Cognitive profiling and proteomic analysis of the modafinil analogue S-CE-123 in experienced aged rats

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 profi...

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Published inScientific reports Vol. 11; no. 1; p. 23962
Main Authors Gyertyán, István, Lubec, Jana, Ernyey, Alíz Judit, Gerner, Christopher, Kassai, Ferenc, Kalaba, Predrag, Kozma, Kata, Cobankovic, Iva, Brenner, Gábor, Wackerlig, Judith, Franschitz, Eva, Urban, Ernst, Langer, Thierry, Malikovic, Jovana, Lubec, Gert
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 14.12.2021
Nature Publishing Group
Nature Portfolio
Subjects
631/154/436
631/378/1595
631/378/1689/132
631/45/475
Aging
Aging - metabolism
Animals
Antioxidants
Benzhydryl Compounds - pharmacology
Cognition - drug effects
Cognitive ability
Cognitive enhancement
Humanities and Social Sciences
Impulsive behavior
Learning - drug effects
Male
Modafinil
Modafinil - analogs & derivatives
Modafinil - pharmacology
Motivation
Motor skill learning
multidisciplinary
Neurodegeneration
Operant conditioning
Prefrontal cortex
Prefrontal Cortex - metabolism
Proteomics
Rats
Science
Science (multidisciplinary)
Social interactions
Spatial discrimination learning
Test systems
Translation
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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.
AbstractList 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.
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.
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.
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.
ArticleNumber 23962
Author Cobankovic, Iva
Ernyey, Alíz Judit
Brenner, Gábor
Franschitz, Eva
Lubec, Gert
Kozma, Kata
Kalaba, Predrag
Urban, Ernst
Lubec, Jana
Malikovic, Jovana
Gyertyán, István
Kassai, Ferenc
Gerner, Christopher
Wackerlig, Judith
Langer, Thierry
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  organization: Core Unit of Biomedical Research, Division of Laboratory Animal Science and Genetics, Medical University of Vienna
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  givenname: Gert
  surname: Lubec
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  email: gert.lubec@lubeclab.com
  organization: Programme of Proteomics, Department of Neuroproteomics, Paracelsus Private Medical University
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CitedBy_id crossref_primary_10_1021_acsomega_3c09348
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crossref_primary_10_1038_s41598_022_24292_5
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Snippet 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...
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...
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...
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SubjectTerms 631/154/436
631/378/1595
631/378/1689/132
631/45/475
Aging
Aging - metabolism
Animals
Antioxidants
Benzhydryl Compounds - pharmacology
Cognition - drug effects
Cognitive ability
Cognitive enhancement
Humanities and Social Sciences
Impulsive behavior
Learning - drug effects
Male
Modafinil
Modafinil - analogs & derivatives
Modafinil - pharmacology
Motivation
Motor skill learning
multidisciplinary
Neurodegeneration
Operant conditioning
Prefrontal cortex
Prefrontal Cortex - metabolism
Proteomics
Rats
Science
Science (multidisciplinary)
Social interactions
Spatial discrimination learning
Test systems
Translation
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Title Cognitive profiling and proteomic analysis of the modafinil analogue S-CE-123 in experienced aged rats
URI https://link.springer.com/article/10.1038/s41598-021-03372-y
https://www.ncbi.nlm.nih.gov/pubmed/34907284
https://www.proquest.com/docview/2609863749
https://search.proquest.com/docview/2610412332
https://pubmed.ncbi.nlm.nih.gov/PMC8671572
https://doaj.org/article/8de4d2688112472988785def180b9487
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