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Title: Regulation of Hippocampal cGMP Levels as a Candidate to Treat Cognitive Deficits in Huntington's Disease
Author: Saavedra, Ana
Giralt Torroella, Albert
Arumí, Helena
Alberch i Vié, Jordi
Pérez Navarro, Esther
Keywords: Corea de Huntington
Teràpia genètica
Experimentació animal
Huntington's chorea
Neural transmission
Gene therapy
Animal experimentation
Issue Date: 5-Sep-2013
Publisher: Public Library of Science (PLoS)
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 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.
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It is part of: PLoS One, 2013, vol. 8, num. 9, p. e73664
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ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Biomedicina)

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