Pharmacokinetics, Metabolism, Disposition, and Neuropharmacological Mechanisms of Jujuboside A: A Review

Insomnia is a frequently occurring sleep disorder that is associated with a reduced quality of life and a higher risk of neuropsychological, metabolic, and inflammatory diseases. Jujuboside A (JuA), a dammarane-type triterpenoid saponin obtained from Ziziphi Spinosae Semen (Suanzaoren), has shown promise as a therapeutic agent for insomnia. The present review summarizes the available evidence re-garding the pharmacokinetics, metabolism, disposition, sedative-hypnotic activity, and neuroprotective effects of JuA. It is believed that JuA acts as a multi-target agent for both the treatment of insomnia and for providing neuroprotection, even though it has a low oral bioavailability (about 1.32%) and limited ability to penetrate the brain (with a brain-to-plasma ratio of 0.1-0.3). JuA is subject to extensive metab-olism in the intestine and liver, this being performed via the body’s glycosidases and by the gut microbi-ota, and is eliminated via both the biliary and renal routes. The drug seems to influence sleep mainly through GABAergic signaling in the Paraventricular Thalamic Nucleus (PVT), and also impacts the monoaminergic and adenosinergic pathways, the circadian rhythm, mitochondrial function in prefrontal neurons, and gut-brain interactions. The neuroprotective effects involve various pathways including Shh/Gli1/Gli2, P2X7R-BDNF, PI3K/Akt/mTOR, MAPK/ERK, Wnt/β-catenin, and YY1-mediated tran-scriptional regulation. Although the existing evidence points to the therapeutic potential of JuA, more research is still required in order to better understand its pharmacological properties and mechanisms of action. This review aims to outline the pharmacological properties and molecular features of JuA, point out the current research gaps, and suggest possible avenues for the development of therapies based on JuA.