Free-Radical Scavenger Edaravone Treatment Confers Neuroprotection Against Traumatic Brain Injury in Rats

Traumatic brain injury (TBI) is a major health concern worldwide and is classified based on severity into mild, moderate, and severe. The mechanical injury in TBI leads to a metabolic and ionic imbalance, which eventually leads to excessive production of reactive oxygen species (ROS) and a state of oxidative stress. To date, no drug has been approved by the food and drug administration (FDA) for the treatment of TBI. Nevertheless, it is thought that targeting the pathology mechanisms would alleviate the consequences of TBI. For that purpose, antioxidants have been considered as treatment options in TBI and were shown to have a neuroprotective effect. In this review, we will discuss oxidative stress in TBI, the history of antioxidant utilization in the treatment of TBI, and we will focus on two novel antioxidants, mitoquinone (MitoQ) and edaravone. MitoQ can cross the blood brain barrier and cellular membranes to accumulate in the mitochondria and is thought to activate the Nrf2/ARE pathway leading to an increase in the expression of antioxidant enzymes. Edaravone is a free radical scavenger that leads to the mitigation of damage resulting from oxidative stress with a possible association to the activation of the Nrf2/ARE pathway as well.

Download Full-text

Therapeutic Time Window for Edaravone Treatment of Traumatic Brain Injury in Mice

BioMed Research International ◽

10.1155/2013/379206 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 11

Author(s):

Kazuyuki Miyamoto ◽

Hirokazu Ohtaki ◽

Kenji Dohi ◽

Tomomi Tsumuraya ◽

Dandan Song ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Neuronal Death ◽

Time Window ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Therapeutic Time Window

Traumatic brain injury (TBI) is a major cause of death and disability in young people. No effective therapy is available to ameliorate its damaging effects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profile of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0 mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. The production of superoxide radicals (O2∙-) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours after CCI, with oxidative stress and neuronal cell death becoming apparent after 6 hours. Edaravone administration after CCI resulted in a significant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease inO2∙-levels was observed when edaravone was administered 3 hours following CCI. These findings suggest that edaravone could prove clinically useful to ameliorate the devastating effects of TBI.

Download Full-text

Cerebral vascular responsiveness after experimental traumatic brain injury: the beneficial effects of delayed hypothermia combined with superoxide dismutase administration

Journal of Neurosurgery ◽

10.3171/jns/2008/109/9/0502 ◽

2008 ◽

Vol 109 (3) ◽

pp. 502-509 ◽

Cited By ~ 19

Author(s):

Anna I. Baranova ◽

Enoch P. Wei ◽

Yuji Ueda ◽

Milton M. Sholley ◽

Hermes A. Kontos ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Superoxide Dismutase ◽

Free Radical ◽

Brain Injury ◽

Vascular Function ◽

Free Radical Scavengers ◽

Therapeutic Window ◽

Radical Scavenger ◽

Vascular Protection ◽

Cerebral Vascular

Object Traumatic brain injury (TBI) induces cerebral vascular dysfunction reflected in altered responses to vasodilators such as acetylcholine and hypercapnia. It has been demonstrated that the use of either posttraumatic hypothermia or free radical scavengers offered vascular protection when those treatments were delivered early after the injury, losing efficacy when the initiation of either treatment was delayed. Because immediate posttraumatic treatment is not realistic in the clinical setting, the authors undertook this study to investigate whether the combination of delayed hypothermia and the delayed administration of the free radical scavenger superoxide dismutase (SOD) could result in improved vascular protection. Methods Male Sprague–Dawley rats were anesthetized and subjected to either an impact-acceleration or sham injury. Animals were treated either with hypothermia (32°C) initiated 60 minutes after TBI, delayed SOD (60 U/ml) applied 90 minutes after TBI, or a combination of delayed hypothermia (32°C) and delayed SOD (60 U/ml) applied 15 minutes prior to the cessation of hypothermia. In this investigation, the diameter of cerebral pial arterioles was measured at rest and then challenged with vasodilator acetylcholine and hypercapnia. Four vessels were assessed per animal prior to injury and then again up to 6 hours after injury. Results Delayed SOD treatment did not enhance vascular function, while delayed hypothermia treatment only partially preserved pial vascular function. However, the combination of delayed hypothermia and delayed SOD significantly preserved vascular function after the injury. Conclusions The results of these studies demonstrate that delayed hypothermia partially preserves vascular function after TBI, while expanding the therapeutic window over which agents such as SOD can now provide enhanced protection.

Download Full-text

Paradoxical Increase in Neuronal DNA Fragmentation after Neuroprotective Free Radical Scavenger Treatment in Experimental Traumatic Brain Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200104000-00003 ◽

2001 ◽

Vol 21 (4) ◽

pp. 344-350 ◽

Cited By ~ 31

Author(s):

Anders Lewén ◽

Ylva Skoglösa ◽

Fredrik Clausen ◽

Niklas Marklund ◽

Pak H. Chan ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Free Radical ◽

Brain Injury ◽

Dna Fragmentation ◽

Caspase 3 ◽

Active Form ◽

Cortical Lesion ◽

Radical Scavenger ◽

Lesion Volume ◽

Screening Process

The mechanisms and role of nerve cell death after traumatic brain injury (TBI) are not fully understood. The authors investigated the effect of pretreatment with the oxygen free radical spin trap α-phenyl- N- tert-butyl-nitrone (PBN) on the number of neurons undergoing apoptosis after TBI in rats. Apoptotic cells were identified by the TUNEL method combined with the nuclear stain, Hoechst 33258, and immunohistochemistry for the active form of caspase-3. Numerous neurons became positive for activated caspase 3 and TUNEL in the cortex at 24 hours after injury, suggesting ongoing biochemical apoptosis. In PBN-treated rats, a significantly greater number of cells were found to be TUNEL positive at 24 hours compared with controls. However, PBN treatment resulted in a reduced cortical lesion volume and improved behavioral outcome two weeks after injury. The authors conclude that a treatment producing an increase in DNA fragmentation in the early phase may be compatible with an overall beneficial effect on outcome after TBI. This should be considered in the screening process for future neuroprotective remedies.

Download Full-text