Skip to main page content (VSports)
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or VSports app下载. mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure V体育官网. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. .

. 2011 Aug;42(8):2308-14.
doi: 10.1161/STROKEAHA.110.608547. Epub 2011 Jun 30.

Natural vitamin E α-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1

Han-A Park  1 , Natalia Kubicki, Surya Gnyawali, Yuk Cheung Chan, Sashwati Roy, Savita Khanna, Chandan K Sen
Affiliations

Natural vitamin E α-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1

"V体育2025版" Han-A Park et al. Stroke. 2011 Aug.

Abstract

Background and purpose: α-Tocotrienol (TCT) represents the most potent neuroprotective form of natural vitamin E that is Generally Recognized As Safe certified by the U. S. Food and Drug Administration. This work addresses a novel molecular mechanism by which α-TCT may be protective against stroke in vivo. Elevation of intracellular oxidized glutathione (GSSG) triggers neural cell death VSports手机版. Multidrug resistance-associated protein 1 (MRP1), a key mediator of intracellular oxidized glutathione efflux from neural cells, may therefore possess neuroprotective functions. .

Methods: Stroke-dependent brain tissue damage was studied in MRP1-deficient mice and α-TCT-supplemented mice. V体育安卓版.

Results: Elevated MRP1 expression was observed in glutamate-challenged primary cortical neuronal cells and in stroke-affected brain tissue. MRP1-deficient mice displayed larger stroke-induced lesions, recognizing a protective role of MRP1. In vitro, protection against glutamate-induced neurotoxicity by α-TCT was attenuated under conditions of MRP1 knockdown; this suggests the role of MRP1 in α-TCT-dependent neuroprotection. In vivo studies demonstrated that oral supplementation of α-TCT protected against murine stroke. MRP1 expression was elevated in the stroke-affected cortical tissue of α-TCT-supplemented mice. Efforts to elucidate the underlying mechanism identified MRP1 as a target of microRNA (miR)-199a-5p. In α-TCT-supplemented mice, miR-199a-5p was downregulated in stroke-affected brain tissue. V体育ios版.

Conclusions: This work recognizes MRP1 as a protective factor against stroke. Furthermore, findings of this study add a new dimension to the current understanding of the molecular bases of α-TCT neuroprotection in 2 ways: by identifying MRP1 as a α-TCT-sensitive target and by unveiling the general prospect that oral α-TCT may regulate miR expression in stroke-affected brain tissue VSports最新版本. .

PubMed Disclaimer

Figures

Figure 1
Figure 1. MRP1 knockdown attenuated the neuroprotection of α-tocotrienol in primary cortical neurons
After 24h of seeding, primary cortical neurons were treated with glutamate (5mmol/L, 24h). Glutamate challenge induced the expression of MRP1 protein (A). After MRP1 siRNA transfection, MRP1 mRNA expression was significantly down-regulated (B). C, Glutamate-challenged primary neurons with MRP1 knockdown exhibited loss of functional MRP1 by retaining more calcein compared to corresponding control cells. D, α-TCT (1μmol/L) was added into cell culture medium 6h before glutamate treatment. After glutamate (5mmol/L, 24h) challenge, LDH leakage was measured. Neuroprotection of α-TCT was compromised under conditions of MRP1 knockdown. Bar=50μm, n=3, *P<0.05 compared with control; §P< 0.05 compared with control siRNA-transfected, glutamate-treated primary neurons.
Figure 2
Figure 2. MCAO-induced brain injury was exacerbated in MRP1 deficient mice
Transient focal cerebral ischemia was induced in MRP1 deficient (n=20) or FVB mice (n=15) by MCAO. A, MRP1 KO mice presented larger stroke-induced lesion compared to FVB mice after 48h reperfusion (FVB, n=8; MRP1 KO, n=12). B, Protein expression of MRP1 was increased in infarct hemisphere of FVB mice (n=3). C, MRP1 deficient mice contained significantly higher level of GSSG in stroke-affected hemisphere compared to that of FVB mice (n=4). *P<0.05 compared with corresponding contralateral hemisphere; †P<0.05 compared with FVB; §P<0.05 compared with infarct hemisphere of FVB.
Figure 3
Figure 3. MCAO-induced neurodegeneration was accentuated in MRP1 deficient mice
A, MRP1 expression was upregulated at the stroke affected cortex of FVB mice (red-MRP1 protein; blue-DAPI stained nuclei) B, The infarct hemisphere of MRP1 deficient mice presented abundant Fluoro-Jade signals in cortical region (green-Fluoro-Jade positive neurons; blue-DAPI stained nuclei). Bar=50μm, n=3, *P<0.05 compared with corresponding contralateral hemisphere; §P<0.05 compared with infarct hemisphere of FVB.
Figure 4
Figure 4. miR-199a-5p silences MRP1 in primary cortical neurons
After 72h of miR-199a-5p mimic delivery, miR-199a-5p expression was significantly upregulated (A) while miR-199a-5p hairpin inhibitor significantly downregulated miR-199a-5p (B). miR-199a-5p mimic/inhibitor negatively regulated protein (C-D) of MRP1 in primary cortical neurons. n=3, *P<0.05 compared with control.
Figure 5
Figure 5. Orally supplemented α-tocotrienol protected against stroke via MRP1 upregulation
C57BL/6 mice were orally gavaged with vitamin E-stripped corn oil (n=18) or 50mg α-TCT per kg body weight (n=23) for 13 weeks then MCAO was performed. A, α-TCT supplementation significantly reduced MCAO-induced brain injury (corn oil supplemented mice, n=9; α-TCT supplemented mice, n=10). miR-199a-5p expression was significantly down-regulated (B) while MRP1 mRNA (C) and protein (D) levels were significantly elevated in the stroke affected tissue of α-TCT fed mice (n=3). *P<0.05 compared with corresponding control; §P<0.05 compared with infarct hemisphere of corn oil fed mice.
Figure 6
Figure 6. Orally supplemented α-tocotrienol attenuated MCAO-induced neurodegeneration and lipid peroxidation
A, The abundance of MRP1 positive cells were significantly upregulated in the stroke affected cortex of α-TCT supplemented mice (red-MRP1 protein; blue-DAPI stained nuclei). B, Fluoro-Jade positive neurons were fewer in the infarct hemisphere of α-TCT fed group compared to those at the infarct site of corn oil fed group (green-Fluoro-Jade; blue-DAPI stained nuclei). C, The abundance of 4-HNE-positive cells was lower in infarct hemisphere of α-TCT supplemented mice. Bar(white)=50μm, Bar(black)=20μm. n=3, *P<0.05 compared with corresponding contralateral hemisphere; §P<0.05 compared with infarct hemisphere of corn oil fed mice.
See this image and copyright information in PMC

References

    1. Khanna S, Roy S, Slivka A, Craft TK, Chaki S, Rink C, et al. Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke. 2005;3610:2258–2264. - V体育安卓版 - PMC - PubMed
    1. Sen CK, Khanna S, Roy S, Packer L. Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells. J Biol Chem. 2000;27517:13049–13055. - PubMed
    1. Khanna S, Roy S, Parinandi NL, Maurer M, Sen CK. Characterization of the potent neuroprotective properties of the natural vitamin E alpha-tocotrienol. J Neurochem. 2006;985:1474–1486. - PMC - PubMed
    1. Park HA, Khanna S, Rink C, Gnyawali S, Roy S, Sen CK. Glutathione disulfide induces neural cell death via a 12-lipoxygenase pathway. Cell Death Differ. 2009;168:1167–1179. - PMC - PubMed
    1. Minich T, Riemer J, Schulz JB, Wielinga P, Wijnholds J, Dringen R. The multidrug resistance protein 1 (Mrp1), but not Mrp5, mediates export of glutathione and glutathione disulfide from brain astrocytes. J Neurochem. 2006;972:373–384. - PubMed

"V体育ios版" Publication types

MeSH terms