Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer's disease

Roberta Ricciarelli; Chiara Brullo; Jos Prickaerts; Ottavio Arancio; Carla Villa; Claudia Rebosio; Elisa Calcagno; Matilde Balbi; Britt T. J. van Hagen; Elentina K. Argyrousi; Hong Zhang; Maria Adelaide Pronzato; Olga Bruno; Ernesto Fedele

doi:10.1038/srep46320

Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer's disease

Roberta Ricciarelli, Chiara Brullo, Jos Prickaerts, Ottavio Arancio, Carla Villa, Claudia Rebosio, Elisa Calcagno, Matilde Balbi, Britt T. J. van Hagen, Elentina K. Argyrousi, Hong Zhang, Maria Adelaide Pronzato, Olga Bruno, Ernesto Fedele^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer's disease.

Original language	English
Article number	46320
Number of pages	14
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/srep46320
Publication status	Published - 12 Apr 2017

Keywords

LONG-TERM POTENTIATION
PROTEIN-KINASE-A
HIPPOCAMPAL SYNAPTIC PLASTICITY
LATE-PHASE
PHOSPHODIESTERASE 4D
COGNITION ENHANCEMENT
RECOGNITION MEMORY
ADENYLYL-CYCLASE
IMPROVES MEMORY
SPATIAL MEMORY

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Cite this

Ricciarelli, R., Brullo, C., Prickaerts, J., Arancio, O., Villa, C., Rebosio, C., Calcagno, E., Balbi, M., van Hagen, B. T. J., Argyrousi, E. K., Zhang, H., Pronzato, M. A., Bruno, O., & Fedele, E. (2017). Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer's disease. Scientific Reports, 7, Article 46320. https://doi.org/10.1038/srep46320

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abstract = "Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer's disease.",

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author = "Roberta Ricciarelli and Chiara Brullo and Jos Prickaerts and Ottavio Arancio and Carla Villa and Claudia Rebosio and Elisa Calcagno and Matilde Balbi and {van Hagen}, {Britt T. J.} and Argyrousi, {Elentina K.} and Hong Zhang and Pronzato, {Maria Adelaide} and Olga Bruno and Ernesto Fedele",

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AU - Ricciarelli, Roberta

AU - Brullo, Chiara

AU - Prickaerts, Jos

AU - Arancio, Ottavio

AU - Villa, Carla

AU - Rebosio, Claudia

AU - Calcagno, Elisa

AU - Balbi, Matilde

AU - van Hagen, Britt T. J.

AU - Argyrousi, Elentina K.

AU - Zhang, Hong

AU - Pronzato, Maria Adelaide

AU - Bruno, Olga

AU - Fedele, Ernesto

PY - 2017/4/12

Y1 - 2017/4/12

N2 - Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer's disease.

AB - Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer's disease.

KW - LONG-TERM POTENTIATION

KW - PROTEIN-KINASE-A

KW - HIPPOCAMPAL SYNAPTIC PLASTICITY

KW - LATE-PHASE

KW - PHOSPHODIESTERASE 4D

KW - COGNITION ENHANCEMENT

KW - RECOGNITION MEMORY

KW - ADENYLYL-CYCLASE

KW - IMPROVES MEMORY

KW - SPATIAL MEMORY

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JO - Scientific Reports

JF - Scientific Reports

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