Steroid sulfatase inhibitor DU-14 protects spatial memory and synaptic plasticity from disruption by amyloid β protein in male rats

Abstract

Alzheimer's disease (AD) is an age-related mental disorder characterized by progressive loss of memory and multiple cognitive impairments. The overproduction and aggregation of Amyloid β protein (Aβ) in the brain, especially in the hippocampus, are closely involved in the memory loss in the patients with AD. Accumulating evidence indicates that the Aβ-induced imbalance of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in the brain plays an important role in the AD pathogenesis and progression. The level of DHEA is elevated, while DHEAS is dramatically decreased in the AD brain. The present study tried to restore the balance between DHEA and DHEAS by using a non-steroidal sulfatase inhibitor DU-14, which increases endogenous DHEAS through preventing DHEAS converted back into DHEA. We found that: (1) DU-14 effectively attenuated the Aβ1-42-induced cognitive deficits in spatial learning and memory of rats in Morris water maze test; (2) DU-14 prevented Aβ1-42-induced decrease in the cholinergic theta rhythm of hippocampal local field potential (LFP) in the CA1 region; (3) DU-14 protected hippocampal synaptic plasticity against Aβ1-42-induced suppression of long term potentiation (LTP). These results provide evidence for the neuroprotective action of DU-14 against neurotoxic Aβ, suggesting that up-regulation of endogenous DHEAS by DU-14 could be beneficial to the alleviation of Aβ-induced impairments in spatial memory and synaptic plasticity.

A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males

“…Differential behavioral effects in the genetic and pharmacological mouse models could also be explained by complete lack of the STS protein in the deletion model versus incomplete (~70%) inhibition of the enzyme in the pharmacological model (Nicolas et al., 2001), or by deletion of additional genes or genetic elements other than Sts in the genetic model (Trent et al., 2013; Trent, Fry, Ojarikre, & Davies, 2014) and possible off‐target effects in the pharmacological model (Ho et al., 2003). There is a growing body of evidence that pharmacological manipulation of the STS axis can influence the aspects of cognition and the underlying neural substrates (Yue et al., 2016). …”

Recent progress in the development of steroid sulphatase inhibitors – examples of the novel and most promising compounds from the last decade

“…Recently, an interesting in vivo study focussed on a derivative of p-O-sulphamoyl-N-alkanoyl tyramine, namely, DU-14 32 (containing an N-tetradecanoyl chain) ( Figure 6), has been described as a potential treatment method of neurodegenerative disorders (e.g. Alzheimer's disease) in rats 71 . Historically, a series of p-O-sulphamoyl-N-alkanoyl tyramines was synthesised as STS inhibitors by Li et al 72 .…”

“…It has been shown 74 that DU-14 can enhance the reversal of amnesia by DHEAS, suggesting that STS inhibition could promote the memory-enhancing properties of DHEAS. Yue et al 71 reported neuroprotective properties of DU-14 against neurotoxic amyloid b protein (Ab), suggesting that upregulation of endogenous DHEAS by DU-14 may be responsible for a beneficial alleviation of impairments in spatial memory and synaptic plasticity induced by Ab in rats.…”

A new molecular risk pathway for postpartum mood disorders: clues from steroid sulfatase–deficient individuals

“…Work in male rodents has shown that deletion of the Sts gene, or acute inhibition of the STS enzyme, is associated with numerous behavioural phenotypes including inattention, anxiety-related behaviours, aggression, perseveration, learning and enhanced memory, and behavioural inhibition (Johnson et al 2000 ; Nicolas et al 2001 ; Davies et al 2009 ; Trent et al 2012b ; Babalola et al 2012 ; Trent et al 2013 ; Davies et al 2014 ); these phenotypes may be partially related to serotonergic and cholinergic differences in the hippocampus (Trent et al 2012a ; Trent et al 2013 ; Yue et al 2016 ). In both rodents and humans, the quality of maternal behaviours is related to maternal executive function (notably offspring-related learning and memory processes, attention to relevant care cues, behavioural flexibility, and impulse regulation) mediated by cholinergic, GABAergic, and serotonergic processes (Davies 2018 ).…”