A novel allosteric PDE4B inhibitor T2409 improves mild cognitive impairment: involvement of cAMP related anti‐inflammatory pathway

Disorders affecting memory and cognition including Alzheimer's disease (AD) affect millions of Americans. Although dozens of compounds have been reported for the treatment of mild cognitive deficits (MCI) in Alzheimer's disease (AD), these drugs have not proven beneficial in ameliorating cognitive impairment in clinic. Phosphodiesterase 4B (PDE4B) plays a crucial role in the mediation of memory due to its primary role in hydrolyzing cyclic adenosine monophosphate (cAMP). However, the development of PDE4B inhibitors is challengeable due to the high conservation of the catalytic site of PDE4, across subtypes, to which classical inhibitors bind. The present study suggested that the newly synthesized allosteric inhibitor of PDE4, T2409, exhibits at least 150-fold PDE4B selectivity. It exhibited low potency in a mouse surrogate model of emesis and nausea, suggesting its low side effects. Chronic treatment of T2409 for 14 days reversed cognitive and memory deficits in the novel object recognition and Morris water maze tests as evidenced by increased discrimination index and reduced the mean latency to platform via decreasing beta amyloid plaques both in the cortex and hippocampus in 8-month-old APP/PS1 mouse model of AD. Further study showed that these effects were related to decreased inflammatory factors, such as IL-6, IL-1β and TNF-α, in the brain, and increased cAMP signaling dependent markers of neuroprotection associated with memory, such as p-CREB and BDNF. These results accelerate the development of highly selective PDE4B inhibitors as novel treatments for illnesses that affect memory and cognitive function, such as AD.