Activation of Heme Oxygenase-2 to Improve Outcome After Traumatic Brain Injury

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Lee, Wallace
Controlled Cortical Impact , Beam Balance , Heme Oxygenase , Spontaneous Locomotor Activity , Spontaneous Alternation Behaviour , Traumatic Brain Injury
Traumatic brain injury (TBI) is an injury of the brain most often caused by blunt force trauma to the head and typically characterized by an increase in reactive oxygen species (ROS), inflammation, and hemorrhaging. Heme oxygenase (HO) catalyzes the breakdown of heme into carbon monoxide (CO), biliverdin which is further reduced to bilirubin, and ferrous iron. There are two active isoforms: HO-1 which is inducible and found predominantly in liver and spleen tissue; and HO-2 which is constitutive and found predominantly in the brain and testis. The metabolites of heme possess cytoprotective properties that can limit damage resulting from TBI. Our laboratory has found a selective HO-2 activator known as menadione (MD) that has been found to increase HO-2 activity by 4-fold while not affecting HO-1 in vitro. Given the higher amounts of HO-2 found in the brain and the cytoprotective properties of heme metabolites, we postulate that activation of HO-2 using menadione would mitigate further damage after TBI. The rat controlled cortical impact (CCI) model was used to simulate TBI with spontaneous locomotor activity (SLA), spontaneous alternation behaviour (SAB), and beam balance (BB) as the behavioural tasks to assess cognitive and motor function. A dose-response study (25, 50, 100, 200 μmol/kg) was performed to ascertain the effect of MD treatment on injured animals comparing to uninjured controls and injured animals treated with the vehicle (saline). We found that BB performance improved to control levels after MD treatment at 25 μmol/kg and 50 μmol/kg whereas animals treated with saline did not improve. SLA and SAB performance did not improve after treatment with MD. The findings suggest that HO-2 activation may be a viable method in mitigating further injury after TBI.
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