期刊
PHARMACEUTICS
卷 10, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics10040248
关键词
nanomedicines; luteolin-loaded micelles; cerebral ischemia reperfusion injury; bioavailability; antioxidative stress
资金
- National Natural Science Foundation of China [81274184, 81473337, 81573563]
- China Postdoctoral Science Foundation [2018M631098]
- National Special Fund for the traditional Chinese medicine resources Research in the Public Interest of China [[2017] 66]
- Sichuan Special Funds of Traditional Chinese Medicine [2016C051]
- Sichuan Project of Science and Technology [2014SZ0212]
Oxidative stress and inflammation are important mechanisms of cerebral ischemia reperfusion (IR) injury. Luteolin (Lu), one of the major active components in the classical Tibetan prescription, which has been used in the treatment of cardiovascular diseases since 700 BC, has potential for IR injury therapy. Its hydrophobicity has impeded its further applications. In this study, we first prepared Lu micelles (M-Lu) by self-assembling with an amphiphilic copolymer via the thin film hydration method to improve the dispersion of Lu in water. The obtained M-Lu was about 30 nm, with a narrow particle size distribution, and a 5% (omega/omega) of Lu. The bioavailability of the micelles was further evaluated in vitro and in vivo. Compared to free Lu, M-Lu had a better penetration efficiency, which enhanced its therapeutic effect in IR injury restoration. M-Lu further strengthened the protection of nerve cells through the nuclear factor-kappa-gene binding kappa (NF-kappa B) and mitogen-activated protein kinases (MAPK) pathways and inhibited the apoptosis of cells by adjusting the expression of B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) in the case of oxidative stress damage. M-Lu induced stem cells to differentiate into neuron-like cells to promote the repair and regeneration of neurons. The results of in vivo pharmacodynamics of Lu on occlusion of the middle cerebral artery model further demonstrated that M-Lu better inhibited inflammation and the oxidative stress response by the down-regulation of the inflammatory cytokine, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6, and the up-regulation of the activity of anti-oxidant kinase, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), which further ameliorated the degree of IR injury. The M-Lu could be a new strategy for IR injury therapy.
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