Worldwide, caffeine is among the most commonly used stimulatory substances. Unfortunately, significant caffeine consumption is associated with several adverse effects, ranging from sleep disturbances (including insomnia) to cardiovascular problems. This study investigates whether treatment with the Evodia rutaecarpa aqueous extract (ERAE) from berries and its major molecular component, evodiamine, can reduce the adverse caffeine-induced sleep-related and excitation effects. We combined measurements from the pentobarbital-induced sleep test, the open field test, and the locomotor activity test in mice that had been dosed with caffeine. We found that ERAE and evodiamine administration reduced the degree of caffeine-induced sleep disruption during the sleep test. Additionally, we found that evodiamine significantly inhibits caffeine-induced excitation during the open field test, as well as decreasing hyperlocomotion in the locomotor activity test. Additional in vitro experiments showed that caffeine administration decreased the expression of γ-aminobutyric acid (GABA)A receptor subunits in the mouse hypothalamus. However, evodiamine treatment significantly reversed this expression reduction. Taken together, our results demonstrate that ERAE and its major compound, evodiamine, provide an excellent candidate for the treatment or prevention of caffeine-induced sleep disturbances and excitatory states, and that the mechanism of these beneficial effects acts, at least in part, through the GABAA-ergic system.

Lespedeza bicolor, a traditional herbal medicine widely used in Australia, North America, and Eastern Asia, has various therapeutic effects on inflammation, nephritis, hyperpigmentation, and diuresis. In this study, to evaluate the effects of L. bicolor on cognitive function, we examined whether L. bicolor improved amyloid beta-induced memory impairment and assessed the possible mechanisms in mice. Catechin, rutin, daidzein, luteolin, naringenin, and genistein were identified in the powdered extract of L. bicolor by HPCL-DAD analyses. In behavioral experiments, L. bicolor (25 and 50 mg/kg, p. o.) significantly improved amyloid beta25 – 35 (6 nmol, intracerebroventricular)-induced cognitive dysfunction in the Y-maze, novel recognition, and passive avoidance tests. Our molecular studies showed L. bicolor (25 and 50 mg/kg, p. o.) significantly recovered the reduced glutathione content as well as increased thiobarbituric acid reactive substance and acetylcholinesterase activities in the hippocampus. Furthermore, we found that L. bicolor significantly increased the expression of brain-derived neurotrophic factor, and phospho-Akt, extracellular signal-regulated kinase, and cAMP response element binding caused by amyloid beta25 – 35 in the hippocampus. In conclusion, L. bicolor exerts a potent memory-enhancing effect on cognitive dysfunction induced by amyloid beta25 – 35 in mice.