Intracerebroventricular streptozotocin-induced Alzheimer's disease-like sleep disorders in rats: Role of the GABAergic system in the parabrachial complex.

AIM: Sleep disorders are common in Alzheimer's disease (AD) and assumed to directly influence cognitive function and disease progression. This study evaluated sleep characteristics in a rat model of AD that was induced by intracerebroventricular streptozotocin (STZ) administration and assessed the possible underlying mechanisms. METHODS: Cognition ability was assessed in the Morris water maze in rats. Sleep parameters were analyzed by electroencephalographic and electromyographic recordings. Neuronal activity in brain areas that regulate sleep-wake states was evaluated by double-staining immunohistochemistry. High-performance liquid chromatography with electrochemical detection was used to detect neurotransmitter levels. RESULTS: Fourteen days after the STZ injection, the rats exhibited sleep disorders that were similar to those in AD patients, reflected by a significant increase in wakefulness and decreases in nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. The c-Fos expression analysis indicated that neuronal activity and the number of neurons in the dorsal raphe nucleus and locus coeruleus decreased in STZ-injected rats. In the ventrolateral preoptic nucleus (VLPO), the activity of γ-aminobutyric acid (GABA) neurons was suppressed. In the arousal-driving parabrachial nucleus (PBN), GABAergic activity was suppressed, whereas glutamatergic activity was promoted. The neurotransmitter analysis revealed a reduction in GABA in the VLPO and PBN and elevation of glutamate in the PBN. A direct injection of the GABAA receptor antagonist bicuculline in the PBN in normal rats induced a similar pattern of sleep disorder as in STZ-injected rats. A microinjection of GABA in the PBN improved sleep disorders that were induced by STZ. CONCLUSION: These results suggest that the reduction in GABAergic inhibition in the PBN and VLPO may be involved in sleep disorders that are induced by STZ. Our novel findings encourage further studies that investigate mechanisms of sleep regulation in sporadic AD.

[Absorption enhancing effects and safety of PAMAM dendrimers on liquiritin].

PAMAM dendrimer is one of the most widely studied dendrimers in recent years, which has a large number of functional groups on the surface and cavities inside, specific three-dimensional structure and good biocompatibility, permeability and stability. It has been widely applied in drug and gene carrier fields and may become a new absorption enhancer. In order to study the absorption enhancing effects of PAMAM dendrimers, liquiritin was selected as the model drug, with the protection of spleen and liver, detoxification and other functions, but it had not been widely used in clinical application because of its difficult absorption, first pass effect, and low bioavailability. This topic was based on the two main determinants (solubility and permeability) of intestinal absorption in the body, researched the physicochemical properties of liquiritin, analyzed the transport volume of liquiritin with or without PAMAM dendrimers by using Caco-2 cell model, and analyzed the cytotoxicity of PAMAM dendrimers on Caco-2 cells by MTT experiments. These results showed that 0.1% of the G4 generation PAG can promote the absorption of liquiritin safely and effectively, and it was suitable for further development into a new type of pharmaceutical excipients.

[Application of magnetic iron oxide nanoparticles in magnetic resonance / photothermal dual-modal imaging].

In this study, water-dispersible magnetic iron oxide (Fe3O4) nanoparticles were synthesized with solvothermal method. The nanoparticles were characterized with a transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). The in vitro magnetic resonance response and photothermal conversion characteristics of the nanoparticles were evaluated. In addition, the cellular uptake, cytotoxicity and biodistribution were studied. Finally, magnetic resonance/photothermal dual-modal imaging effect of the as-synthesized Fe3O4 nanoparticles was investigated in the tumor-bearing mice. The results showed that the obtained magnetic nanoparticles were uniform with a mean diameter of about 125 nm. Moreover, the superparamagnetic Fe3O4 nanoparticles showed remarkable magnetic resonance response and photothermal conversion properties. The results of cellular experiments showed that the cell viability was nearly 85% even the concentration of the nanoparticles was up to 1 000 µg·mL−1, an indicator of good biocompatibility. In addition, the nanoparticles could be taken up by the tumor cells and then located in the cytoplasm. After intravenous injection, the nanoparticles were tended to enrich in the tumor over time, which is helpful in achieving dual-modal magnetic resonance/photothermal imaging. In sum, the obtained Fe 3O4 nanoparticles showed great potential to be applied for multi-modal bio-imaging which may play an important role in the diagnosis of tumors.

[Preparation and in vitro evaluation of doxorubicin-loaded magnetic iron oxide nanoparticles].

PEG-modified magnetic Fe3O4 (Fe3O4-PEG) nanoparticles were sythesized using a solvothermal reaction and characterized with transmission electron microscopy (TEM) and thermo gravimetric analysis (TGA). The photothermal effect and photothermal destruction of cancer cells were evaluated. Then the doxorubicin loaded Fe3O4-PEG (DOX-Fe3O4-PEG) nanoparticles were prepared. The cytotoxicity and combined chemotherapy/photothermal therapy (PTT) effect were investigated. Uniform PEG coated Fe3O4 nanoparticles with particle size of 155 nm were obtained in the experiment. The loading and release of doxorubicin on Fe3O4-PEG were pH-dependent. The drug loading capacity in water was 21%. The results of MTT indicated a good biocompatiblity of Fe3O4-PEG nanoparticles and high cytotoxicity of DOX-Fe3O4-PEG. In combined therapy experiment, photothermal therapy demonstrated unambiguously enhanced chemotherapy efficacy. In conclusion, the obtained Fe3O4-PEG nanoparticles which exhibit good photothermal effect and drug loading capacity can be used for chemotherapy and photothermal therapy. The synergetic anti-tumor activity indicates the potential for the combined application of chemotherapy and photothermal therapy in cancer treatment.

Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo.

AIM: To formulate proliposomes with a polyphase dispersed system composed of soybean phospholipids, cholesterol, isopropyl myristate and sodium cholate to improve the oral bioavailability of dehydrosilymarin, an oxidized form of herbal drug silymarin. METHODS: Dehydrosilymarin was synthesized from air oxidation of silymarin in the presence of pyridine, and proliposomes were prepared by a film dispersion-freeze drying method. Morphological characterization of proliposomes was observed using a transmission electron microscope. Particle size and encapsulation efficiency of proliposomes were measured. The in vitro release of dehydrosilymarin from suspension and proliposomes was evaluated. The oral bioavailability of dehydrosilymarin suspension and proliposomes was investigated in rabbits. RESULTS: The proliposomes prepared under the optimum conditions were spherical and smooth with a mean particle size in the range of 7 to 50 nm. Encapsulation efficiency was 81.59%±0.24%. The in vitro accumulative release percent of dehydrosilymarinloaded proliposomes was stable, which was slow in pH 1.2, and increased continuously in pH 6.8, and finally reached 86.41% at 12 h. After oral administration in rabbits, the relative bioavailability of proliposomes versus suspension in rabbits was 228.85%. CONCLUSION: Proliposomes may be a useful vehicle for oral delivery of dehydrosilymarin, a drug poorly soluble in water.

[Preparation and evaluation of enteric-coated and taste masking clarithromycin granules].

The study is to prepare taste masking and enteric-coated clarithromycin granules by melting and fluid bed coating technology. Clarithromycin and matrix materials were melted at a certain temperature, and then made into particles by fluidized bed coating. X-ray powder diffraction and scanning electron microscopy were used to identify the crystal and morphology of drug loading granules. In vitro dissolution method was used for the observation of the drug release behavior. The results showed that the drug particles size range was 0.2 - 0.6 mm; the crystal form of clarithromycin in the granule did not change; enteric-coated granules accumulated release in 0.1 mol L(-1) hydrochloric acid in 2 h was less than 10%, while in pH 6.8 phosphate buffer in 1 h was more than 80%. The taste masking and enteric-coated clarithromycin granules not only have good taste masking effect, but also have a good release behavior. It is expected to have better clinical application.