Suppression of oxidative stress and 5-lipoxygenase activation by edaravone improves depressive-like behavior after concussion.
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 weight-drop 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.
1 Department of Neurosurgery, Kochi Medical School, Kochi University , Kochi, Japan .
Youichirou
Y
Higashi
Michihiro
M
Hoshijima
Toshio
T
Yawata
Atsuya
A
Nobumoto
Masayuki
M
Tsuda
Takahiro
T
Shimizu
Motoaki
M
Saito
Tetuya
T
Ueba
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D001924:Brain Concussion / Q000150:complications* / Q000473:pathology / Q000523:psychology*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology*; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D004789:Enzyme Activation / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects; D013550:Swimming / Q000523:psychology
D016859:Lipoxygenase Inhibitors; D018696:Neuroprotective Agents; D001094:Arachidonate 5-Lipoxygenase; D000077553:Edaravone; D000983:Antipyrine
5-lipoxygenase; concussion; depression; edaravone