Response to comment: ‘‘A note on the relevance of [6]-gingerol for the prevention and/or treatment of Alzheimer’s disease’’

Abstract

We gratefully appreciate Dr. Wiart for the careful review on our article entitled ‘[6]-Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system’ (Lee et al., 2011). We absolutely agree that [6]-gingerol is very rapidly cleared from the plasma and heavily metabolized to (S)-[6]-gingerol-4’-O-β-glucuronide, vanillic acid, ferulic acid, (S)-(+)-4-hydroxy-6-oxo-8-(4-hydroxy-3-methoxyphenyl) octanoic acid, 4-(4-hydroxy-3-methoxyphenyl) butanoic acid, 9-hydroxy [6]-gingerol, (S)-(+)-[6]-gingerol, and gingerdiol after oral administration ( Nakazawa and Ohsawa, 2002). However, [6]-gingerol (Lee et al., 2011) and its metabolites such as vanillin (Kim et al., 2007) and ferulic acid (Perluigi et al., 2006) exhibited neuroprotective properties in vitro cell culture or in vivo animal models of neurological disorders. In addition, Bhattarai et al. suggested a possibility of inter-conversion between [6]-gingerol and [6]-shogaol in simulated gastric fluid ( Bhattarai et al., 2007) and [6]-shogaol was reported to have neuroprotective effect via inhibiting microglia-mediated neuroinflammation (Ha et al., 2012). Although we argue that [6]-gingerol may not directly exert pharmacological activities after oral administration under certain physiological conditions, there are still possibilities that [6]-gingerol can reach its site of action in the body with being less biotransformed (for instance, hydroxylation and/or glucuronide- and sulfate-conjugation) by using different route of administration and that [6]-gingerol is readily distributed to other tissues. Jiang et al. suggested that [6]-gingerol has small molecular size, good lipophilicity and a high oil/water partition coefficient, which make it well distributed to other tissues including brain as indicated by tissue to plasma ratios being greater than 1 (Jiang et al., 2008). Furthermore, based on our recent findings (unpublished data), in the experimental animal models of amnesia caused by scopolamine and Alzheimer’s disease (AD) induced by β-amyloid, oral administration of [6]-gingerol significantly improved memory impairments as assessed by diverse behavior studies including Y-maze, Morris water maze, passive avoidance and fear conditioning tests. Therefore, we would like to reaffirm that ‘[6]-Gingerol exhibited neuroprotective effect against β-amyloid-induced oxidative cell death particularly in vitro SH-SY5Y cell cultures via fortifying cellular antioxidant defense system thereby having preventive and therapeutic potentials for the prevention and/or treatment of AD’. To this end, we look forward to learning more about the memory enhancing activities of [6]-gingerol or its metabolites and their underlying molecular mechanisms in preclinical as well as clinical conditions.