The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling.

// Gang Wang 1 , Ling Chen 1 , Xiaoyu Pan 2 , Jiechun Chen 3 , Liqun Wang 4 , Weijie Wang 5 , Ruochuan Cheng 2 , Fan Wu 6 , Xiaoqing Feng 4 , Yingcong Yu 6 , Han-Ting Zhang 7 , James M. O’Donnell 5 and Ying Xu 5 1 Department of Clinical Pharmacy, Hangzhou First People’s Hospital, Hangzhou, Zhejiang Province, China 2 Department of Thyroid Surgery, Kunming Medical University Affiliated First People’s Hospital, Kunming, Yunnan Province, China 3 Department of Neurology, Lianyungang Second People’s Hospital, Lianyungang, Jiangsu Province, China 4 School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, Jiangsu Province, China 5 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America 6 Brain Institute, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang Province, China 7 Department of Behavioral Medicine and Psychiatry, West Virginia University, Morgantown, West Virginia, United States of America Correspondence to: Gang Wang, email: // Ying Xu, email: // Keywords : resveratrol; beta amyloid peptide; learning and memory; PDE4; apoptosis; Gerotarget Received : November 18, 2015 Accepted : February 21, 2016 Published : March 13, 2016 Abstract Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer’s disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol’s effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling.