Cilostazol improves cognitive function in mice by increasing the production of insulin-like growth factor-I in the hippocampus

Abstract

Insulin-like growth factor I (IGF-I) exerts beneficial effects on cognitive function by inducing angiogenesis and neurogenesis in the hippocampus. We demonstrated that stimulation of sensory neurons in the gastrointestinal tract increased IGF-I production in the hippocampus, and thereby improved cognitive function in mice. Since cAMP plays a critical role in stimulation of sensory neurons, the type III phosphodiesterase (PDE3) inhibitor cilostazol might increase IGF-I production in the hippocampus by stimulating sensory neurons and thus improve cognitive function in mice. We tested this hypothesis in the present study. Cilostazol increased the release of calcitonin gene-related peptide (CGRP) and levels of cAMP in dorsal root ganglion (DRG) neurons isolated from wild-type (WT) mice. Tissue levels of cAMP in the DRG and hippocampus and those of CGRP, IGF-I, and IGF-I mRNA in the hippocampus were increased after 4-week oral administration of cilostazol to WT mice. Levels of expression of c-fos in the spinal dorsal horns, parabrachial nuclei, the solitary tract nucleus, and the hippocampus were also increased in these animals. Significant enhancement of angiogenesis and neurogenesis was observed in the dentate gyrus of the hippocampus after cilostazol administration in WT mice. Significant improvement of spatial learning was also observed in WT mice administered cilostazol. However, none of these effects in WT mice were observed in CGRP-knockout mice. These observations suggest that cilostazol may improve cognitive function in mice by increasing the hippocampal production of IGF-I through stimulation of sensory neurons.