title: Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington's disease.
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.
authors.affiliation: Departament de Biologia Cel·lular, Immunologia Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain ; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Saavedra
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.forename: Helena
authors.initials: H
authors.lastname: Arumí
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez-Navarro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D001344:Autopsy; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D003072:Cognition Disorders / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D006152:Cyclic GMP / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D052248:Nitric Oxide Synthase Type I; D006152:Cyclic GMP
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