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2013-09-05

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cc-by (c) Saavedra, A. et al., 2013
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/49179

Regulation of Hippocampal cGMP Levels as a Candidate to Treat Cognitive Deficits in Huntington's Disease

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http://dx.doi.org/10.1371/journal.pone.0073664

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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Corea de Huntington, Neurotransmissió, Teràpia genètica, Experimentació animal

Subject (English)

Huntington's chorea, Neural transmission, Gene therapy, Animal experimentation

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Articles publicats en revistes (Biomedicina)

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SAAVEDRA, Ana, et al. Regulation of Hippocampal cGMP Levels as a Candidate to Treat Cognitive Deficits in Huntington's Disease. PLoS One. 2013. Vol. 8, num. 9, pags. e73664. ISSN 1932-6203. [consulted: 12 of August of 2026]. Available at: https://hdl.handle.net/2445/49179

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