Diabetic Theory in Anti-Alzheimer’s Drug Research and Development. Part 2: Therapeutic Potential of cAMP-Specific Phosphodiesterase Inhibitors

Alzheimer's disease (AD) is one of the most prevalent age-related neurodegenerative disease that affects the cognition, behavior, and daily activities of individuals. Studies indicate that this disease is characterized by several pathological mechanisms, including the accumulation of amyloid-beta peptide, hyperphosphorylation of tau protein, impairment of cholinergic neurotransmission, and increase in inflammatory responses within the central nervous system. Chronic neuroinflammation associated with AD is closely related to disturbances in metabolic processes, including insulin release and glucose metabolism. As AD is also called type III diabetes, diverse compounds having antidiabetic effects have been investigated as potential drugs for its symptomatic and disease-modifying treatment. In addition to insulin and oral antidiabetic drugs, scientific attention has been paid to cyclic-3',5'-adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) inhibitors that can modulate the concentration of glucose and related hormones and exert beneficial effects on memory, mood, and emotional processing. In this review, we present the most recent reports focusing on the involvement of cAMP-specific PDE4, PDE7, and PDE8 in glycemic and inflammatory response controls as well as the potential utility of the PDE inhibitors in the treatment of AD. Besides the results of in vitro and in vivo studies, the review also presents recent reports from clinical trials.