Pomalidomide Ameliorates H₂O₂-Induced Oxidative Stress Injury and Cell Death in Rat Primary Cortical Neuronal Cultures by Inducing Anti-Oxidative and Anti-Apoptosis Effects.

Yan-Rou Tsai,Barry Hoffer,John Wu,Jing-Huei Lai,Nigel Greig,Kai-Yun Chen,Shuo-Jhen Kang,Yung-Hsiao Chiang,Yen-Hua Chen,Weiming Luo,Cheng-Fu Chang,David Tweedie

doi:10.3390/ijms19103252

Abstract

Due to its high oxygen demand and abundance of peroxidation-susceptible lipid cells, the brain is particularly vulnerable to oxidative stress. Induced by a redox state imbalance involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system, oxidative stress plays a central role in a common pathophysiology that underpins neuronal cell death in acute neurological disorders epitomized by stroke and chronic ones such as Alzheimer’s disease. After cerebral ischemia, for example, inflammation bears a key responsibility in the development of permanent neurological damage. ROS are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Using H2O2-treated rat primary cortical neuronal cultures, we found POM displayed neuroprotective effects against oxidative stress and cell death that associated with changes in the nuclear factor erythroid derived 2/superoxide dismutase 2/catalase signaling pathway. POM also suppressed nuclear factor kappa-light-chain-enhancer (NF-κB) levels and significantly mitigated cortical neuronal apoptosis by regulating Bax, Cytochrome c and Poly (ADP-ribose) polymerase. In summary, POM exerted neuroprotective effects via its anti-oxidative and anti-inflammatory actions against H2O2-induced injury. POM consequently represents a potential therapeutic agent against brain damage and related disorders and warrants further evaluation.

Highlights

Neurological diseases account for the world’s largest cause of disability, consequent to 250.7 million disability-adjusted life years (DALYs) that were lost during 2015 together with 9.4 million deaths [1]
We demonstrate that POM prevented H2O2-induced oxidative stress injury in rat primary cortical neuronal cultures by inducing anti-oxidative and anti-apoptosis effects and preventing neuronal cell death
The pathophysiology of neurodegenerative disorders, whether acute as epitomized by stroke, or chronic as in AD, is complex and involves different vulnerable cell types across different brain regions responding to a diverse array of extrinsic and intrinsic challenges

Summary

Introduction

Neurological diseases account for the world’s largest cause of disability, consequent to 250.7 million disability-adjusted life years (DALYs) that were lost during 2015 together with 9.4 million deaths [1]. Stroke accounts for the largest proportion of these DALYs, at 47.3% of the total (some 118.6 million) and deaths, at 67.3% (6.3 million) [1]. Stroke is the second major cause of death and the leading cause of long-term neurological disability worldwide [2], with Alzheimer’s disease and related dementias representing the second largest contributor to deaths and DALYs from neurological disorders. Mitochondrial function is impaired by free radical-mediated breakdown of the inner mitochondrial membrane and the oxidation of proteins that mediate electron transport, H+ extrusion and adenosine triphosphate (ATP) production. Substrate cleavage causes DNA injury and subsequently leads to apoptotic cell death [15]

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Results

Conclusion