The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents

Abstract

The present study investigated the putative pro-cognitive effects of the novel selective PDE9 inhibitor BAY 73-6691. The effects on basal synaptic transmission and long-term potentiation (LTP) were investigated in rat hippocampal slices. Pro-cognitive effects were assessed in a series of learning and memory tasks using rodents as subjects. BAY 73-6691 had no effect on basal synaptic transmission in hippocampal slices prepared from young adult (7- to 8-week-old) Wistar rats. A dose of 10 microM, but not 30 microM, BAY 73-6691 enhanced early LTP after weak tetanic stimulation. The dose effective in young adult Wistar rats did not affect LTP in hippocampal slices prepared from young (7- to 8-week-old) Fischer 344 X Brown Norway (FBNF1) rats, probably reflecting strain differences. However, it increased basal synaptic transmission and enhanced early LTP after weak tetanic stimulation in hippocampal slices prepared from very old (31- to 35-month-old) FBNF1 rats. BAY 73-6691 enhanced acquisition, consolidation, and retention of long-term memory (LTM) in a social recognition task and tended to enhance LTM in an object recognition task. Bay 73-6691 attenuated the scoplamine-induced retention deficit in a passive avoidance task, and the MK-801-induced short-term memory deficits in a T-maze alternation task. The mechanism of action, possibly through modulation of the NO/cGMP-PKG/CREB pathway, is discussed. Our findings support the notion that PDE9 inhibition may be a novel target for treating memory deficits that are associated with aging and neurodegenerative disorders such as Alzheimer's disease.

Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system

“…In fact, aging process has been associated with an increase in PDE expression and activity and a decrease in cyclic GMP concentration (for review, see Domek-Łopacińska and Strosznajder 2010). This notion is in agreement with data indicating that inhibitors of PDE2 and PDE9 improve learning and memory in older rats (van der Staay et al 2008) as well as in rat model of hepatic encephalopathy Cauli et al 2010).…”

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

“…NO-mediated increases in cGMP and PKG activation are reported to increase mitochondrial biogenesis and abundance of the uncoupling protein in brown fat (Haas et al, 2009). PKGI-mediated regulation of gene expression and protein levels is implicated in 542 some models of neuronal plasticity and learning, as well as in pathological conditions such as Alzheimer's disease and schizophrenia (Monfort et al, 2002;Monfort and Felipo, 2005;van der Staay et al, 2008;Nugent et al, 2009).…”

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

“…9,17,36 Pfizer has developed PF-4447943 (10), a potent, selective, and brain-penetrant PDE9A inhibitor (logBB = −0.4, IC 50 = 12 nM) that increases brain levels of cGMP in vivo 88 and that is 78 times more selective for PDE9A than for other PDE family members (tested on all isoforms and some splice variants, 17 in total). 153 The in vivo effects of PDE9A inhibitors suggest a role for this enzyme in the regulation of monoaminergic circuits associated with sensory processing and memory.…”

“…35 Moreover, in several animals models, beneficial effects of PDE9 inhibitors have been reported on cognitive function, which appear to be mediated by increased levels of this second messenger. 36 Only one gene (PDE10A) has been identified for PDE10, although four variants may be generated.…”