Trauma-induced spinal cord injury (SCI) is the most prevalent form of spinal cord injury affecting over 80% of the 36,000 Canadians living with this condition. The pathophysiological profile of traumatic SCI consists of an initial stage of direct damage followed by a series of secondary events, including reduced blood flow and increased generation of free radicals that leads to excitotoxicity, oxidative stress, hemorrhagic necrosis, inflammation, and apoptosis. We examined the hypotheses that delayed administration of the flavonoid quercetin inhibits the propagation of secondary events and promotes functional recovery after traumatic SCI by inhibiting inflammatory processes and signaling pathways that promote apoptosis and thereby promoting axon survival. To determine whether delayed quercetin treatment promoted functional recovery following SCI, male Wistar rats were subjected to a spinal cord compression injury by application of a 50 g modified aneurysm clip at the mid thoracic cord level. A treatment regimen of 75 µmol quercetin per kg rat or saline only (controls) was administered for a period of 3 days, 1 week or 2 weeks beginning at 2 weeks post surgery. Delayed quercetin treatment improved locomotion in injured animals although with severe deficit. To determine whether improved functional outcome correlated with improved tissue preservation and reduced scarring, we performed histological examinations at the injury site. In saline treated animals, at 8 weeks post injury we found over 80% of tissue loss with the majority of the remaining cells undergoing apoptosis. However, with 2 weeks delayed quercetin treatment, at least 50% of the tissue was still present at 8 weeks post surgery with a significant reduction of apoptosis. Quercetin treated animals also showed a reduction of reactive gliosis. To determine which intracellular signaling pathways may mediate the protective effects of quercetin, we carried out Western blots and immunocytochemical analyses of a number of potential pro-apoptotic pathways. We found that quercetin reduced the levels of the phosphorylated (activated) forms of the MAPK p38, ERK 1/2 (p42/44) and SAPK/JNK seen after SCI. We conclude that delayed quercetin treatment likely rescues neurons that would otherwise have died between the third and sixth weeks following injury by inhibiting apoptosis of glia cells. Quercetin may be acting via selective inhibition of kinase pathways that have been shown to be involved in apoptosis and cell growth. These findings not only reveal the protective effects of quercetin in reducing secondary damage after chronic SCI but also shed some light on some of the mechanisms underlying its actions.

Trauma-induced spinal cord injury (SCI) is the most prevalent form of spinal cord injury affecting over 80% of the 36,000 Canadians living with this condition. The pathophysiological profile of traumatic SCI consists of an initial stage of direct damage followed by a series of secondary events, including reduced blood flow and increased generation of free radicals that leads to excitotoxicity, oxidative stress, hemorrhagic necrosis, inflammation, and apoptosis. We examined the hypotheses that delayed administration of the flavonoid quercetin inhibits the propagation of secondary events and promotes functional recovery after traumatic SCI by inhibiting inflammatory processes and signaling pathways that promote apoptosis and thereby promoting axon survival. To determine whether delayed quercetin treatment promoted functional recovery following SCI, male Wistar rats were subjected to a spinal cord compression injury by application of a 50 g modified aneurysm clip at the mid thoracic cord level. A treatment regimen of 75 µmol quercetin per kg rat or saline only (controls) was administered for a period of 3 days, 1 week or 2 weeks beginning at 2 weeks post surgery. Delayed quercetin treatment improved locomotion in injured animals although with severe deficit. To determine whether improved functional outcome correlated with improved tissue preservation and reduced scarring, we performed histological examinations at the injury site. In saline treated animals, at 8 weeks post injury we found over 80% of tissue loss with the majority of the remaining cells undergoing apoptosis. However, with 2 weeks delayed quercetin treatment, at least 50% of the tissue was still present at 8 weeks post surgery with a significant reduction of apoptosis. Quercetin treated animals also showed a reduction of reactive gliosis. To determine which intracellular signaling pathways may mediate the protective effects of quercetin, we carried out Western blots and immunocytochemical analyses of a number of potential pro-apoptotic pathways. We found that quercetin reduced the levels of the phosphorylated (activated) forms of the MAPK p38, ERK 1/2 (p42/44) and SAPK/JNK seen after SCI. We conclude that delayed quercetin treatment likely rescues neurons that would otherwise have died between the third and sixth weeks following injury by inhibiting apoptosis of glia cells. Quercetin may be acting via selective inhibition of kinase pathways that have been shown to be involved in apoptosis and cell growth. These findings not only reveal the protective effects of quercetin in reducing secondary damage after chronic SCI but also shed some light on some of the mechanisms underlying its actions.

Oxidative stress has been associated with many disease conditions in adults and neonates based on clinical and post mortem studies. Trauma is the commonest cause of oxidative stress. However a gap in knowledge of the natural history of oxidative stress in humans was identified as most studies have been post mortem or in animals. <p>The aim of this research is to understand treat and oxidative stress in trauma and surgical patients. The study involved three components including: the development and evaluation of the novel oxistress assay; study of clinical trauma and oxidative stress; and clinical trial of alanyl-glutamine supplementation following major surgery. The novel oxistress assay was used on urine samples in the normal population to determine reference values and subsequently on hospital patients to determine sensitivity and specificity. The study of clinical trauma and oxidative stress evaluated plasma antioxidants (FRAP assay), red cell glutathione (Asensis method), plasma and urine protein carbonyl (Levines method) and total oxidants in plasma and urine (oxistress assay) over 7 day period following trauma. The clinical trial was a double blind study of 69 major surgery patients evaluating biochemical and clinical parameters over 7 day period in comparison with pre-operative status. <p>The novel oxistress assay proves to be a sensitive and accurate bedside diagnostic tool for oxidative stress. It can also be used in the laboratory setting. Oxidative stress is associated with increased trauma severity resulting in antioxidant depletion, strong oxidant production and protein degradation. The presence of pre-morbid medical factors also increased oxidative stress in trauma patients. Oral alanyl-glutamine supplementation (0.3 g/kg) increased plasma glutamine and antioxidant levels while decreasing urine oxidant levels. It significantly reduced hospital stay in non-cancer and higher disease complexity patients. The intervention also reduced the resource intensity weighting (RIW) score. <p>Oxidative stress is a clinical problem in surgery and trauma patients that can now be easily diagnosed at the bedside using the novel oxistress assay. Treatment with alanyl-glutamine is effective in reducing oxidative stress and improving clinical outcome. It is highly recommended probably at a higher dose in order to achieve optimal results.

Oxidative stress has been associated with many disease conditions in adults and neonates based on clinical and post mortem studies. Trauma is the commonest cause of oxidative stress. However a gap in knowledge of the natural history of oxidative stress in humans was identified as most studies have been post mortem or in animals. <p>The aim of this research is to understand treat and oxidative stress in trauma and surgical patients. The study involved three components including: the development and evaluation of the novel oxistress assay; study of clinical trauma and oxidative stress; and clinical trial of alanyl-glutamine supplementation following major surgery. The novel oxistress assay was used on urine samples in the normal population to determine reference values and subsequently on hospital patients to determine sensitivity and specificity. The study of clinical trauma and oxidative stress evaluated plasma antioxidants (FRAP assay), red cell glutathione (Asensis method), plasma and urine protein carbonyl (Levines method) and total oxidants in plasma and urine (oxistress assay) over 7 day period following trauma. The clinical trial was a double blind study of 69 major surgery patients evaluating biochemical and clinical parameters over 7 day period in comparison with pre-operative status. <p>The novel oxistress assay proves to be a sensitive and accurate bedside diagnostic tool for oxidative stress. It can also be used in the laboratory setting. Oxidative stress is associated with increased trauma severity resulting in antioxidant depletion, strong oxidant production and protein degradation. The presence of pre-morbid medical factors also increased oxidative stress in trauma patients. Oral alanyl-glutamine supplementation (0.3 g/kg) increased plasma glutamine and antioxidant levels while decreasing urine oxidant levels. It significantly reduced hospital stay in non-cancer and higher disease complexity patients. The intervention also reduced the resource intensity weighting (RIW) score. <p>Oxidative stress is a clinical problem in surgery and trauma patients that can now be easily diagnosed at the bedside using the novel oxistress assay. Treatment with alanyl-glutamine is effective in reducing oxidative stress and improving clinical outcome. It is highly recommended probably at a higher dose in order to achieve optimal results.