The Nootropic Drug Α-Glyceryl-Phosphoryl-Ethanolamine Exerts Neuroprotective Effects in Human Hippocampal Cells

Abstract

Brain aging involves changes in the lipid membrane composition that lead to a decrease in membrane excitability and neurotransmitter release. These membrane modifications have been identified as contributing factors in age-related memory decline. In this sense, precursors of phospholipids (PLs) can restore the physiological composition of cellular membranes and produce valuable therapeutic effects in brain aging. Among promising drugs, alpha-glycerylphosphorylethanolamine (GPE) has demonstrated protective effects in amyloid-injured astrocytes and in an aging model of human neural stem cells. However, the compound properties on mature neuronal cells remain unexplored. Herein, GPE was tested in human hippocampal neurons, which are involved in learning and memory, and characterized by a functional cholinergic transmission, thus representing a valuable cellular model to explore the beneficial properties of GPE. GPE induced the release of the main membrane phospholipids and of the acetylcholine neurotransmitter. Moreover, the compound reduced lipid peroxidation and enhanced membrane fluidity of human brain cells. GPE counteracted the DNA damage and viability decrease observed in in vitro aged neurons. Among GPE treatment effects, the autophagy was found positively upregulated. Overall, these results confirm the beneficial effects of GPE treatment and suggest the compound as a promising drug to preserve hippocampal neurons and virtually memory performances.

α‐Glyceryl‐phosphoryl‐ethanolamine protects human hippocampal neurons from ageing‐induced cellular alterations

“…The cells were cultured for 21 DIV (days in vitro) in order to mimic a state of neuronal ageing, as reported in the literature and verified in previous experiments (Calvo-Rodríguez et al, 2017;Daniele et al, 2020;Daniele, Da Pozzo, et al, 2016). Human hippocampal neurons at 3 DIV were used as "young neurons".…”

Maternal immune activation primes deficiencies in adult hippocampal neurogenesis

“…To overcome this technical issue, it might be worth artificially ageing the in vitro model ( Mertens et al, 2018 ). This can be done using various strategies; by manipulation of age-related genes or telomerases ( Cozzi et al, 2019 , Liang, 2020 , Miller et al, 2013 , Vera et al, 2016 ), by exposure to x-ray irradiation ( Carlessi et al, 2009 , Schneider et al, 2013 , Schneider and Zheng, 2014 , Zhu et al, 2019 , Limbad et al, 2020 ), hydroxyurea ( Daniele et al, 2016 , de Lucia et al, 2020 , Dong et al, 2014 ), repeated passaging ( de Lucia et al, 2020 , Han et al, 2021 , Liu et al, 2012 , Zhu et al, 2019 ) or long term culture ( Daniele et al, 2020 , Bigagli et al, 2016 ) to induce senescence-like changes into the hiPSC-derived cultures for a more aged-like phenotype.…”

Mechanisms of Hydroxyurea‐Induced Cellular Senescence: An Oxidative Stress Connection?

“…In addition, this pharmaceutical agent provokes a downregulation of Bcl-2-associated X protein (BAX), a critical proapoptotic factor that may contribute to the decreased apoptosis observed in senescent NSCs [ 154 , 172 ]. In addition, HU-induced NSC cellular senescence is counteracted by α -glycerylphosphorylethanolamine (GPE) [ 173 ], which is a precursor biomolecule of phospholipid synthesis and exerts neuroprotective effects in human hippocampal cells [ 174 ]. For instance, GPE protects NSCs from the induction of DNA damage caused by phosphorylated γ H2AX levels and rescues cell proliferation from HU inhibition.…”