sildenafil-citrate and Huntington-Disease

The phosphodiesterase-5 inhibitor sildenafil was postulated to reduce the risk for Alzheimer's Disease. Since preclinical data revealed beneficial effects in Huntington's Disease (HD), we now for the first time investigated effects of sildenafil in HD patients using the database ENROLL-HD. We demonstrate beneficial effects on motoric, functional and cognitive capacities in cross-sectional data. Those effects were not explained by underlying fundamental molecular genetic or demographic data. It remains unsolved, if effects are due to behavioral differences or due to direct dose-dependent neurobiological modulations.

Topics: Alzheimer Disease; Cross-Sectional Studies; Humans; Huntington Disease; Sildenafil Citrate

Huntington's disease (HD) patients and mouse models show learning and memory impairment associated with hippocampal dysfunction. The neuronal nitric oxide synthase/3',5'-cyclic guanosine monophosphate (nNOS/cGMP) pathway is implicated in synaptic plasticity, and in learning and memory processes. Here, we examined the nNOS/cGMP pathway in the hippocampus of HD mice to determine whether it can be a good therapeutic target for cognitive improvement in HD. We analyzed hippocampal nNOS and phosphodiesterase (PDE) 5 and 9 levels in R6/1 mice, and cGMP levels in the hippocampus of R6/1, R6/2 and Hdh(Q7/Q111) mice, and of HD patients. We also investigated whether sildenafil, a PDE5 inhibitor, could improve cognitive deficits in R6/1 mice. We found that hippocampal cGMP levels were 3-fold lower in 12-week-old R6/1 mice, when they show deficits in object recognition memory and in passive avoidance learning. Consistent with hippocampal cGMP levels, nNOS levels were down-regulated, while there were no changes in the levels of PDE5 and PDE9 in R6/1 mice. A single intraperitoneal injection of sildenafil (3 mg/Kg) immediately after training increased cGMP levels, and improved memory in R6/1 mice, as assessed by using the novel object recognition and the passive avoidance test. Importantly, cGMP levels were also reduced in R6/2 mouse and human HD hippocampus. Therefore, the regulation of hippocampal cGMP levels can be a suitable treatment for cognitive impairment in HD.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anxiety; Autopsy; Avoidance Learning; Blotting, Western; Cognition Disorders; Cyclic GMP; Down-Regulation; Female; Hippocampus; Humans; Huntington Disease; Male; Memory; Mice; Mice, Transgenic; Middle Aged; Motor Activity; Nitric Oxide Synthase Type I; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones