Abstract
Traumatic brain injury (TBI) involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Oxidative stress is one of the most celebrated secondary injury mechanisms. A close relationship exists between levels of oxidative stress and the pathogenesis of TBI. However, other cascades, such as an increase in proinflammatory cytokines, also play important roles in the overall response to the trauma. Pharmacologic intervention, in order to be successful, requires a multifaceted approach. Naturally occurring flavonoids are unique in possessing not only tremendous free radical scavenging properties but also the ability to modulate cellular homeostasis leading to a reduction in inflammation and cell toxicity. This study evaluated the therapeutic role of Pycnogenol (PYC), a patented combinational bioflavonoid. Young adult Sprague-Dawley rats were subjected to a unilateral moderate cortical contusion and treated post injury with PYC or vehicle. At either 48 or 96 h post trauma, the animals were killed and the cortex and hippocampus analyzed for changes in enzymatic and non-enzymatic oxidative stress markers. In addition, possible changes in both pre- and post-synaptic proteins (synapsin-1, PSD-95, drebrin, synapse associated protein-97) were analyzed. Finally, a separate cohort of animals was used to evaluate two proinflammatory cytokines (IL-6, TNF-α). Following the trauma there was a significant increase in oxidative stress in both the injured cortex and the ipsilateral hippocampus. Animals treated with PYC significantly ameliorated levels of protein carbonyls, lipid peroxidation, and protein nitration. The PYC treatment also significantly reduced the loss of key pre- and post-synaptic proteins with some levels in the hippocampus of PYC treated animals not significantly different from sham operated controls. Although levels of the proinflammatory cytokines were significantly elevated in both injury groups, the cohort treated with PYC showed a significant reduction compared to vehicle treated controls. These results are the first to show a neuroprotective effect of PYC following TBI. They also suggest that the diverse effects of bioflavonoids may provide a unique avenue for possible therapeutic intervention following head trauma.