Suppression of Oxidative Stress and 5-Lipoxygenase Activation by Edaravone Improves Depressive-Like Behavior after Concussion

Abstract

Brain concussions are a serious public concern and are associated with neuropsychiatric disorders, such as depression. Patients with concussion who suffer from depression often experience distress. Nevertheless, few pre-clinical studies have examined concussion-induced depression, and there is little information regarding its pharmacological management. Edaravone, a free radical scavenger, can exert neuroprotective effects in several animal models of neurological disorders. However, the effectiveness of edaravone in animal models of concussion-induced depression remains unclear. In this study, we examined whether edaravone could prevent concussion-induced depression. Mice were subjected to a weightdrop injury and intravenously administered edaravone (3.0 mg/kg) or vehicle immediately after impact. Serial magnetic resonance imaging showed no abnormalities of the cerebrum on diffusion T1-and T2-weighted images. We found that edaravone suppressed concussion-induced depressive-like behavior in the forced swim test, which was accompanied by inhibition of increased hippocampal and cortical oxidative stress (OS) and suppression of 5-lipoxygenase (5-LOX) translocation to the nuclear envelope in hippocampal astrocytes. Hippocampal OS in concussed mice was also prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin, and administration of BWB70C, a 5-LOX inhibitor, immediately and 24 h after injury prevented depressive-like behaviors in concussed mice. Further, antidepressant effects of edaravone were observed in mice receiving 1.0 or 3.0 mg/kg of edaravone immediately after impact, but not at a lower dose of 0.1 mg/kg. This antidepressant effect persisted up to 1 h after impact, whereas edaravone treatment at 3 h after impact had no effect on concussion-induced depressive-like behavior. These results suggest that edaravone protects against concussion-induced depression, and this protection is mediated by suppression of OS and 5-LOX translocation.

Traumatic Brain Injury: Oxidative Stress and Novel Anti-Oxidants Such as Mitoquinone and Edaravone

“…Regarding the therapeutic time window, a study found that edaravone can exert its effect when administered up to six hours after injury [ 65 ]. On the other hand, in a study on closed head injury, edaravone only exerted a significant effect when it was administered 1 h after injury, and the effect was dose-dependent [ 69 ].…”

“…Additionally, the expression of Nrf2, a transcription factor, and its downstream genes were elevated by edaravone [ 65 ]. Similarly, in a mouse model of concussion, NT levels were decreased in the cortex and hippocampus when edaravone was administered [ 69 ]. In one study, H 2 O 2 level decreased, and SOD and GPx increased following edaravone treatment [ 70 ].…”

“…Moreover, at acute and subacute time points following TBI, in the edaravone treated group, 4-hydroxy-2-nonenal (4-HNE, another lipid peroxidation marker) immunopositive cells were scarcely present around the injured brain area [ 67 , 68 ]. Similarly, in a mouse model of concussion, 4-HNE was significantly suppressed in the cortex and hippocampus 1 day after injury, when edaravone was administered immediately after concussion [ 69 ].…”

“…Similarly, in a mouse model of brain concussion, depressive-like behavior was prevented by edaravone, as evident by the decrease in immobility time in the forced swim test (FST). The latter was also negatively correlated with the dose of edaravone administered [ 69 ].…”

Blood and semen paraoxonase-arylesterase activities in normozoospermic and azoospermic men

“…Many diverse clinical conditions as systemic infection, depression and stress have been shown to cause significant changes in oxidative balance. (Bhatt, Radhakrishnan, Jindal, Devadoss, & Dhar, 2014;Higashi et al, 2014). Studies have demonstrated emergence of psychological changes in both men and women after establishment of infertility.…”