Oleanolic Acid Cubic Liquid Crystal Nanoparticle-Based Thermosensitive Gel Attenuates Depression Symptoms in Chronic Unpredictable Mild Stress Rats.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-02-01 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S484567

Zhiqi Shi, Qing Wang, Qing Li, Fan Jia, Weifeng Xu

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引用次数: 0

Abstract

Purpose: Major depressive disorder (MDD) is a global health concern. Studies have demonstrated that oleanolic acid (OA) has a regulatory effect on MDD. However, OA is poorly soluble, has low oral bioavailability, and faces challenges in crossing the blood-brain barrier. In this study, building upon a previous formulation of OA cubic liquid crystal nanoparticles (OA-LCNP), we combined nanoparticles with a thermosensitive gel for nasal administration and investigated the pharmacological effects of OA-LCNP thermosensitive gel (OANG) on depression. This study aimed to evaluate the effects of OANG on depression symptoms in rats.

Methods: OANG was prepared using Poloxamer F127 and F68 as the gel matrix, and the ratios of F127 and F68 were investigated. The pharmacokinetics of OANG was studied in rats, and OA content was determined using liquid chromatography-mass spectrometry (LC-MS). The pharmacological effects of OANG on depression were evaluated in chronic unpredictable mild stress (CUMS) model rats.

Results: The phase transition temperature of the gel was 34°C, and the release of OA from OANG was slow according to the Higuchi kinetic equation. The AUC_0-t of brain tissue after nasal OANG administration was 1.21 times that observed after intravenous administration. Additionally, the brain-targeting efficiency and nasal-brain direct transfer were 29.91% and 9.44% higher, respectively, than those observed after intravenous administration, indicating the brain-targeting capability of the OANG delivery system. Network pharmacological analysis revealed that the anti-depressant effects may be linked to neuroactive ligand-receptor interactions, the PPAR signaling pathway, and efferocytosis signaling pathways. Experimental results from CUMS rats showed that the gel significantly affected interleukin (IL)-4, IL-6, acetylcholinesterase, acetylcholine, 5-hydroxytryptamine, and brain-derived neurotrophic factor, and improved depression-like behavior in rats, as measured by sucrose preference, forced swimming, and box shuttle tests.

Conclusion: The OANG nasal drug delivery system has specific brain-targeting properties and exerts anti-depressant effects.

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公司名称

产品信息

阿拉丁

phytantriol

阿拉丁

Sodium dodecyl sulfate (SDS)

来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.