Upregulation of neurotrophins by S 47445, a novel positive allosteric modulator of AMPA receptors in aged rats

Francesca Calabrese,Elisa Savino,Elisabeth Mocaer,Sylvie Bretin,Giorgio Racagni,Marco A Riva

doi:10.1016/j.phrs.2017.04.019

Abstract

At molecular levels, it has been shown that aging is associated with alterations in neuroplastic mechanisms. In this study, it was examined if the altered expression of neurotrophins observed in aged rats could be corrected by a chronic treatment with S 47445 (1–3–10mg/kg, p.o.), a novel selective positive allosteric modulator of the AMPA receptors. Both the mRNA and the protein levels of the neurotrophins Bdnf, NT-3 and Ngf were specifically measured in the prefrontal cortex and hippocampus (ventral and dorsal) of aged rats. It was found that 2-week-treatment with S 47445 corrected the age-related deficits of these neurotrophins and/or positively modulated their expression in comparison to vehicle aged rats in the range of procognitive and antidepressant active doses in rodents.Collectively, the ability of S 47445 to modulate various neurotrophins demonstrated its neurotrophic properties in two major brain structures involved in cognition and mood regulation suggesting its therapeutic potential for improving several diseases such as Alzheimer’s disease and/or Major Depressive Disorders.

Highlights

Aging is often accompanied by a decline of memory and executive functions, the neurobiological mechanisms that contribute to age-related cognitive decline remain largely unknown.Several evidence showed that aging is associated with a reduction of the number as well as the plasticity of dendritic spines in the prefrontal cortex [1] and with alterations in neuroplastic mechanisms [2,3]
Our results provide evidence that prolonged treatment with the AMPA-PAM, S 47445, positively modulated neuroplastic mechanisms in aged rats by acting on different kind of neurotrophins in cerebral regions involved both in memory processes and in regulation of mood
Since the prefrontal cortex and the dorsal part of the hippocampus play a key role in cognitive functions [32], these alterations confirmed that aging is associated with reduced plasticity that may, in turn, underlie the cognitive decline observed in the elderly subjects [33]

Summary

Introduction

Aging is often accompanied by a decline of memory and executive functions, the neurobiological mechanisms that contribute to age-related cognitive decline remain largely unknown. Several evidence showed that aging is associated with a reduction of the number as well as the plasticity of dendritic spines in the prefrontal cortex [1] and with alterations in neuroplastic mechanisms [2,3]. While exposure to chronic stress reduces dendritic complexity at all ages in rat models, young adult (3 month-old) animals are capable of reversing these structural changes with a 3-week recovery period. 12 month-old and 20 month-old rats fail to reverse these changes within the same stress-free recovery time [2]. Since aging represents a period of vulnerability to environmental stressors, test novel therapeutics directed at increasing the capacity for adaptive neuronal responses during this period may provide interesting information on their potential to promote neuroprotection against insults.

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