Environmental Enrichment Prevent the Juvenile Hypoxia-Induced Developmental Loss of Parvalbumin-Immunoreactive Cells in the Prefrontal Cortex and Neurobehavioral Alterations Through Inhibition of NADPH Oxidase-2-Derived Oxidative Stress

Abstract

We compared the expression of phenotype of parvalbumin (PV)-immunoreactive cells in the prefrontal cortex (PFC) of juvenile rats reared in enriched environment (EE) after daily intermittent hypoxia (IH) exposure to those reared in standard environment (SE) and investigated the involvement of NADPH oxidase-2 (NOX2)-derived oxidative stress in the IH-induced neurodevelopmental and neurobehavioral consequences in a juvenile rat model of obstructive sleep apnea. Postnatal day 21 (P21) rats were exposed to IH or room air 8 h daily for 14 consecutive days. After the daily exposure, the rats were raised in SE or EE. In the PFC of P34 rats, we determined the impact (i) of IH exposures on NOX2-derived oxidative stress and PV immunoreactivity, (ii) of pharmacological NOX2 inhibition on IH-induced oxidative stress and PV immunoreactivity, and (iii) of EE on the IH-induced oxidative stress and PV immunoreactivity. Behavioral testing of psychiatric anxiety was carried out consecutively in the open-field test and elevated plus maze at P35 and P36. The results showed IH exposures increased NOX2 expression in the PFC of P34 rats, which was accompanied with elevation of NOX activity and indirect markers of oxidative stress (4-HNE). IH exposures increased 4-HNE immunoreactivity in cortical PV cells, which was accompanied with reduction of PV immunoreactivity. Treatment of IH rats with the antioxidant/NOX inhibitor apocynin prevented the PV cells loss in the PFC and reversed the IH-induced psychiatric anxiety. EE attenuated the NOX2-derived oxidative stress and reversed the PV-immunoreactivity reduction in the PFC induced by IH. Our data suggest that EE might prevent the juvenile hypoxia-induced developmental loss of PV cells in the PFC and attenuate the neurobehavioral alterations through inhibition of NOX2-derived oxidative stress.

HIF-1α-Mediated, NADPH Oxidase-Derived ROS Contributes to Laryngeal Airway Hyperreactivity Induced by Intermittent Hypoxia in Rats

“…Additionally, we recently found (Yang et al, 2016) that ROS are essential for the sensitization of capsaicinsensitive vagal afferents and the development of lower airway hyperreactivity induced by 14 days IH. The activation of NADPH oxidase is known to be a major source of ROS in various tissues in response to IH (Peng et al, 2009;Williams et al, 2015;Zhang et al, 2016;Liu et al, 2019). Indeed, the increased levels of lipid peroxidation in laryngeal tissues observed in this study were totally inhibited by apocynin, suggesting that ROS may be derived from the activation of NADPH oxidase.…”

Alteration of Energy Metabolism and Antioxidative Processing in the Hippocampus of Rats Reared in Long-Term Environmental Enrichment

“…Abnormal production of NOX2-derived ROS occurs not only in neurodegenerative diseases and ischemic conditions, but also in psychiatric disorders [53]. Zhang et al [54] showed that EE attenuates NOX2-derived oxidative stress induced by daily intermittent hypoxia exposure. The above finding in conjunction with our results indicates that positively stimulating environments may reduce the expression of NOX and, thus, a lower level of ROS production leading to less damage to ROS-sensitive proteins.…”

Effect of Hypoxic Injury in Mood Disorder

“…In the mouse model, PFC damage induced by hypoxic conditions including ghost cells, increased the neuronal death and upregulated the expression of molecules such as VEGF, Glut1, Hif-1, and lactate dehydrogenase A, which might cause a local excitability in PFC neurons [ 81 , 87 ]. In addition, NADPH oxidase-2 induced the oxidative stress that might contribute to the developmental loss of parvalbumin- (PV-) positive cells (PV-cells) in the PFC and progression of psychiatric anxiety in rat models [ 72 , 88 ]. Moreover, the loss of PV-cells in the PFC and the IH-induced psychiatric anxiety can be alleviated by inhibiting the NADPH oxidase-2-induced oxidative stress [ 88 ].…”

“…In addition, NADPH oxidase-2 induced the oxidative stress that might contribute to the developmental loss of parvalbumin- (PV-) positive cells (PV-cells) in the PFC and progression of psychiatric anxiety in rat models [ 72 , 88 ]. Moreover, the loss of PV-cells in the PFC and the IH-induced psychiatric anxiety can be alleviated by inhibiting the NADPH oxidase-2-induced oxidative stress [ 88 ].…”