Role of NADPH oxidase-2 in the progression of the inflammatory response secondary to striatum excitotoxic damage

Abstract

Background During excitotoxic damage, neuronal death results from the increase in intracellular calcium, the induction of oxidative stress, and a subsequent inflammatory response. NADPH oxidases (NOX) are relevant sources of reactive oxygen species (ROS) during excitotoxic damage. NADPH oxidase-2 (NOX-2) has been particularly related to neuronal damage and death, as well as to the resolution of the subsequent inflammatory response. As ROS are crucial components of the regulation of inflammatory response, in this work, we evaluated the role of NOX-2 in the progression of inflammation resulting from glutamate-induced excitotoxic damage of the striatum in an in vivo model. Methods The striata of wild-type C57BL/6 J and NOX-2 KO mice (gp91 Cybbtm1Din/J ) were stereotactically injected with monosodium glutamate either alone or in combination with IL-4 or IL-10. The damage was evaluated in histological sections stained with cresyl violet and Fluoro-Jade B. The enzymatic activity of caspase-3 and NOX were also measured. Additionally, the cytokine profile was identified by ELISA and motor activity was verified by the tests of the cylinder, the adhesive tape removal, and the inverted grid. Results Our results show a neuroprotective effect in mice with a genetic inhibition of NOX-2, which is partially due to a differential response to excitotoxic damage, characterized by the production of anti-inflammatory cytokines. In NOX-2 KO animals, the excitotoxic condition increased the production of interleukin-4, which could contribute to the production of interleukin-10 that decreased neuronal apoptotic death and the magnitude of striatal injury. Treatment with interleukin-4 and interleukin-10 protected from excitotoxic damage in wild-type animals. Conclusions The release of proinflammatory cytokines during the excitotoxic event promotes an additional apoptotic death of neurons that survived the initial damage. During the subsequent inflammatory response to excitotoxic damage, ROS generated by NOX-2 play a decisive role in the extension of the lesion and consequently in the severity of the functional compromise, probably by regulating the anti-inflammatory cytokines production. Electronic supplementary material The online version of this article (10.1186/s12974-019-1478-4) contains supplementary material, which is available to authorized users.

NADPH and Mito-Apocynin Treatment Protects Against KA-Induced Excitotoxic Injury Through Autophagy Pathway

“…Lesions in the striatum can lead to impaired voluntary movement and muscle tone, especially in the forelimbs ( Hidalgo-Balbuena et al, 2019 ). So we detect impaired motor function as an indicator of neural dysfunction due to excitotoxicity, by performing the adhesive removal test and the cylinder test of forelimb asymmetry ( Hernández-Espinosa et al, 2019 ). Before stereotactic KA injection, the mice could quickly remove the adhesive label and gave priority to touch ( Hernández-Espinosa et al, 2019 ) the container wall with both forelimbs.…”

“…So we detect impaired motor function as an indicator of neural dysfunction due to excitotoxicity, by performing the adhesive removal test and the cylinder test of forelimb asymmetry ( Hernández-Espinosa et al, 2019 ). Before stereotactic KA injection, the mice could quickly remove the adhesive label and gave priority to touch ( Hernández-Espinosa et al, 2019 ) the container wall with both forelimbs. KA resulted in a significant delay to remove and reduction of bilateral touch in each group.…”

“…Put the animals into the test cage to move freely, observe and record for 60 s or until strip is removed. The result is the waiting time for strip removal ( Hernández-Espinosa et al, 2019 ).…”

“…Record the frequency of unilateral and bilateral explorations for 3 min. The proportion of unilateral touch assessed limb asymmetry ( Hernández-Espinosa et al, 2019 ).…”

Cerium Oxide Nanoparticles: Recent Advances in Tissue Engineering

“…In the presence of oxidative stress, the generation of oxidants like ROS augments to excess, as compared to that of endogenous antioxidants, in such a way that cells fail to maintain the balance [ 83 ]. Despite the evidence that a short-term and relatively small upregulation of ROS is of the utmost importance for the redox signaling that plays a pivotal role in multiple processes, including inflammation [ 84 , 85 ] or angiogenesis [ 86 , 87 , 88 ], a long-term and relatively large elevation of ROS leads to the impairment of major cellular macromolecules, deoxyribonucleic acid (DNA), proteins, or lipids that is more likely to induce the formation of many pathological conditions, such as diabetes [ 89 , 90 ] and neurodegenerative diseases [ 91 ].…”