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Delayed Cell Death after Traumatic Brain Injury: Role of Reactive Oxygen Species
Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
2004 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Institutionen för neurovetenskap , 2004. , s. 75
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1359
Emneord [en]
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
Emneord [sv]
Neurovetenskap
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-4296ISBN: 91-554-5990-0 (tryckt)OAI: oai:DiVA.org:uu-4296DiVA, id: diva2:164767
Disputas
2004-06-05, Grönwallsalen, Uppsala Akademiska Sjukhus, Ing. 70 Uppsala Akademiska Sjukhus, Uppsala, 13:15
Opponent
Veileder
Tilgjengelig fra: 2004-05-12 Laget: 2004-05-12bibliografisk kontrollert
Delarbeid
1. Intracranial Pressure Changes During Fluid Percussion, Controlled Cortical Impact and Weight Drop Injury in Rats
Åpne denne publikasjonen i ny fane eller vindu >>Intracranial Pressure Changes During Fluid Percussion, Controlled Cortical Impact and Weight Drop Injury in Rats
Artikkel i tidsskrift (Fagfellevurdert) Submitted
Identifikatorer
urn:nbn:se:uu:diva-91890 (URN)
Tilgjengelig fra: 2004-05-12 Laget: 2004-05-12bibliografisk kontrollert
2. Free Radical Scavenger Posttreatment Improves Functional and Morphological Outcome after Fluid Percussion Injury in the Rat
Åpne denne publikasjonen i ny fane eller vindu >>Free Radical Scavenger Posttreatment Improves Functional and Morphological Outcome after Fluid Percussion Injury in the Rat
2001 Inngår i: Journal of Neurotrauma, Vol. 18, nr 8, s. 821-32Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-91891 (URN)
Tilgjengelig fra: 2004-05-12 Laget: 2004-05-12bibliografisk kontrollert
3. Monitoring of Reactive Oxygen Species Production after Traumatic Brain Injury in Rats with Microdialysis and the 4-Hydroxybenzoic Acid Trapping Method
Åpne denne publikasjonen i ny fane eller vindu >>Monitoring of Reactive Oxygen Species Production after Traumatic Brain Injury in Rats with Microdialysis and the 4-Hydroxybenzoic Acid Trapping Method
2001 Inngår i: Journal of Neurotrauma, Vol. 18, nr 11, s. 1217-27Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-91892 (URN)
Tilgjengelig fra: 2004-05-12 Laget: 2004-05-12bibliografisk kontrollert
4. Effects of the Nitrone Radical Scavengers PBN and S-PBN on In Vivo Trapping of Reactive Oxygen Species after Traumatic Brain Injury in Rats
Åpne denne publikasjonen i ny fane eller vindu >>Effects of the Nitrone Radical Scavengers PBN and S-PBN on In Vivo Trapping of Reactive Oxygen Species after Traumatic Brain Injury in Rats
2001 Inngår i: Journal of Cerebral Blood Flow and Metabolism, Vol. 21, nr 11, s. 1259-67Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-91893 (URN)
Tilgjengelig fra: 2004-05-12 Laget: 2004-05-12bibliografisk kontrollert
5.
Åpne denne publikasjonen i ny fane eller vindu >>
Vise andre…
Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-91894 (URN)
Tilgjengelig fra: 2004-05-12 Laget: 2004-05-12bibliografisk kontrollert
6. Oxygen Free Radical Dependent Activation of Extracellular Signal-regulated Kinase (ERK) Mediates Apoptosis-like Cell Death after Traumatic Brain Injury
Åpne denne publikasjonen i ny fane eller vindu >>Oxygen Free Radical Dependent Activation of Extracellular Signal-regulated Kinase (ERK) Mediates Apoptosis-like Cell Death after Traumatic Brain Injury
Vise andre…
Artikkel i tidsskrift (Fagfellevurdert) Submitted
Identifikatorer
urn:nbn:se:uu:diva-91895 (URN)
Tilgjengelig fra: 2004-05-12 Laget: 2004-05-12bibliografisk kontrollert

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