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Diosgenin, a yam-derived compound, was found to facilitate the repair of axonal atrophy and synaptic degeneration and improve memory dysfunction in a transgenic mouse model of Alzheimer’s disease (AD). It was also found to enhance neuronal excitation and memory function even in normal mice. We hypothesized that diosgenin, either isolated or in an extract, may represent a new category of cognitive enhancers with essential activities that morphologically and functionally reinforce neuronal networks. This study aimed to investigate the effects of a diosgenin-rich yam extract on cognitive enhancement in healthy volunteers. For this placebo-controlled, randomized, double-blind, crossover study, 28 healthy volunteers (age: 20–81 years) were recruited from Toyama Prefecture, Japan, and was randomly assigned to receive either a yam extract or placebo. Preliminary functional animal experiments indicated that an oil solvent mediated the most efficient distribution of diosgenin into the blood and brain after oral administration, and was a critical factor in the cognitive benefits. Therefore, test samples (placebo and yam extract) were prepared with olive oil and formulated as soft capsules. The intake period was 12 weeks, and a 6-week washout period separated the two crossover intake periods. The Japanese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test was used for neurocognitive assessment, and the adverse effects were monitored through blood testing. Diosgenin-rich yam extract consumption for 12 weeks yielded significant increases in total RBANS score. Among the 12 individual standard cognitive subtests, diosgenin-rich yam extract use significantly improved the semantic fluency. No adverse effects were reported. The diosgenin-rich yam extract treatment appeared to safely enhance cognitive function in healthy adults.

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Animals Male Wistar rats weighing 370-420 g were purchased from Japan SLC (Shizuoka, Japan). They were kept in an animal room at an ambient temperature of 23Ϯ1°C under a 12-h dark-light cycle. Experimental protocols met the "Guidelines for Animal Experimentation" approved by the Japanese Association of Laboratory Animal Science and the Japanese Pharmacological Society.Preparation of Rat Aorta Rats were anesthetized (50 mg/kg i.p. pentobarbital) and sacrificed by cutting their abdominal aorta. Fats and connective tissues were removed from a section of the thoracic aorta, and 3-mm-wide aortic rings were prepared. For an endothelium-free aorta, the endothelial lining of each ring was removed by pressing the ring and rolling it gently onto a filter paper a few times. The endothelium was considered to be intact when relaxation induced by 1 mM of acetylcholine was over 20% of the maximal tension obtained by 60 mM KCl-induced contraction, and the removal of the endothelium was confirmed by the absence of acetylcholine-induced relaxation.Vasodilative Effect of Cinnamaldehyde on Isolated Aortic Rings The aortic rings were mounted on steel hooks in a Magnus chamber (Kishimoto UC-5TD, Kyoto, Japan). One end of the aorta was attached to a force-displacement transducer (Kishimoto UM-203) so that its isometric contraction could be recorded (NEC RECTI-HORIZ-8K, Tokyo, Japan). The baths were filled with 5 ml of Krebs solution containing the following (mM): NaCl 120, KCl 4.7, NaHCO 3 25.0, KH 2 PO 4 1.2, MgSO 4 · 7H 2 O 1.2, CaCl 2 2.5, and glucose 10.0. The solution was maintained at 37°C and bubbled continuously with 5% CO 2 in O 2 at pH 7.4. The rings were equilibrated for 45 min at an initial resting tension of 1 g. During this period, the Krebs solution in the bath was

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