Ladostigil Attenuates Induced Oxidative Stress in Human Neuroblast-like SH-SY5Y Cells.

Keren Zohar,Tsiona Eliyahu,Michal Linial,Elyad Lezmi

doi:10.3390/biomedicines9091251

Keren Zohar, Tsiona Eliyahu + Show 2 more

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https://doi.org/10.3390/biomedicines9091251

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Journal: Biomedicines	Publication Date: Sep 17, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: Hebrew University of Jerusalem

Abstract

A hallmark of the aging brain is the robust inflammation mediated by microglial activation. Pathophysiology of common neurodegenerative diseases involves oxidative stress and neuroinflammation. Chronic treatment of aging rats by ladostigil, a compound with antioxidant and anti-inflammatory function, prevented microglial activation and learning deficits. In this study, we further investigate the effect of ladostigil on undifferentiated SH-SY5Y cells. We show that SH-SY5Y cells exposed to acute (by H2O2) or chronic oxidative stress (by Sin1, 3-morpholinosydnonimine) induced apoptotic cell death. However, in the presence of ladostigil, the decline in cell viability and the increase of oxidative levels were partially reversed. RNA-seq analysis showed that prolonged oxidation by Sin1 resulted in a simultaneous reduction of the expression level of endoplasmic reticulum (ER) genes that participate in proteostasis. By comparing the differential gene expression profile of Sin1 treated cells to cells incubated with ladostigil before being exposed to Sin1, we observed an over-expression of Clk1 (Cdc2-like kinase 1) which was implicated in psychophysiological stress in mice and Alzheimer’s disease. Ladostigil also suppressed the expression of Ccpg1 (Cell cycle progression 1) and Synj1 (Synaptojanin 1) that are involved in ER-autophagy and endocytic pathways. We postulate that ladostigil alleviated cell damage induced by oxidation. Therefore, under conditions of chronic stress that are observed in the aging brain, ladostigil may block oxidative stress processes and consequently reduce neurotoxicity.

Highlights

A decline in cognitive function is a hallmark of normal brain aging
Once the cellular compensatory mechanisms can no longer cope with the stress [14], pathological processes are induced [15,16] as observed following brain injury [17] and in neurodegenerative diseases
A recent study compared rat brain transcriptomes from young and old rats (6.5 and 22 months, respectively) in brain regions that participate in information integration

Summary

Introduction

A decline in cognitive function is a hallmark of normal brain aging. Morphological changes and alterations in cell-type composition are often observed in the aged brain [1].The deficit in learning and memory shows a decreased number of neurons, reduction of synaptic sites, and changes in the properties of dendritic spines [2,3]. A decline in the brain’s higher functions is associated with apoptotic death [4], reduced mitochondrial function [5], proteotoxicity [6,7], and enhanced autophagy [8]). A characteristic phenomenon of the aging brain cells is the reduced capacity to cope with oxidative stress compared to cells from young-adult brains [9]. A failure in antioxidant defense mechanisms in the aging brain [10,11] and impaired mitochondrial function [12] are associated with memory decline [13]. Once the cellular compensatory mechanisms can no longer cope with the stress [14], pathological processes are induced [15,16] as observed following brain injury [17] and in neurodegenerative diseases

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