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- Title
Regulation of Hippocampal cGMP Levels as a Candidate to Treat Cognitive Deficits in Huntington’s Disease.
- Authors
Saavedra, Ana; Giralt, Albert; Arumí, Helena; Alberch, Jordi; Pérez-Navarro, Esther
- Abstract
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 HdhQ7/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.
- Subjects
HUNTINGTON disease; GUANOSINE monophosphate phosphodiesterase; COGNITION disorders treatment; HIPPOCAMPUS physiology; NITRIC-oxide synthases; NEUROPLASTICITY; LABORATORY mice; PATIENTS
- Publication
PLoS ONE, 2013, Vol 8, Issue 9, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0073664