cerebral artery occlusion‑induced motor deficits and improves angiogenesis and survival of cerebral endothelial cells via upregulating hypoxia‑inducible factor‑1α

Molecular Medicine Reports ◽

10.3892/mmr.2019.10578 ◽

2019 ◽

Author(s):

Zhiwen Zhou ◽

Xiang Ren ◽

Wensheng Zhou ◽

Lijun Zheng

Keyword(s):

Endothelial Cells ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Hypoxia Inducible Factor ◽

Artery Occlusion ◽

Motor Deficits ◽

Cerebral Endothelial Cells ◽

Movement Training ◽

Cerebral Artery Occlusion

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Lipocalin-2 Deficiency Attenuates Neuroinflammation and Brain Injury after Transient Middle Cerebral Artery Occlusion in Mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.83 ◽

2014 ◽

Vol 34 (8) ◽

pp. 1306-1314 ◽

Cited By ~ 54

Author(s):

Myungwon Jin ◽

Jong-Heon Kim ◽

Eunha Jang ◽

Young Mi Lee ◽

Hyung Soo Han ◽

...

Keyword(s):

Endothelial Cells ◽

Brain Injury ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Artery Occlusion ◽

Lipocalin 2 ◽

Ischemic Brain ◽

Cerebral Artery Occlusion

Lipocalin-2 (LCN2) is a secreted protein of the lipocalin family, but little is known about the expression or the role of LCN2 in the central nervous system. Here, we investigated the role of LCN2 in ischemic stroke using a rodent model of transient cerebral ischemia. Lipocalin-2 expression was highly induced in the ischemic brain and peaked at 24 hours after reperfusion. After transient middle cerebral artery occlusion, LCN2 was predominantly expressed in astrocytes and endothelial cells, whereas its receptor (24p3R) was mainly detected in neurons, astrocytes, and endothelial cells. Brain infarct volumes, neurologic scores, blood–brain barrier (BBB) permeabilities, glial activation, and inflammatory mediator expression were significantly lower in LCN2-defkient mice than in wild-type animals. Lipocalin-2 deficiency also attenuated glial neurotoxicity in astrocyte/neuron cocultures after oxygen-glucose deprivation. Our results indicate LCN2 has a critical role in brain injury after ischemia/reperfusion, and that LCN2 may contribute to neuronal cell death in the ischemic brain by promoting neurotoxic glial activation, neuroinflammation, and BBB disruption.

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