Behavioral, neuroplasticity and metabolic effects of 7,8-dihydroxy-4-methylcoumarin associated with physical activity in mice.

Priscilla Karla Fernandes Lopes,Licio Augusto Velloso,Natalia Oliveira Bertolini,Rodrigo Ferreira De Moura,Chrystian Araujo Pereira,Moisés Silvestre De Azevedo Martins,Daiane Fátima Engel,Sérgio Scherrer Thomasi

doi:10.1007/s11011-021-00849-7

Abstract

The search for strategies to develop resilience against metabolic and neuropsychiatric disorders has motivated the clinical and experimental assessment of early life interventions such as lifestyle-based and use of unconventional pharmacological compounds. In this study, we assessed the effects of voluntary physical activity and 7,8-Dihydroxy-4-methylcoumarin (DHMC), independently or in combination, over mice physiological and behavioral parameters, adult hippocampal and hypothalamic neurogenesis, and neurotrophic factors expression in the hypothalamus. C57Bl/6J mice were submitted to a 29-day treatment with DHMC and allowed free access to a running wheel. We found that DHMC treatment alone reduced fasting blood glucose levels. Moreover, physical activity showed an anxiolytic effect in the elevated plus maze task and DHMC produced additional anxiolytic behavior, evidenced by reduced activity during the light cycle in the physical activity group. Although we did not find any differences in hypothalamic or hippocampal adult neurogenesis, DHMC increased gene expression levels of VEGF, which was correlated to the reduced fasting glucose levels. In conclusion, our data emphasize the potential of physical activity in reducing development of neuropsychiatric conditions, such as anxiety, and highlights DHMC as an attractive compound to be investigated in future studies addressing neuropsychiatric disorders associated with metabolic conditions.

Highlights

Disruption of synaptic plasticity processes, neuronal growth and remodeling, neurogenesis, and eventually, progressive neuronal loss, underlies the development of several neuropsychiatric and metabolic disorders (Myers and Olson 2012; Dugger and Dickson 2017; Estrada and Contreras 2019)
We did not find any differences in hypothalamic or hippocampal adult neurogenesis, DHMC increased gene expression of vascular endothelial growth factor (VEGF), which was correlated to the reduced fasting glucose levels
Our data emphasize the potential of physical activity in reducing development of neuropsychiatric conditions, such as anxiety, and highlights DHMC as an attractive compound to be investigated in future studies addressing neuropsychiatric disorders associated with metabolic conditions

Summary

Introduction

Disruption of synaptic plasticity processes, neuronal growth and remodeling, neurogenesis, and eventually, progressive neuronal loss, underlies the development of several neuropsychiatric and metabolic disorders (Myers and Olson 2012; Dugger and Dickson 2017; Estrada and Contreras 2019). Coumarins are polyphenols that constitute a large class of heterocyclic oxygen compounds, initially found as secondary plant metabolites. They have high bioavailability, low molecular weight and simple processes for synthesis (Wu et al 2009). Regarding the central nervous system (CNS) these molecules have shown experimental results in neuroprotection in human (Molina-Jiménez et al 2005), mouse (Yao et al 2015) and rat (Kang and Kim 2007) neuronal cells in vitro, adult neurogenesis, cognitive function improvement in mice (Gao et al 2015) and antidepressant effect in rats (Yang et al 2020). The 7,8-Dihydroxy-4-methylcoumarin (DHMC) is a coumarin synthetized by relatively simple, low-cost and good yielding processes (Potdar et al 2001). In the CNS coumarins seem to improve cell survival, promoting neuroprotection and promoting favorable conditions for neuronal expansion in mice and rats (Gao et al 2014; SkalickaWoźniak et al 2016; Qin et al 2017)

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Conclusion