The results from this doctoral thesis are concordant with other studies
demonstrating that occasionally, long after the initial injury, ongoing
inflammation and cell loss is evidenced. There are a number of studies
like this but they are hard to find. It is an example of why anyone who
experiences brain injury of any severity should immediately boost their
antioxidant intake. This is true of many traumas, not just TBI. As one
neurosurgeon I read recently commented, people with trauma have
massively elevated metabolic rates, hence nutritional intervention is
wise and should be adopted. This is beginning to happen but there still
seems to be considerable resistance to the idea that enhanced nutrition
can play a vital role in the recovery process from any significant
trauma.
John.
Doctoral thesis
Language: English [en]
Keywords: 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
Defence: 2004-06-05, Grönwallsalen, Uppsala Akademiska Sjukhus, Ing.
70 Uppsala Akademiska Sjukhus, Uppsala, 13:15, Swedish
Opponent: Mathiesen, Tiit, Docent, Karolinska Institutet, Stockholm,
Sweden
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 a-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.
