Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington's disease

PLoS One. 2013 Sep 5;8(9):e73664. doi: 10.1371/journal.pone.0073664. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Anxiety / genetics
  • Anxiety / physiopathology
  • Anxiety / prevention & control
  • Autopsy
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology
  • Blotting, Western
  • Cognition Disorders / genetics
  • Cognition Disorders / physiopathology*
  • Cognition Disorders / prevention & control
  • Cyclic GMP / metabolism*
  • Down-Regulation / drug effects
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / physiopathology*
  • Huntington Disease / prevention & control
  • Male
  • Memory / drug effects
  • Memory / physiology*
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Motor Activity / physiology
  • Nitric Oxide Synthase Type I / metabolism
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Piperazines / pharmacology
  • Purines / pharmacology
  • Sildenafil Citrate
  • Sulfones / pharmacology

Substances

  • Phosphodiesterase 5 Inhibitors
  • Piperazines
  • Purines
  • Sulfones
  • Sildenafil Citrate
  • Nitric Oxide Synthase Type I
  • Cyclic GMP

Grants and funding

This work was supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI10/01072 to EP-N), Redes Temáticas de Investigación Cooperativa Sanitaria (grant number RD06/0010/0006), Ministerio de Economia y Competitividad, Spain (SAF2011-29507 to JA), and Generalitat de Catalunya, Spain (2009SGR-00326 to JA). AS and AG and are supported by Ministerio de Economia y Competitividad, Spain (Juan de la Cierva subprograme, JCI-2010-08207 and CAPLE2009-0089, respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.