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The NADPH oxidase NOX2 mediates loss of parvalbumin interneurons in traumatic brain injury: human autoptic immunohistochemical evidence.

ABSTRACT: Pharmacological interventions for traumatic brain injury (TBI) are limited. Together with parvalbumin (PV) loss, increased production of reactive oxygen species (ROS) by the NADPH oxidase NOX enzymes represents a key step in TBI. Here, we investigated the contribution of NOX2-derived oxidative stress to the loss of PV immunoreactivity associated to TBI, performing immunohistochemistry for NOX2, 8-hydroxy-2'-deoxyguanosine (8OHdG) and PV on post mortem brain samples of subjects died following TBI, subjects died from spontaneous intracerebral hemorrhage (SICH) and controls (CTRL). We detected an increased NOX2 expression and 8OHdG immunoreactivity in subjects died from TBI with respect to CTRL and SICH. NOX2 increase was mainly observed in GABAergic PV-positive interneurons, with a minor presence in microglia. No significant differences in other NADPH oxidase isoforms (NOX1 and NOX4) were detected among experimental groups. NOX2-derived oxidative stress elevation appeared a specific TBI-induced phenomenon, as no alterations in the nitrosative pathway were detected. Our results suggest that NOX2-derived oxidative stress might play a crucial role in the TBI-induced loss of PV-positive interneurons.

SUBMITTER: Schiavone S

PROVIDER: S-EPMC5562735 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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The NADPH oxidase NOX2 mediates loss of parvalbumin interneurons in traumatic brain injury: human autoptic immunohistochemical evidence.

Schiavone Stefania S Neri Margherita M Trabace Luigia L Turillazzi Emanuela E

Scientific reports 20170818 1

Pharmacological interventions for traumatic brain injury (TBI) are limited. Together with parvalbumin (PV) loss, increased production of reactive oxygen species (ROS) by the NADPH oxidase NOX enzymes represents a key step in TBI. Here, we investigated the contribution of NOX2-derived oxidative stress to the loss of PV immunoreactivity associated to TBI, performing immunohistochemistry for NOX2, 8-hydroxy-2'-deoxyguanosine (8OHdG) and PV on post mortem brain samples of subjects died following TBI ...[more]

PMID: 28821783

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Project description:Doxorubicin is a highly effective cancer treatment whose use is severely limited by dose-dependent cardiotoxicity. It is well established that doxorubicin increases reactive oxygen species (ROS) production. In this study, we investigated contributions to doxorubicin cardiotoxicity from Nox2 NADPH oxidase, an important ROS source in cardiac cells, which is known to modulate several key processes underlying the myocardial response to injury. Nox2-deficient mice (Nox2-/-) and wild-type (WT) controls were injected with doxorubicin (12 mg/kg) or vehicle and studied 8 weeks later. Echocardiography indicated that doxorubicin-induced contractile dysfunction was attenuated in Nox2-/- versus WT mice (fractional shortening: 29.5±1.4 versus 25.7±1.0%; P<0.05). Similarly, in vivo pressure-volume analysis revealed that systolic and diastolic function was preserved in doxorubicin-treated Nox2-/- versus WT mice (ejection fraction: 52.6±2.5 versus 28.5±2.3%, LVdP/dtmin: -8,379±416 versus -5,198±527 mmHg s(-1); end-diastolic pressure-volume relation: 0.051±0.009 versus 0.114±0.012; P<0.001). Furthermore, in response to doxorubicin, Nox2-/- mice exhibited less myocardial atrophy, cardiomyocyte apoptosis, and interstitial fibrosis, together with reduced increases in profibrotic gene expression (procollagen III?I, transforming growth factor-?3, and connective tissue growth factor) and matrix metalloproteinase-9 activity, versus WT controls. These alterations were associated with beneficial changes in NADPH oxidase activity, oxidative/nitrosative stress, and inflammatory cell infiltration. We found that adverse effects of doxorubicin were attenuated by acute or chronic treatment with the AT1 receptor antagonist losartan, which is commonly used to reduce blood pressure. Our findings suggest that ROS specifically derived from Nox2 NADPH oxidase make a substantial contribution to several key processes underlying development of cardiac contractile dysfunction and remodeling associated with doxorubicin chemotherapy.

Dataset Information

The NADPH oxidase NOX2 mediates loss of parvalbumin interneurons in traumatic brain injury: human autoptic immunohistochemical evidence.

Publications

The NADPH oxidase NOX2 mediates loss of parvalbumin interneurons in traumatic brain injury: human autoptic immunohistochemical evidence.

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