We examined whether resveratrol increases insulin-like growth factor-I (IGF-I) production in the hippocampus by stimulating sensory neurons in the gastrointestinal tract, thereby improving cognitive function in mice. Resveratrol increased calcitonin gene-related peptide (CGRP) release from dorsal root ganglion (DRG) neurons isolated from wild-type (WT) mice. Increases in tissue levels of CGRP, IGF-I, and IGF-I mRNA and immunohistochemical expression of IGF-I were observed in the hippocampus at 3 weeks after oral administration of resveratrol in WT mice. Significant enhancement of angiogenesis and neurogenesis was observed in the dentate gyrus of the hippocampus in these animals (P<.01). Improvement of spatial learning in the Morris water maze was observed in WT mice after administration of resveratrol. None of the effects of resveratrol observed in WT mice were seen after resveratrol administration in CGRP-knockout (CGRP(-/-)) mice. Although red wine containing 20 mg/L of resveratrol produced effects similar to those of resveratrol administrationl in WT mice, neither red wine containing 3.1 mg/L of resveratrol nor white wine exhibited such effects in WT mice. Resveratrol was undetectable in the hippocampus of WT mice administered resveratrol and red wine containing 20 mg/L of resveratrol. These observations strongly suggest that resveratrol increases hippocampal IGF-I production via sensory neuron stimulation in the gastrointestinal tract, thereby improving cognitive function in mice.
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