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Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
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Article in journal (Refereed) Published
URN: urn:nbn:se:uu:diva-91894OAI: oai:DiVA.org:uu-91894DiVA: diva2:164765
Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved
In thesis
1. Delayed Cell Death after Traumatic Brain Injury: Role of Reactive Oxygen Species
Open this publication in new window or tab >>Delayed Cell Death after Traumatic Brain Injury: Role of Reactive Oxygen Species
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic brain injury (TBI) is a leading cause of death and disability TBI survivors often suffer from severe disturbances of cognition, memory and emotions. Improving the treatment is of great importance, but as of yet no specific neuroprotective treatment has been found. After TBI there are changes in ion homeostasis and protein regulation, causing generation of reactive oxygen species (ROS). Overproduction of ROS can lead to damage cellmembranes, proteins and DNA and secondary cell death. In the present thesis experimental TBI in rats were used to study the effects of the ROS scavengers α-phenyl-N-tert-butyl-nitrone (PBN) and 2-sulfophenyl-N-tert-butyl-nitrone (S-PBN) on morphology, function, intracellular signalling and apoptosis.

Posttreatment with PBN and S-PBN resulted in attenuation of tissue loss after TBI and S-PBN improved cognitive function evaluated in the Morris water maze (MWM). Pretreatment with PBN protected hippocampal morphology, which correlated to better MWM-performance after TBI.

To detect ROS-generation in vivo, a method using 4-hydroxybenzoic acid (4-HBA) microdialysis in the injured cortex was refined. 4-HBA reacts with ROS to form 3,4-DHBA, which can be quantified using HPLC, revealing that ROS-formation was increased for 90 minutes after TBI. It was possible to attenuate the formation significantly with PBN and S-PBN treatment.

The activation of extracellular signal-regulated kinase (ERK) is generally considered beneficial for cell survival. However, persistent ERK activation was found in the injured cortex after TBI, coinciding with apoptosis-like cell death 24 h after injury. Pretreatment with the MEK-inhibitor U0126 and S-PBN significantly decreased ERK activation and reduced apoptosis-like cell death. Posttreatment with U0126 or S-PBN showed robust protection of cortical tissue.

To conclude: ROS-mediated mechanisms play an important role in secondary cell death following TBI. The observed effects of ROS in intracellular signalling may be important for defining new targets for neuroprotective intervention.

Place, publisher, year, edition, pages
Uppsala: Institutionen för neurovetenskap, 2004. 75 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1359
Neurosciences, Traumatic Brain Injury, Reactive oxygen species, Fluid percussion injury, Controlled cortical impact, weight drop injury, Extracellular-signal regulated kinase, apoptosis, free radical scavenging, morphology, functional outcome, Neurovetenskap
National Category
urn:nbn:se:uu:diva-4296 (URN)91-554-5990-0 (ISBN)
Public defence
2004-06-05, Grönwallsalen, Uppsala Akademiska Sjukhus, Ing. 70 Uppsala Akademiska Sjukhus, Uppsala, 13:15
Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved

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