Abstract
The lack of novel cognitive enhancer drugs in the clinic highlights the prediction problems of animal assays. The objective of the current study was to test a putative cognitive enhancer in a rodent cognitive test system with improved translational validity and clinical predictivity. Cognitive profiling was complemented with post mortem proteomic analysis. Twenty-seven male Lister Hooded rats (26 months old) having learned several cognitive tasks were subchronically treated with S-CE-123 (CE-123) in a randomized blind experiment. Rats were sacrificed after the last behavioural procedure and plasma and brains were collected. A label-free quantification approach was used to characterize proteomic changes in the synaptosomal fraction of the prefrontal cortex. CE-123 markedly enhanced motivation which resulted in superior performance in a new-to-learn operant discrimination task and in a cooperation assay of social cognition, and mildly increased impulsivity. The compound did not affect attention, spatial and motor learning. Proteomic quantification revealed 182 protein groups significantly different between treatment groups containing several proteins associated with aging and neurodegeneration. Bioinformatic analysis showed the most relevant clusters delineating synaptic vesicle recycling, synapse organisation and antioxidant activity. The cognitive profile of CE-123 mapped by the test system resembles that of modafinil in the clinic showing the translational validity of the test system. The findings of modulated synaptic systems are paralleling behavioral results and are in line with previous evidence for the role of altered synaptosomal protein groups in mechanisms of cognitive function.
Highlights
The lack of novel cognitive enhancer drugs in the clinic highlights the prediction problems of animal assays
Modafinil is approved as an eugeroic, its cognitive effects have long been studied in healthy v olunteers[1,2,3] as well as in sleep-deprived individuals[2,4] and attention deficit hyperactivity disorder (ADHD) patients[5]
The aim of the study was on one hand the cognitive profiling of CE-123 in aged experienced animals with subsequent proteomic analysis, and on the other hand showing and proposing the utility of the test system described above
Summary
The lack of novel cognitive enhancer drugs in the clinic highlights the prediction problems of animal assays. A complex rat cognitive test system designed to improve the predictivity and translational value of animal studies was used to investigate procognitive effect of CE-123. This population is exposed to a certain intervention impairing their cognitive performance, a “patient population” is created This “patient population” serves as subjects of a clinical trial-like study with a putative cognitive enhancer. Previous results obtained in the m odel[15,16] showed that experienced animals are quite resistant to the impairing interventions This finding adds an important, and so far overlooked aspect to the human relevance of the system. The aim of the study was on one hand the cognitive profiling of CE-123 in aged experienced animals with subsequent proteomic analysis, and on the other hand showing and proposing the utility of the test system described above
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