Development and in vivo Evaluation of Hydroxy-α-Sanshool Intranasal Liposomes as a Potential Remedial Treatment for Alzheimer’s Disease

Hydroxy-α-sanshool (HAS) improves cognitive dysfunction, but its structural instability has limited its clinical application. The present study was conducted to investigate the optimal formulation of hydroxy-α-sanshool liposomes (HAS-LPs) and its effect on ameliorating learning and memory disorders in an Alzheimer's disease (AD) model.In this study, HAS was prepared as HAS-LP using a thin film dispersion method. After selecting the optimal preparation conditions, HAS-LP was characterized using transmission electron microscopy (TEM) and by measuring the zeta potential, particle size, and in vitro drug release. Next, evaluated the effect of HAS-LP on the rat nasal mucosa and then applied it to AD mice. By performing behaviour experiments, pathological test and related pharmacokinetic parameters, we explored its effect on attenuating learning and memory impairment in mice.When the mass ratio of HAS:cholesterol:soybean lecithin was 1:4:16 and 15 mL of ultrapure water were added, the highest encapsulation efficiency and drug loading were obtained. HAS-LP had a particle size of 181.77 nm, a polydispersity index of 0.207 and a zeta potential of -53.8 mV, and it remained stable at 25 °C for 1 week and 4 °C for 8 weeks. Moreover, HAS-LP exhibited slow drug release and was highly consistent with the Higuchi release model. HAS-LP was not significantly toxic to the nasal mucosa and effectively alleviated D-galactose-induced learning memory deficits and protected mouse hippocampal neuronal cells. HAS-LP was highly enriched in plasma and brain tissue after administration via the nasal route and obtained some ability to target the brain.HAS encapsulated in soybean lecithin and cholesterol was successfully developed, suggesting that treatment with the nanoparticles might reverse some AD symptoms. Therefore, these nanoparticles might be used as promising new candidates for the delivery of HAS to treat AD.