Osthole/borneol thermosensitive gel via intranasal administration enhances intracerebral bioavailability to improve cognitive impairment in APP/PS1 transgenic mice

Fanchang Wu; Mingjun Huang; Xue Zuo; Ruiye Xie; Jinman Liu; Junyu Ke; Weirong Li; Qi Wang; Yong Liang

doi:10.3389/fphar.2023.1224856

Osthole/borneol thermosensitive gel via intranasal administration enhances intracerebral bioavailability to improve cognitive impairment in APP/PS1 transgenic mice

Front Pharmacol. 2023 Jul 13:14:1224856. doi: 10.3389/fphar.2023.1224856. eCollection 2023.

Authors

Fanchang Wu^{1

2}, Mingjun Huang^{1

2}, Xue Zuo^{1

2}, Ruiye Xie^{1

2}, Jinman Liu³, Junyu Ke⁴, Weirong Li^{1

2}, Qi Wang^{1

2}, Yong Liang^{1

2}

Affiliations

¹ Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
² Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China.
³ Affiliated Jiangmen TCM Hospital of Jinan University, Jiangmen, China.
⁴ School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.

Abstract

Alzheimer's disease (AD) poses a significant threat to the global elderly population. Traditional Chinese medicine (TCM) has been widely utilized in the treatment of AD. Osthole, a bioactive ingredient classified as an "emperor" in many TCM formulas, has been demonstrated to effectively alleviate AD symptoms. However, its low bioavailability in the brain has limited its clinical application. This study aimed to increase the intracerebral bioavailability of osthole by using borneol as a "courier," based on the classical "Emperor-Minister-Assistant-Courier" model, and to investigate the enhanced pharmacological performance of osthole on AD. Results indicated that a suitable in situ thermosensitive gel matrix for intranasal administration mixed with osthole and borneol consists of P407 at 20%, P188 at 7%, and PEG300 at 6%. The concentration of osthole in the cerebrospinal fluid increased almost tenfold after intranasal administration of osthole/borneol compared to oral administration. Mechanisms showed that borneol as a "courier" opened up intercellular space and loosened the tight junctions of the nasal mucosa by suppressing ZO-1 and occludin expression, thereby expediting the nose-to-brain route and guiding osthole as "emperor" to its target in the brain. Osthole assisted by borneol demonstrated significantly improved efficiency in suppressing cleaved caspase-3 expression, increasing the Bcl-2/Bax ratio, improving T-SOD and catalase expression, reducing malondialdehyde levels, inhibiting neuron apoptosis, and decreasing Aβ levels by inhibiting BACE1 expression to alleviate cognitive impairment in APP/PS1 mice compared to osthole alone. Overall, our study demonstrated that the intracerebral bioavailability of osthole profoundly improved with intranasal administration of osthole/borneol and provided a wider application of TCM for AD treatment with higher intracerebral bioavailability.

Keywords: APP/PS1 mice; bioavailability; borneol; intranasal administration; osthole; thermosensitive gel.

Grants and funding

This work was supported by the National Natural Science Foundation of China (Nos 81973918, 21904110, and 82074505) and the Science and Technology Program of Guangzhou (No. 202201011195).