The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP Levels in hippocampal slices

Rutten, Kris; Vente, Jan de; Şık, Ayhan; Ittersum, Marjanne Markerink‐van; Prickaerts, Jos; Blokland, Arjan

doi:10.1016/j.bbr.2005.04.021

Cited by 107 publications

(68 citation statements)

References 21 publications

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“…The function of this pathway in hippocampus modulates long-term potentiation and spatial learning in the Morris water maze or object recognition. 24 The ability to learn a Y-maze conditional discrimination task is also modulated by the function of the glutamate-NO-cGMP pathway function in cerebellum. This was shown by Yamada et al 25 who showed that blocking NMDA receptors or inhibiting nitric oxide synthase impaired memory in a Y-maze in mice.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMP Pathway and Extracellular GABA in Cerebellum and Learning and Motor Coordination in Hyperammonemic Rats

González-Usano

Cauli

Agustí

et al. 2013

ACS Chem. Neurosci.

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Around 40% of cirrhotic patients show minimal hepatic encephalopathy (MHE), with mild cognitive impairment which reduces their quality of life and life span. Treatment of MHE is unsatisfactory, and there are no specific treatments for the neurological alterations in MHE. Hyperammonemia is the main contributor to neurological alterations in MHE. New agents acting on molecular targets involved in brain mechanisms leading to neurological alterations are needed to treat MHE. Chronic hyperammonemia impairs learning of a Y-maze task by impairing the glutamate-nitric-oxide (NO)-cGMP pathway in cerebellum, in part by enhancing GABA A receptor activation, which also induces motor in-coordination. Acute pregnenolone sulfate (PregS) restores the glutamate-NO-cGMP pathway in hyperammonemic rats. This work aimed to assess whether chronic treatment of hyperammonemic rats with PregS restores (1) motor coordination; (2) extracellular GABA in cerebellum; (3) learning of the Ymaze task; (4) the glutamate-NO-cGMP pathway in cerebellum. Chronic intracerebral administration of PregS normalizes motor coordination likely due to extracellular GABA reduction. PregS restores learning ability by restoring the glutamate-NO-cGMP pathway, likely due to both enhanced NMDA receptor activation and reduced GABA A receptor activation. Similar treatments would improve cognitive and motor alterations in patients with MHE.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMP Pathway and Extracellular GABA in Cerebellum and Learning and Motor Coordination in Hyperammonemic Rats

González-Usano

Cauli

Agustí

et al. 2013

ACS Chem. Neurosci.

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“…In addition, PDEs may be targeted for cognitive enhancement, and inhibitors of PDEs have proven to be useful experimental tools in exploring mechanisms of learning and memory Prickaerts et al, 2004). Selective PDE inhibitors of at least five types, inhibitors of PDE2 (Boess et al, 2004;Rutten et al, 2007b), PDE4 (Barad et al, 1998;Rutten et al, 2006), PDE5 (Devan et al, 2004;Rutten et al, 2005), and PDE9 (van der Staay et al, 2008) have all been shown to enhance memory in different behavioral paradigms and in different species (for review see Reneerkens et al, 2009). This study investigated the effects of PDE inhibition on spatial memory in the OLT.…”

Section: Discussionmentioning

confidence: 99%

“…PDE inhibitors present a novel therapeutic approach with which to arrest cognitive decline (Gong et al, 2004;Vitolo et al, 2002) or possibly reverse the decline with cognition enhancement Halene and Siegel 2007;Menniti et al, 2006;Rutten et al, 2008). Three promising targets through which memory improvement may be effected are cAMP-selective PDE4 (Barad et al, 1998;Rose et al, 2005;Rutten et al, 2007a;Zhang et al, 2005); cGMP-selective PDE5 (Prickaerts et al, 2004;Rutten et al, 2005); and PDE2, which hydrolyzes both cAMP and cGMP (Boess et al, 2004;Rutten et al, 2007b;Van Donkelaar et al, 2008). Evidence is accumulating that second messenger molecules, cGMP and cAMP, are important in memory processes in general and long-term potentiation in particular (Bach et al, 1999;Bernabeu et al, 1996;Bourtchouladze et al, 1998;Frey et al, 1993;Lu et al, 1999;Prickaerts et al, 2002a;Son et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

Rutten

Donkelaar

Ferrington

et al. 2009

Neuropsychopharmacol

112

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Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [ 14 C]-iodoantipyrine and [ 14 C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60-7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.

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“…Involvement of PDE5 in many other processes continues to be a major point of interest to the scientific and medical communities (Rutten et al, 2005;Burnett et al, 2006;Heymann, 2006;Sandner et al, 2007). The K m of the PDE5 catalytic site for cGMP is 2 to 5 M, and the k cat is ϳ4.3 s Ϫ1 .…”

Section: Isoenzymementioning

confidence: 99%

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

2010

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The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP Levels in hippocampal slices

Cited by 107 publications

References 21 publications

Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMP Pathway and Extracellular GABA in Cerebellum and Learning and Motor Coordination in Hyperammonemic Rats

Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMP Pathway and Extracellular GABA in Cerebellum and Learning and Motor Coordination in Hyperammonemic Rats

Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

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