Abstract
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% (w/w) 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-κ-gene binding κ (NF-κB) 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)-α, interleukin (IL)-1β, 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.
Highlights
Cerebral ischemia reperfusion (IR) injury generally causes permanent deterioration of the central nervous system (CNS), which is a main cause of death and the most common neurological disease resulting in long-term disability worldwide [1,2,3]
Based on the many reports and our previous study, Lu is a natural flavone with neuroprotective effects, which is one of the main active components in the traditional formulation that has been used for the treatment of cardiovascular diseases including IR injury
Under transmission electron microscopy (TEM) (Figure 2B), the morphology of M-Lu was observed as homogeneous spheroid, and the observed size was consistent with the measurements
Summary
A large number of studies indicated that some pathological features are associated with IR injury, including the production of radical oxygen species, calcium overload, energy failure, cell apoptosis, and inflammatory reaction. They precipitate the reduction in neuronal death and neurological dysfunction [4,5,6]. Among these pathological mediators, inflammation and oxidative stress play important roles in the pathogenesis of IR injury [7,8]. Ginrojuwryin. gGerxopweriinmgenextapleervimideenntcael ienvdidiceanteces tihndatictahtesfathilautrethoef fmaielutareboolficmretaacbtioolnicsrdeuacrtiinognsIRduleraindgs ItRo tlheaedesletvoatthioeneloefvraatidoincaolforxaydgiceanl sopxeycgiesn(sRpOecSi)e,sw(hRiOchS)f,uwrthiecrhinfudrutcheesr oinxidduacteivseodxaidmaatigvee [d1a1,m12a]g.eA[s11a,1re2s]u. lAt,sinaflraemsumlta, tionrfylarmesmpaotnosrey arnesdpoxnisdeaatinvde sotxreidssatciovme mstroenslsycpormomotnelyapporpotmosoitseoafpthope tnoesrisveocf etlhlseannedrvpeercmelalsneanntdlypdearmagnenthtley
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