Abstract
The aim of this study is to fabricate reactive oxygen species (ROS)-sensitive nanoparticles composed of succinyl β-cyclodextrin (bCDsu), memantine and thioketal linkages for application in Alzheimer’s disease, and to investigate the suppression of N-methyl-d-aspartate (NMDA) receptor 1 (NMDAR1) in cells. Thioketal diamine was attached to the carboxyl group of bCDsu to produce thioketal-decorated bCDsu conjugates (bCDsu-thioketal conjugates) and memantine was conjugated with thioketal dicarboxylic acid (memantine-thioketal carboxylic acid conjugates). Memantine-thioketal carboxylic acid conjugates were attached to bCDsu-thioketal conjugates to produce bCDsu-thioketal-memantine (bCDsuMema) conjugates. SH-SY5Y neuroblastoma cells and U87MG cells were used for NMDAR1 protein expression and cellular oxidative stress. Nanoparticles of bCDsuMema conjugates were prepared by means of a dialysis procedure. Nanoparticles of bCDsuMema conjugates had small particle sizes less than 100 nm and their morphology was found to be spherical in transmission electron microscopy observations (TEM). Nanoparticles of bCDsuMema conjugates responded to H2O2 and disintegrated or swelled in aqueous solution. Then, the nanoparticles rapidly released memantine according to the concentration of H2O2. In an in vivo animal imaging study, thioketal-decorated nanoparticles labelled with fluorescent dye such as chlorin e6 (Ce6) showed that the fluorescence intensity was stronger in the brain than in other organs, indicating that bCDsuMema nanoparticles can efficiently target the brain. When cells were exposed to H2O2, the viability of cells was time-dependently decreased. Memantine or bCDsuMema nanoparticles did not practically affect the viability of the cells. Furthermore, a western blot assay showed that the oxidative stress produced in cells using H2O2 increased the expression of NMDAR1 protein in both SH-SY5Y and U87MG cells. Memantine or bCDsuMema nanoparticles efficiently suppressed the NMDAR1 protein, which is deeply associated with Alzheimer’s disease. Fluorescence microscopy also showed that H2O2 treatment induced green fluorescence intensity, which represents intracellular ROS levels. Furthermore, H2O2 treatment increased the red fluorescence intensity, which represents the NMDAR1 protein, i.e., oxidative stress increases the expression of NMDAR1 protein level in both SH-SY5Y and U87MG cells. When memantine or bCDsuMema nanoparticles were treated in cells, the oxidative stress-mediated expression of NMDAR1 protein in cells was significantly decreased, indicating that bCDsuMema nanoparticles have the capacity to suppress NMDAR1 expression in brain cells, which has relevance in terms of applications in Alzheimer’s disease.
Highlights
Oxidative stress in the human body is associated with inflammatory pathways and the progression of various kinds of disease such as cancer, neurodegenerative disease, diabetes and hypertension [1,2,3,4,5,6]
These findings suggested that the viability of SH-SY5Y and U87MG cells was affected by reactive oxygen species (ROS), but not by memantine and bCDsuMema nanoparticles
Cells was suppressed by treatment with memantine or bCDsuMema nanoparticles. These results indicated that bCDsuMema nanoparticles are able to suppress the oxidativestress-induced expression of the NMDAR1 protein in SH-SY5Y neuroblastoma cells or
Summary
Oxidative stress in the human body is associated with inflammatory pathways and the progression of various kinds of disease such as cancer, neurodegenerative disease, diabetes and hypertension [1,2,3,4,5,6]. Oxidative stress derived from elevated levels of ROS can be considered as a biomarker since various molecular receptors including the N-methyl-D-aspartate (NMDA). The NMDA receptors in neuronal and/or brain endothelial cells are known to be upregulated according to the increase in oxidative stress [13,15]. The presence of NMDA receptor upregulation induced by oxidative stress can be used as a biomarker for Alzheimer’s disease [15]. There is no curative option for Alzheimer’s disease up to now and these regimens are still limited to palliative therapy
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