Effect of ladostigil treatment of aging rats on gene expression in four brain areas associated with regulation of memory

Linial, Michal; Stern, Amos; Weinstock, Marta

doi:10.1016/j.neuropharm.2020.108229

Cited by 12 publications

(24 citation statements)

References 90 publications

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“…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 and memory consolidation [ 22 ]. Chronic treatment with ladostigil in rats (from 16 to 22 months) resulted in improved performance in learning and memory tasks.…”

Section: Resultsmentioning

confidence: 99%

“…Chronic treatment with ladostigil in rats (from 16 to 22 months) resulted in improved performance in learning and memory tasks. Treatment with ladostigil attenuated the activation of microglia in the aged brain [ 22 , 23 ]. Therefore, we ask whether ladostigil can dissipate induced stress at a cellular level.…”

Section: Resultsmentioning

confidence: 99%

“…Aged rats that were treated with ladostigil for a long period (6 months) confirmed the drug’s anti-inflammatory activity [ 19 , 20 ]. Such treatment partially blocked the age-dependent decline in learning and memory [ 19 , 21 , 22 ]. In addition, ladostigil treatment changed the degree of microglial activation in aging rats [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…Ladostigil treatment affected the profile of gene expression in the aging brain. Many of these affected genes act in neurogenesis, synapse formation, calcium, and fatty-acid homeostasis [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…The antiinflammatory activity mediated by microglia underlies the neuroprotective action of ladostigil [22,26]. Results from RNA-seq analysis of aged rat brains revealed substantial alterations in gene expression in different brain areas as a consequence of long-term ladostigil treatment [21] (Figure 1). However, the complexity of the cell composition in the brain (e.g., microglia, neurons, astrocytes) masked cell-specific effects.…”

Section: Discussionmentioning

confidence: 99%

Ladostigil attenuates the oxidative and ER stress in human neuroblast-like SH-SY5Y cells

Zohar

Lezmi

Eliyahu

et al. 2021

Preprint

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A hallmark of the aging brain is the robust inflammation mediated by microglial activation. Neuroinflammation resulting from the induction of oxidative stress in neurodegenerative diseases and following brain injury. 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 investigate the effect of ladostigil on neuronal-like 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 oxidative levels were partially reversed. RNA-seq analysis showed that chronic oxidation by Sin1 resulted in coordinated suppression of endoplasmic reticulum (ER) quality control and ER stress response gene sets. Chronic oxidative stress impacted ER proteostasis and induced the expression of numerous lncRNAs. Pre-incubation with ladostigil before exposing SH-SY5Y cells to Sin1 induced Clk1 (Cdc2-like kinase 1) which was implicated in psychophysiological stress in mice and Alzheimer disease. Ladostigil also suppressed the expression of Ccpg1 (Cell cycle progression 1) and Synj1 (Synaptojanin 1) that function in ER-autophagy and endocytic pathways. We postulate that ladostigil alleviated cell damage by oxidation and ER stress. Therefore, it may attenuate neurotoxicity and cell death that accompany chronic stress conditions in the aging brain.

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Profiles and Dynamics of the Transcriptome of Microglial Cells Reveal their Inflammatory Status

Zohar

Lezmi

Reichert

et al. 2021

Preprint

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The primary role of microglia in the maintenance of brain homeostasis is to respond to disturbances in the microenvironment. In this study, we cultured murine neonatal microglia and activated them with lipopolysaccharide (LPS) and benzoyl ATP (bzATP) to characterize changes in the transcriptome in response to various in vivo stimuli caused by pathogens, injury, or toxins. Activation by bzATP, an agonist of purinergic receptors, induces a transient wave of transcriptional changes. However, a long-lasting transcriptional profile affecting thousands of genes occurs only following a combination of bzATP and LPS. This profile is dominated by a coordinated induction of cytokines (e.g., IL1-alpha; and IL1-beta), chemokines, and their direct regulators. Many of these inflammatory-related genes are up-regulated by several orders of magnitude. We identified the TNF-alpha and NF-kB pathways as the principal hubs for signaling of interleukin and chemokine induction in this cell system. We propose that primary microglia under controlled activation paradigms can be used for testing reagents that could attenuate their activated state. Such a microglial system could serve as a model for changes occurring in the aging brain and neurodegenerative diseases.

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Effect of ladostigil treatment of aging rats on gene expression in four brain areas associated with regulation of memory

Cited by 12 publications

References 90 publications

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

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

Ladostigil attenuates the oxidative and ER stress in human neuroblast-like SH-SY5Y cells

Profiles and Dynamics of the Transcriptome of Microglial Cells Reveal their Inflammatory Status

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