Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

Lulu Pang; Siqing Zhu; Jinqiu Ma; Lin Zhu; Yijing Liu; Ge Ou; Ruiteng Li; Yaxin Wang; Yi Liang; Xu Jin; Lina Du; Yiguang Jin

doi:10.1016/j.apsb.2021.01.014

Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

Acta Pharm Sin B. 2021 Jul;11(7):2031-2047. doi: 10.1016/j.apsb.2021.01.014. Epub 2021 Jan 24.

Authors

Lulu Pang^{1

2}, Siqing Zhu^{1

3}, Jinqiu Ma^{1

2}, Lin Zhu¹, Yijing Liu^{1

2}, Ge Ou^{1

4}, Ruiteng Li^{1

2}, Yaxin Wang⁵, Yi Liang⁵, Xu Jin⁵, Lina Du^{1

2

3}, Yiguang Jin^{1

3}

Affiliations

¹ Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
² College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
³ College of Pharmacy, Anhui Medical University, Hefei 230001, China.
⁴ Pharmacy Department, Chinese PLA General Hospital, Beijing 100853, China.
⁵ Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.

Abstract

Post-traumatic stress disorder (PTSD) is a psychiatric disease that seriously affects brain function. Currently, selective serotonin reuptake inhibitors (SSRIs) are used to treat PTSD clinically but have decreased efficiency and increased side effects. In this study, nasal cannabidiol inclusion complex temperature-sensitive hydrogels (CBD TSGs) were prepared and evaluated to treat PTSD. Mice model of PTSD was established with conditional fear box. CBD TSGs could significantly improve the spontaneous behavior, exploratory spirit and alleviate tension in open field box, relieve anxiety and tension in elevated plus maze, and reduce the freezing time. Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex, amygdala, and hippocampus CA1. CBD TSGs could reduce the level of tumor necrosis factor-α caused by PTSD. Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1A receptor. Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration, as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs. Overall, nasal CBD TSGs are safe and effective and have controlled release. There are a novel promising option for the clinical treatment of PTSD.

Keywords: AUC, area under the curve; BBB, blood‒brain barrier; Blood‒brain barrier; Brain targeting; CBD TSGs, cannabidiol inclusion complex temperature-sensitive hydrogels; CNS, central nervous system; COVID-19, coronavirus disease 2019; Cannabidiol; DSC, differential scanning calorimetry; HP-β-CD, hydroxypropyl-β-cyclodextrin; Hydrogels; Hydroxypropyl-β-cyclodextrin; IR, infrared; IS, internal standard; Inclusion complex; Intranasal administration; MRM, multiple reaction monitoring; PPV, percentage of persistent vibration; PTSD, post-traumatic stress disorder; PVD, persistent vibration duration; Post-traumatic stress disorder; SSRIs, selective serotonin reuptake inhibitors; TNF-α, tumor necrosis factor-α; WB, Western blot.