Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury

Abstract

Oxidative stress, an imbalance between oxidants and antioxidants, contributes to the pathogenesis of traumatic brain injury (TBI). Oxidative neurodegeneration is a key mediator of exacerbated morphological responses and deficits in behavioral recoveries. The present study assessed early hippocampal sequential imbalance to possibly enhance antioxidant therapy. Young adult male Sprague-Dawley rats were subjected to a unilateral moderate cortical contusion. At various times post TBI, animals were killed and the hippocampus analyzed for antioxidants (GSH, GSSG, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase, superoxide dismutase and catalase), and oxidants (acrolein,, protein carbonyl [PC] and 3-nitrotyrosine. Synaptic markers (synapsin-I, post synaptic density-95 [PSD-95], synapse associated protein-97 [SAP-97], growth associated protein-43 were also analyzed. All values were compared to sham operated animals. Significant time-dependent changes in antioxidants were observed as early as 3 h post trauma and paralleled increases in oxidants (4-HNE, acrolein and PC) with peak values obtained at 24-48 h. Time dependent changes in synaptic proteins (synapsin-I, PSD-95 and SAP-97) occurred well after levels of oxidants peaked. These results indicate that depletion of antioxidant systems following trauma could adversely affect synaptic function and plasticity. Early onset of oxidative stress suggests that the initial therapeutic window following TBI appears to be relatively short and it may be necessary to stagger selective types of anti-oxidant therapy to target specific oxidative components.

Mechanisms of Dendritic Spine Remodeling in a Rat Model of Traumatic Brain Injury

“…Since dendritic spines form most of the excitatory synapses in the brain, their collapse may physically de-stabilize and disrupt synapses. Indeed, lateral TBI is associated with synapse degeneration, as is evident by the loss of synaptic proteins reported in previous studies (Ansari et al, 2008a(Ansari et al, ,2008b, and the loss of PSD-95 immunoreactivity observed in the present study. Thus, a pathological increase in cofilin activity may result in not only a loss of dendritic spines, but a loss of spine synapses (Shankar et al, 2007).…”

Age-Related Mitochondrial Changes after Traumatic Brain Injury

“…With age the production of oxidants increases, and there is a decrease in antioxidant protection, and=or the damage oxidants inflict begins to exceed the cell's ability to repair the resulting damage (Butterfield et al, 2001). When the production of oxidants exceeds antioxidant defenses, the condition is known as oxidative stress, and this has is known to play a substantial role in accelerated aging, and in the damage seen after TBI (Ansari et al, 2008a(Ansari et al, , 2008b. Accumulation of damage to various complexes, proteins, and membranes, may explain this increased vulnerability to perturbations, and is supported by age-related differences in cortical tissue sparing seen after TBI (Shao et al, 2006).…”

Dose- and Time-Dependent Neuroprotective Effects of Pycnogenol® following Traumatic Brain Injury

“…[19][20][21] We have previously shown that following TBI there is a significant loss of synaptic proteins in both the cortex and hippocampus. 22,23 This synaptic change occurs much later than the increase in levels of oxidative stress, which is a very early and longlasting event. This early increase in oxidative stress and related cascades may play important role in synaptic loss following TBI and be responsible for behavioral dysfunction as a consequence of the injury.…”