Selective phosphodiesterase (PDE)-4 inhibitors: a novel approach to treating memory deficit?
Phosphodiesterase-4 (PDE4) belongs to an important family of proteins that regulates the intracellular level of cyclic adenosine monophosphate (cAMP). Several lines of evidence indicate that targeting PDE4 with selective inhibitors may offer novel strategies in the treatment of age-related memory impairment and Alzheimer's disease. The rationale for such an approach stems from preclinical studies indicating that PDE4 inhibitors can counteract deficits in long-term memory caused by pharmacological agents, aging or overexpression of mutant forms of human amyloid precursor proteins. In addition to their pro-cognitive and pro-synaptic plasticity properties, PDE4 inhibitors are potent neuroprotective, neuroregenerative and anti-inflammatory agents. Based on the fact that Alzheimer's disease is a progressive neurodegenerative disorder that is characterised by cognitive impairment, and that neuroinflammation is now recognised as a prominent feature in Alzheimer's pathology, we have concluded that targeting PDE4 with selective inhibitors may offer a novel therapy aimed at slowing progression, prevention and, eventually, therapy of Alzheimer's disease.
Neuroscience Discovery Research, Wyeth Research, Monmouth Junction, New Jersey 08852-2718, USA. ghavamia@wyeth.com
Afshin
A
Ghavami
Warren D
WD
Hirst
Thomas J
TJ
Novak
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D003071:Cognition / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy; D009416:Nerve Regeneration / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D009435:Synaptic Transmission / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4