Modulating nitric oxide signaling in the CNS for Alzheimer's disease therapy.

Nitric oxide (NO)/solube GC (sGC)/cGMP signaling is important for modulating synaptic transmission and plasticity in the hippocampus and cerebral cortex, which are critical for learning and memory. Physiological concentrations of NO also elicit anti-apoptotic/prosurvival effects against various neurotoxic challenges and brain insults through multiple mechanisms. Depression of the NO/sGC pathway is a feature of Alzheimer's disease (AD), attributed to amyloid-β neuropathology, and altered expression and activity of NOS, sGC and PDE enzymes. Different classes of NO-releasing hybrid drugs, including nomethiazoles, NO-NSAIDs and NO-acetylcholinesterase inhibitors were designed to deliver low concentrations of exogenous NO to the CNS while targeting other underlying disease mechanisms, such as excitotoxicity, neuro-inflammation and acetylcholine deficiency, respectively. Incorporating a NO-donating moiety may also reduce gastrointestinal and liver toxicity of the parent drugs. Progress has also been made in targeting downstream sGC and PDE enzymes. The PDE9 inhibitor PF-04447943 has completed Phase II clinical trials for AD. The search for effective NO-donating hybrid drugs, CNS-targeting sGC stimulators/activators and selective PDE inhibitors is an important goal for pharmacotherapy that manipulates NO biochemical pathways involved in cognitive function and neuroprotection. Rigorous preclinical validation of target engagement, and optimization of pharmacokinetic and toxicity profiles are likely to advance more drug candidates into clinical trials for mild cognitive impairment and early stage AD.