Noradrenaline Acting on Alpha1 Adrenoceptor as well as by Chelating Iron Reduces Oxidative Burden on the Brain: Implications With Rapid Eye Movement Sleep.

Abhishek Singh,Gitanjali Das,Manjeet Kaur,Birendra N Mallick

doi:10.3389/fnmol.2019.00007

Abhishek Singh, Gitanjali Das + Show 2 more

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https://doi.org/10.3389/fnmol.2019.00007

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Abstract

The noradrenaline (NA) level in the brain is reduced during rapid eye movement sleep (REMS). However, upon REMS deprivation (REMSD) its level is elevated, which induces apoptosis and the degeneration of neurons in the brain. In contrast, isolated studies have reported that NA possesses an anti-oxidant property, while REMSD reduces lipid peroxidation (LP) and reactive oxygen species (ROS). We argued that an optimum level of NA is likely to play a physiologically beneficial role. To resolve the contradiction and for a better understanding of the role of NA in the brain, we estimated LP and ROS levels in synaptosomes prepared from the brains of control and REMS deprived rats with or without in vivo treatment with either α1-adrenoceptor (AR) antagonist, prazosin (PRZ) or α2-AR agonist, clonidine (CLN). REMSD significantly reduced LP and ROS in synaptosomes; while the effect on LP was ameliorated by both PRZ and CLN; ROS was prevented by CLN only. Thereafter, we evaluated in vitro the effects of NA, vitamin E (Vit E), vitamin C (Vit C), and desferrioxamine (DFX, iron chelator) in modulating hydrogen peroxide (H2O2)-induced LP and ROS in rat brain synaptosomes, Neuro2a, and C6 cells. We observed that NA prevented ROS generation by chelating iron (inhibiting a Fenton reaction). Also, interestingly, a lower dose of NA protected the neurons and glia, while a higher dose damaged the neurons and glia. These in vitro and in vivo results are complementary and support our contention. Based on the findings, we propose that REMS maintains an optimum level of NA in the brain (an antioxidant compromised organ) to protect the latter from continuous oxidative onslaught.

Highlights

The brain is metabolically highly active, resulting in the continuous production of a high amount of reactive oxygen species (ROS; Vallyathan and Shi, 1997; Seaver and Imlay, 2004), whose level is proportional to the neuronal activities (Dugan et al, 1995; Demaurex and Scorrano, 2009)
We explored the dose-dependent possible mechanism of action of NA in preventing an oxidative load induced damage to neurons and glia
The findings of this study that a lower dose of NA prevents conversion of Fe3+ to Fe2+ and reduces reactive oxygen species (ROS) generation through Fenton reaction and prevents neuronal death partly help in resolving the paradox

Summary

Introduction

The brain is metabolically highly active, resulting in the continuous production of a high amount of reactive oxygen species (ROS; Vallyathan and Shi, 1997; Seaver and Imlay, 2004), whose level is proportional to the neuronal activities (Dugan et al, 1995; Demaurex and Scorrano, 2009). Upon REMS deprivation (REMSD), the NA level is elevated in the brain (Porkka-Heiskanen et al, 1995; Mehta et al, 2017) and that by acting on adrenoceptor (AR) induces REMSDassociated neuronal damage (Majumdar and Mallick, 2005; Biswas et al, 2006; Jaiswal and Mallick, 2009; Ranjan et al, 2010; Somarajan et al, 2016) These isolated, independent, apparently contradictory findings raise an intriguing but fundamental question: what basic purpose does NA serve in the brain so that its level changes through sleep-waking-REMS states?

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